|
Inhibitory activity of compound against human carbonic anhydrase II
|
None
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with the antipsychotic drug sulpiride.
Year : 2004
Volume : 14
Issue : 2
First Page : 337
Last Page : 341
Authors : Abbate F, Coetzee A, Casini A, Ciattini S, Scozzafava A, Supuran CT.
Abstract : The X-ray crystal structure for the adduct of human carbonic anhydrase (hCA) II with sulpiride, a sulfonamide derivative clinically used as antipsychotic drug, has been resolved at a resolution of 1.6 A. This compound is an effective inhibitor of the physiologically most relevant isozyme hCA II (K(i) of 40 nM), being only a moderate or moderate-weak inhibitor of the cytosolic isozyme hCA I (K(i) of 1200 nM) and the membrane-bound isozyme hCA IV (K(i) of 620 nM). Sulpiride shows CA inhibitory properties of the same magnitude as dichlorophenamide, a clinically used antiglaucoma sulfonamide, or valdecoxib, a COX-2 selective inhibitor recently shown to inhibit CA. The binding of sulpiride to the hCA II active site is similar to that of other sulfonamide inhibitors, considering the interactions of the sulfonamide zinc anchoring group, but differs considerably when the organic scaffold of the molecule is analyzed. Indeed, one unprecedented hydrogen bond involving the imino moiety of the carboxamido group of sulpiride and a water molecule was observed, together with a unique stacking interaction of the N-methyl-pyrrolidine ring of the inhibitor and the aromatic ring of Phe 131 of the enzyme active site, which has been observed only recently in another CA-sulfonamide complex.
|
Inhibitory activity against human carbonic anhydrase II was determined
|
None
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition.
Year : 2004
Volume : 47
Issue : 3
First Page : 550
Last Page : 557
Authors : Weber A, Casini A, Heine A, Kuhn D, Supuran CT, Scozzafava A, Klebe G.
Abstract : By optimizing binding to a selected target protein, modern drug research strives to develop safe and efficacious agents for the treatment of disease. Selective drug action is intended to minimize undesirable side effects from scatter pharmacology. Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1. While rofecoxib contains a methyl sulfone constituent, celecoxib and valdecoxib possess an unsubstituted arylsulfonamide moiety. The latter group is common to many carbonic anhydrase (CA) inhibitors. Using enzyme kinetics and X-ray crystallography, we demonstrate an unexpected nanomolar affinity of the COX-2 specific arylsulfonamide-type celecoxib and valdecoxib for isoenzymes of the totally unrelated carbonic anhydrase (CA) family, such as CA I, II, IV, and IX, whereas the rofecoxib methyl sulfone-type has no effect. When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder. The crystal structure of celecoxib in complex with CA II reveals part of this inhibition to be mediated via binding of the sulfonamide group to the catalytic zinc of CA II. To investigate the structural basis for cross-reactivity of these compounds between COX-2 and CA II, we compared the molecular recognition properties of both protein binding pockets in terms of local physicochemical similarities among binding site-exposed amino acids accommodating different portions of the drug molecules. Our approach Cavbase, implemented into Relibase, detects similarities between the sites, suggesting some potential to predict unexpected cross-reactivity of drugs among functionally unrelated target proteins. The observed cross-reactivity with CAs may also contribute to differences in the pharmacological profiles, in particular with respect to glaucoma and anticancer therapy and may suggest new opportunities of these COX-2 selective NSAIDs.
|
Inhibitory activity against human carbonic anhydrase II (hCA II) by using esterase assay method
|
None
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Inhibition of cytosolic isozyme XIII with aromatic and heterocyclic sulfonamides: a novel target for the drug design.
Year : 2004
Volume : 14
Issue : 14
First Page : 3757
Last Page : 3762
Authors : Lehtonen JM, Parkkila S, Vullo D, Casini A, Scozzafava A, Supuran CT.
Abstract : The inhibition of the newly discovered cytosolic carbonic anhydrase isozyme XIII (CA XIII) has been investigated with a series of aromatic and heterocyclic sulfonamides, including some of the clinically used derivatives, such as acetazolamide, methazolamide, dichlorophenamide, dorzolamide, and valdecoxib. Inhibition data for the physiologically relevant isozymes I and II (cytosolic forms) and the tumor associated isozyme IX (transmembrane) were also provided for comparison. A very interesting and unusual inhibition profile against CA XIII with these sulfonamides has been observed. The clinically used compounds (except valdecoxib, which was a weak CA XIII inhibitor) potently inhibit CA XIII, with Ki's in the range of 17-23 nM, whereas sulfanilamide, halogenated sulfanilamides, homosulfanilamide, 4-aminoethylbenzenesulfonamide, and orthanilamide were slightly less effective, with Ki's in the range of 32-56 nM. Several low nanomolar (Ki's in the range of 1.3-2.4 nM) CA XIII inhibitors have also been detected, all of them belonging to the sulfanilyl-sulfonamide type of inhibitors, of which aminobenzolamide is the best known representative. Because CA XIII is an active isozyme predominantly expressed in salivary glands, kidney, brain, lung, gut, uterus, and testis, where it probably plays an important role in pH regulation, its inhibition by sulfonamides may lead to novel therapeutic applications for this class of pharmacological agents.
|
Inhibitory activity of compound against bovine carbonic anhydrase IV
|
None
|
340.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with the antipsychotic drug sulpiride.
Year : 2004
Volume : 14
Issue : 2
First Page : 337
Last Page : 341
Authors : Abbate F, Coetzee A, Casini A, Ciattini S, Scozzafava A, Supuran CT.
Abstract : The X-ray crystal structure for the adduct of human carbonic anhydrase (hCA) II with sulpiride, a sulfonamide derivative clinically used as antipsychotic drug, has been resolved at a resolution of 1.6 A. This compound is an effective inhibitor of the physiologically most relevant isozyme hCA II (K(i) of 40 nM), being only a moderate or moderate-weak inhibitor of the cytosolic isozyme hCA I (K(i) of 1200 nM) and the membrane-bound isozyme hCA IV (K(i) of 620 nM). Sulpiride shows CA inhibitory properties of the same magnitude as dichlorophenamide, a clinically used antiglaucoma sulfonamide, or valdecoxib, a COX-2 selective inhibitor recently shown to inhibit CA. The binding of sulpiride to the hCA II active site is similar to that of other sulfonamide inhibitors, considering the interactions of the sulfonamide zinc anchoring group, but differs considerably when the organic scaffold of the molecule is analyzed. Indeed, one unprecedented hydrogen bond involving the imino moiety of the carboxamido group of sulpiride and a water molecule was observed, together with a unique stacking interaction of the N-methyl-pyrrolidine ring of the inhibitor and the aromatic ring of Phe 131 of the enzyme active site, which has been observed only recently in another CA-sulfonamide complex.
|
Inhibitory activity against bovine carbonic anhydrase IV was determined
|
None
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition.
Year : 2004
Volume : 47
Issue : 3
First Page : 550
Last Page : 557
Authors : Weber A, Casini A, Heine A, Kuhn D, Supuran CT, Scozzafava A, Klebe G.
Abstract : By optimizing binding to a selected target protein, modern drug research strives to develop safe and efficacious agents for the treatment of disease. Selective drug action is intended to minimize undesirable side effects from scatter pharmacology. Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1. While rofecoxib contains a methyl sulfone constituent, celecoxib and valdecoxib possess an unsubstituted arylsulfonamide moiety. The latter group is common to many carbonic anhydrase (CA) inhibitors. Using enzyme kinetics and X-ray crystallography, we demonstrate an unexpected nanomolar affinity of the COX-2 specific arylsulfonamide-type celecoxib and valdecoxib for isoenzymes of the totally unrelated carbonic anhydrase (CA) family, such as CA I, II, IV, and IX, whereas the rofecoxib methyl sulfone-type has no effect. When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder. The crystal structure of celecoxib in complex with CA II reveals part of this inhibition to be mediated via binding of the sulfonamide group to the catalytic zinc of CA II. To investigate the structural basis for cross-reactivity of these compounds between COX-2 and CA II, we compared the molecular recognition properties of both protein binding pockets in terms of local physicochemical similarities among binding site-exposed amino acids accommodating different portions of the drug molecules. Our approach Cavbase, implemented into Relibase, detects similarities between the sites, suggesting some potential to predict unexpected cross-reactivity of drugs among functionally unrelated target proteins. The observed cross-reactivity with CAs may also contribute to differences in the pharmacological profiles, in particular with respect to glaucoma and anticancer therapy and may suggest new opportunities of these COX-2 selective NSAIDs.
|
Inhibitory activity against human carbonic anhydrase IX was determined
|
None
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition.
Year : 2004
Volume : 47
Issue : 3
First Page : 550
Last Page : 557
Authors : Weber A, Casini A, Heine A, Kuhn D, Supuran CT, Scozzafava A, Klebe G.
Abstract : By optimizing binding to a selected target protein, modern drug research strives to develop safe and efficacious agents for the treatment of disease. Selective drug action is intended to minimize undesirable side effects from scatter pharmacology. Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1. While rofecoxib contains a methyl sulfone constituent, celecoxib and valdecoxib possess an unsubstituted arylsulfonamide moiety. The latter group is common to many carbonic anhydrase (CA) inhibitors. Using enzyme kinetics and X-ray crystallography, we demonstrate an unexpected nanomolar affinity of the COX-2 specific arylsulfonamide-type celecoxib and valdecoxib for isoenzymes of the totally unrelated carbonic anhydrase (CA) family, such as CA I, II, IV, and IX, whereas the rofecoxib methyl sulfone-type has no effect. When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder. The crystal structure of celecoxib in complex with CA II reveals part of this inhibition to be mediated via binding of the sulfonamide group to the catalytic zinc of CA II. To investigate the structural basis for cross-reactivity of these compounds between COX-2 and CA II, we compared the molecular recognition properties of both protein binding pockets in terms of local physicochemical similarities among binding site-exposed amino acids accommodating different portions of the drug molecules. Our approach Cavbase, implemented into Relibase, detects similarities between the sites, suggesting some potential to predict unexpected cross-reactivity of drugs among functionally unrelated target proteins. The observed cross-reactivity with CAs may also contribute to differences in the pharmacological profiles, in particular with respect to glaucoma and anticancer therapy and may suggest new opportunities of these COX-2 selective NSAIDs.
|
Inhibitory activity against human carbonic anhydrase IX (hCA IX) by using CO2 hydrase assay method
|
None
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Inhibition of cytosolic isozyme XIII with aromatic and heterocyclic sulfonamides: a novel target for the drug design.
Year : 2004
Volume : 14
Issue : 14
First Page : 3757
Last Page : 3762
Authors : Lehtonen JM, Parkkila S, Vullo D, Casini A, Scozzafava A, Supuran CT.
Abstract : The inhibition of the newly discovered cytosolic carbonic anhydrase isozyme XIII (CA XIII) has been investigated with a series of aromatic and heterocyclic sulfonamides, including some of the clinically used derivatives, such as acetazolamide, methazolamide, dichlorophenamide, dorzolamide, and valdecoxib. Inhibition data for the physiologically relevant isozymes I and II (cytosolic forms) and the tumor associated isozyme IX (transmembrane) were also provided for comparison. A very interesting and unusual inhibition profile against CA XIII with these sulfonamides has been observed. The clinically used compounds (except valdecoxib, which was a weak CA XIII inhibitor) potently inhibit CA XIII, with Ki's in the range of 17-23 nM, whereas sulfanilamide, halogenated sulfanilamides, homosulfanilamide, 4-aminoethylbenzenesulfonamide, and orthanilamide were slightly less effective, with Ki's in the range of 32-56 nM. Several low nanomolar (Ki's in the range of 1.3-2.4 nM) CA XIII inhibitors have also been detected, all of them belonging to the sulfanilyl-sulfonamide type of inhibitors, of which aminobenzolamide is the best known representative. Because CA XIII is an active isozyme predominantly expressed in salivary glands, kidney, brain, lung, gut, uterus, and testis, where it probably plays an important role in pH regulation, its inhibition by sulfonamides may lead to novel therapeutic applications for this class of pharmacological agents.
|
Inhibitory activity against murine carbonic anhydrase XIII (mCA XIII) by using CO2 hydrase assay method
|
None
|
425.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Inhibition of cytosolic isozyme XIII with aromatic and heterocyclic sulfonamides: a novel target for the drug design.
Year : 2004
Volume : 14
Issue : 14
First Page : 3757
Last Page : 3762
Authors : Lehtonen JM, Parkkila S, Vullo D, Casini A, Scozzafava A, Supuran CT.
Abstract : The inhibition of the newly discovered cytosolic carbonic anhydrase isozyme XIII (CA XIII) has been investigated with a series of aromatic and heterocyclic sulfonamides, including some of the clinically used derivatives, such as acetazolamide, methazolamide, dichlorophenamide, dorzolamide, and valdecoxib. Inhibition data for the physiologically relevant isozymes I and II (cytosolic forms) and the tumor associated isozyme IX (transmembrane) were also provided for comparison. A very interesting and unusual inhibition profile against CA XIII with these sulfonamides has been observed. The clinically used compounds (except valdecoxib, which was a weak CA XIII inhibitor) potently inhibit CA XIII, with Ki's in the range of 17-23 nM, whereas sulfanilamide, halogenated sulfanilamides, homosulfanilamide, 4-aminoethylbenzenesulfonamide, and orthanilamide were slightly less effective, with Ki's in the range of 32-56 nM. Several low nanomolar (Ki's in the range of 1.3-2.4 nM) CA XIII inhibitors have also been detected, all of them belonging to the sulfanilyl-sulfonamide type of inhibitors, of which aminobenzolamide is the best known representative. Because CA XIII is an active isozyme predominantly expressed in salivary glands, kidney, brain, lung, gut, uterus, and testis, where it probably plays an important role in pH regulation, its inhibition by sulfonamides may lead to novel therapeutic applications for this class of pharmacological agents.
|
Inhibition of human Prostaglandin G/H synthase 2
|
None
|
5.012
nM
|
|
Journal : J. Med. Chem.
Title : Three-dimensional quantitative structure-activity relationships of cyclo-oxygenase-2 (COX-2) inhibitors: a comparative molecular field analysis.
Year : 2001
Volume : 44
Issue : 20
First Page : 3223
Last Page : 3230
Authors : Chavatte P, Yous S, Marot C, Baurin N, Lesieur D.
Abstract : The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to an extensive series of 305 varied diarylheterocyclic derivatives known as COX-2 selective inhibitors. X-ray crystal structure of COX-2 bound with SC-558, a selective COX-2 inhibitor, was used to derive the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (229 compounds) and subsequently validated with the corresponding test sets (76 compounds). The best predictive model (n = 229, q(2) = 0.714, N = 8, r(2) = 0.905, s = 0.291, F = 261.545) was selected for further comparison of the CoMFA contour maps obtained for steric, electrostatic, and lipophilic fields with the enzyme structure. The high level of compatibility with the COX-2 enzyme topology shows the great accuracy of this model that can predict inhibitory activities for a wide range of compounds and offers important structural insight into designing novel antiinflammatory drugs prior to their synthesis.
|
Compound was evaluated for in vivo antiinflammatory activity with prostaglandin G/H synthase 2 inhibition of PGE-2 formation at an oral dose of 15 umol/kg
|
None
|
98.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
Year : 2004
Volume : 47
Issue : 9
First Page : 2180
Last Page : 2193
Authors : Ranatunge RR, Augustyniak M, Bandarage UK, Earl RA, Ellis JL, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schroeder JD, Shumway MJ, Tam SW, Trocha AM, Young DV.
Abstract : The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
|
Compound was evaluated for in vivo antiinflammatory activity with prostaglandin G/H synthase 2 inhibition of white-cell infiltration at an oral dose of 15 umol/kg
|
None
|
37.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
Year : 2004
Volume : 47
Issue : 9
First Page : 2180
Last Page : 2193
Authors : Ranatunge RR, Augustyniak M, Bandarage UK, Earl RA, Ellis JL, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schroeder JD, Shumway MJ, Tam SW, Trocha AM, Young DV.
Abstract : The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
|
Compound was tested for its inhibitory activity against recombinant human Prostaglandin G/H synthase 2
|
None
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : N-[[(5-methyl-3-phenylisoxazol-4-yl)-phenyl]sulfonyl]propanamide, sodium salt, parecoxib sodium: A potent and selective inhibitor of COX-2 for parenteral administration.
Year : 2000
Volume : 43
Issue : 9
First Page : 1661
Last Page : 1663
Authors : Talley JJ, Bertenshaw SR, Brown DL, Carter JS, Graneto MJ, Kellogg MS, Koboldt CM, Yuan J, Zhang YY, Seibert K.
|
In Vitro activity of compound against human recombinant Prostaglandin G/H synthase 2
|
None
|
5.0
nM
|
|
In Vitro activity of compound against human recombinant Prostaglandin G/H synthase 2
|
None
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2.
Year : 2000
Volume : 43
Issue : 5
First Page : 775
Last Page : 777
Authors : Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K.
|
In vivo activity determined using minimum of four dose points, 5 animals/group in rat carrageenan edema.
|
Rattus norvegicus
|
10.2
mg kg-1
|
|
In vivo activity determined using minimum of four dose points, 5 animals/group in rat carrageenan edema.
|
Rattus norvegicus
|
10.2
mg kg-1
|
|
Journal : J. Med. Chem.
Title : 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2.
Year : 2000
Volume : 43
Issue : 5
First Page : 775
Last Page : 777
Authors : Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K.
|
In vivo activity determined using minimum of four dose points, 8-10 animals/group in rat adjuvant arthritis.
|
Rattus norvegicus
|
0.032
mg kg-1
|
|
In vivo activity determined using minimum of four dose points, 8-10 animals/group in rat adjuvant arthritis.
|
Rattus norvegicus
|
0.032
mg kg-1
|
|
Journal : J. Med. Chem.
Title : 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2.
Year : 2000
Volume : 43
Issue : 5
First Page : 775
Last Page : 777
Authors : Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K.
|
In vivo activity in rat air pouch.
|
Rattus norvegicus
|
0.05
mg kg-1
|
|
Journal : J. Med. Chem.
Title : 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2.
Year : 2000
Volume : 43
Issue : 5
First Page : 775
Last Page : 777
Authors : Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K.
|
In vivo activity in rat air pouch.
|
Rattus norvegicus
|
0.05
mg kg-1
|
|
Journal : J. Med. Chem.
Title : 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2.
Year : 2000
Volume : 43
Issue : 5
First Page : 775
Last Page : 777
Authors : Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K.
|
In vitro assay for PGE-2 production as a function of COX-2 inhibition in whole human blood cultured with lipopolysaccharide (LPS)
|
Homo sapiens
|
890.0
nM
|
|
In vitro assay for PGE-2 production as a function of COX-2 inhibition in whole human blood cultured with lipopolysaccharide (LPS)
|
Homo sapiens
|
890.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2.
Year : 2000
Volume : 43
Issue : 5
First Page : 775
Last Page : 777
Authors : Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K.
|
Inhibitory activity against human carbonic anhydrase II (hCAII)
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Inhibition of the membrane-bound human and bovine isozymes IV with sulfonamides.
Year : 2005
Volume : 15
Issue : 4
First Page : 1149
Last Page : 1154
Authors : Innocenti A, Firnges MA, Antel J, Wurl M, Scozzafava A, Supuran CT.
Abstract : An inhibition study of the human and bovine membrane-associated isozymes of carbonic anhydrase (CA, EC 4.2.1.1), hCA IV and bCA IV, with a series of sulfonamides and sulfamates, some of which are widely clinically used, such as acetazolamide, methazolamide, ethoxzolamide, topiramate, dorzolamide, dichlorophenamide, celecoxib, and valdecoxib among others, is reported. In contrast to bCA IV, which is generally strongly inhibited by most of these derivatives, hCA IV has a rather different inhibition profile. Several of these compounds such as acetazolamide, ethoxzolamide, and bromosulfanilamide are potent hCA IV inhibitors (K(i)'s of 74-93 nM), others, such as celecoxib and some halogenated sulfanilamides are medium potency inhibitors (K(i)'s of 450-880 nM) whereas most of them are weak hCA IV inhibitors (methazolamide: 6.2 microM; dorzolamide 8.5 microM; topiramate 4.9 microM; dichlorophenamide: 15.3 microM). The hCA IV/bCA IV inhibition ratios for all the investigated compounds ranged between 1.05 (for acetazolamide) and 198.37 (for dorzolamide). Based on these results, we doubt that hCA IV is indeed one of the main contributors to the intraocular pressure (IOP) lowering effects of sulfonamide CA inhibitors, in addition to hCA II, as hypothesized earlier by Maren et al. (Mol. Pharmacol.1993, 44, 901-906). Indeed, both the very good hCA IV inhibitors (acetazolamide and ethoxzolamide) as well as the quite weak hCA IV inhibitors (methazolamide, dorzolamide, or dichlorophanamide) are effective in lowering IOP when administered either systemically or topically. The membrane-associated isozyme which probably is critical for aqueous humor secretion is hCA XII and not hCA IV.
|
Inhibitory activity against bovine carbonic anhydrase IV (bCAIV)
|
Bos taurus
|
340.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Inhibition of the membrane-bound human and bovine isozymes IV with sulfonamides.
Year : 2005
Volume : 15
Issue : 4
First Page : 1149
Last Page : 1154
Authors : Innocenti A, Firnges MA, Antel J, Wurl M, Scozzafava A, Supuran CT.
Abstract : An inhibition study of the human and bovine membrane-associated isozymes of carbonic anhydrase (CA, EC 4.2.1.1), hCA IV and bCA IV, with a series of sulfonamides and sulfamates, some of which are widely clinically used, such as acetazolamide, methazolamide, ethoxzolamide, topiramate, dorzolamide, dichlorophenamide, celecoxib, and valdecoxib among others, is reported. In contrast to bCA IV, which is generally strongly inhibited by most of these derivatives, hCA IV has a rather different inhibition profile. Several of these compounds such as acetazolamide, ethoxzolamide, and bromosulfanilamide are potent hCA IV inhibitors (K(i)'s of 74-93 nM), others, such as celecoxib and some halogenated sulfanilamides are medium potency inhibitors (K(i)'s of 450-880 nM) whereas most of them are weak hCA IV inhibitors (methazolamide: 6.2 microM; dorzolamide 8.5 microM; topiramate 4.9 microM; dichlorophenamide: 15.3 microM). The hCA IV/bCA IV inhibition ratios for all the investigated compounds ranged between 1.05 (for acetazolamide) and 198.37 (for dorzolamide). Based on these results, we doubt that hCA IV is indeed one of the main contributors to the intraocular pressure (IOP) lowering effects of sulfonamide CA inhibitors, in addition to hCA II, as hypothesized earlier by Maren et al. (Mol. Pharmacol.1993, 44, 901-906). Indeed, both the very good hCA IV inhibitors (acetazolamide and ethoxzolamide) as well as the quite weak hCA IV inhibitors (methazolamide, dorzolamide, or dichlorophanamide) are effective in lowering IOP when administered either systemically or topically. The membrane-associated isozyme which probably is critical for aqueous humor secretion is hCA XII and not hCA IV.
|
Inhibitory activity against alpha carbonic anhydrase (Co-Cam) from Methanosarcina thermophila
|
Methanosarcina thermophila
|
240.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Inhibition of the prokariotic beta and gamma-class enzymes from Archaea with sulfonamides.
Year : 2004
Volume : 14
Issue : 24
First Page : 6001
Last Page : 6006
Authors : Zimmerman S, Innocenti A, Casini A, Ferry JG, Scozzafava A, Supuran CT.
Abstract : A detailed inhibition study of carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the beta- and gamma-families from Archaea with sulfonamides has been performed. Compounds included in this study were the clinically used sulfonamide CA inhibitors, such as acetazolamide, methazolamide, ethoxzolamide, topiramate, valdecoxib, celecoxib, dorzolamide, sulfanilamide, dichlorophanamide, as well as sulfanilamide analogs, halogenated sulfanilamides, and some 1,3-benzenedisulfonamide derivatives. The two gamma-CAs from Methanosarcina thermophila (Zn-Cam and Co-Cam) showed very different inhibitory properties with these compounds, as compared to the alpha-CA isozymes hCA I, II, and IX, and the beta-CA from Methanobacterium thermoautotrophicum (Cab). The best Zn-Cam inhibitors were sulfamic acid and acetazolamide, with inhibition constants in the range of 63-96 nM, whereas other investigated aromatic/heterocylic sulfonamides showed a rather levelled behavior, with KIs in the range of 0.12-1.70 microM. The best Co-Cam inhibitors were topiramate and p-aminoethyl-benzenesulfonamide, with KIs in the range of 0.12-0.13 microM, whereas the worst one was homosulfanilamide (KI of 8.50 microM). In the case of Cab, the inhibitory power of these compounds varied to a much larger extent, with sulfamic acid and sulfamide showing millimolar affinities (KIs in the range of 44-103 mM), whereas the best inhibitor was ethoxzolamide, with a KI of 5.35 microM. Most of these sulfonamides showed inhibition constants in the range of 12-100 microM against Cab. Thus, the three CA families investigated up to now possess a very diverse affinity for sulfonamides, the inhibitors with important medicinal, and environmental applications.
|
Inhibitory activity against alpha carbonic anhydrase (Zn-Cam) from Methanosarcina thermophila
|
Methanosarcina thermophila
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Inhibition of the prokariotic beta and gamma-class enzymes from Archaea with sulfonamides.
Year : 2004
Volume : 14
Issue : 24
First Page : 6001
Last Page : 6006
Authors : Zimmerman S, Innocenti A, Casini A, Ferry JG, Scozzafava A, Supuran CT.
Abstract : A detailed inhibition study of carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the beta- and gamma-families from Archaea with sulfonamides has been performed. Compounds included in this study were the clinically used sulfonamide CA inhibitors, such as acetazolamide, methazolamide, ethoxzolamide, topiramate, valdecoxib, celecoxib, dorzolamide, sulfanilamide, dichlorophanamide, as well as sulfanilamide analogs, halogenated sulfanilamides, and some 1,3-benzenedisulfonamide derivatives. The two gamma-CAs from Methanosarcina thermophila (Zn-Cam and Co-Cam) showed very different inhibitory properties with these compounds, as compared to the alpha-CA isozymes hCA I, II, and IX, and the beta-CA from Methanobacterium thermoautotrophicum (Cab). The best Zn-Cam inhibitors were sulfamic acid and acetazolamide, with inhibition constants in the range of 63-96 nM, whereas other investigated aromatic/heterocylic sulfonamides showed a rather levelled behavior, with KIs in the range of 0.12-1.70 microM. The best Co-Cam inhibitors were topiramate and p-aminoethyl-benzenesulfonamide, with KIs in the range of 0.12-0.13 microM, whereas the worst one was homosulfanilamide (KI of 8.50 microM). In the case of Cab, the inhibitory power of these compounds varied to a much larger extent, with sulfamic acid and sulfamide showing millimolar affinities (KIs in the range of 44-103 mM), whereas the best inhibitor was ethoxzolamide, with a KI of 5.35 microM. Most of these sulfonamides showed inhibition constants in the range of 12-100 microM against Cab. Thus, the three CA families investigated up to now possess a very diverse affinity for sulfonamides, the inhibitors with important medicinal, and environmental applications.
|
Inhibition of human cyclooxygenase-2 expressed in COS cells
|
Homo sapiens
|
183.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of 2,3-diaryl-pyrazolo[1,5-b]pyridazines as potent and selective cyclooxygenase-2 inhibitors.
Year : 2004
Volume : 14
Issue : 21
First Page : 5445
Last Page : 5448
Authors : Beswick P, Bingham S, Bountra C, Brown T, Browning K, Campbell I, Chessell I, Clayton N, Collins S, Corfield J, Guntrip S, Haslam C, Lambeth P, Lucas F, Mathews N, Murkit G, Naylor A, Pegg N, Pickup E, Player H, Price H, Stevens A, Stratton S, Wiseman J.
Abstract : GW406381 (8), currently undergoing clinical evaluation for the treatment of inflammatory pain is a member of a novel series of 2,3-diaryl-pyrazolo[1,5-b]pyridazine based cyclooxygenase-2 (COX-2) inhibitors, which have been shown to be highly potent and selective. Several examples of the series, in addition to possessing favourable pharmacokinetic profiles and analgesic activity in vivo, have also demonstrated relatively high brain penetration in the rat compared with the clinically available compounds, which may ultimately prove beneficial in the treatment of pain.
|
In vitro inhibitory concentration against Prostaglandin G/H synthase 2 in human whole blood assay
|
Homo sapiens
|
570.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel synthesis of 3,4-diarylisoxazole analogues of valdecoxib: reversal cyclooxygenase-2 selectivity by sulfonamide group removal.
Year : 2004
Volume : 47
Issue : 20
First Page : 4881
Last Page : 4890
Authors : Di Nunno L, Vitale P, Scilimati A, Tacconelli S, Patrignani P.
Abstract : 3,4-Diarylisoxazole analogues of valdecoxib [4-(5-methyl-3-phenylisoxazol-4-yl)-benzensulfonamide], a selective cyclooxygenase-2 (COX-2) inhibitor, were synthesized by 1,3-dipolar cycloaddition of arylnitrile oxides to the enolate ion of phenylacetone regioselectively prepared in situ with lithium diisopropylamide at 0 degrees C. The corresponding 3-aryl-5-methyl-4-phenylisoxazoles were easily generated by a dehydration/aromatization reaction under basic conditions of 3-aryl-5-hydroxy-5-methyl-4-phenyl-2-isoxazolines and further transformed into their benzenesulfonamide derivatives. The biochemical COX-1/COX-2 selectivity was evaluated in vitro by using the human whole blood assays of COX isozyme activity. Three compounds not bearing the sulfonamide group present in valdecoxib were selective COX-1 inhibitors.
|
Inhibitory activity against human recombinant cyclooxygenase 2
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 4-(5-[18F]fluoromethyl-3-phenylisoxazol-4-yl)benzenesulfonamide, a new [18F]fluorinated analogue of valdecoxib, as a potential radiotracer for imaging cyclooxygenase-2 with positron emission tomography.
Year : 2005
Volume : 15
Issue : 21
First Page : 4699
Last Page : 4702
Authors : Toyokuni T, Kumar JS, Walsh JC, Shapiro A, Talley JJ, Phelps ME, Herschman HR, Barrio JR, Satyamurthy N.
Abstract : Fluoroalkyl and fluoroaryl analogues of valdecoxib were found to possess potent inhibitory activities against cyclooxygenase-2 comparable to that of the parent valdecoxib. Among them, the fluoromethyl analogue was chosen for 18F-labeling. Thus, 4-(5-[18F]fluoromethyl-3-phenylisoxazol-4-yl)benzenesulfonamide (approximately 2000 Ci/mmol at end of synthesis) was synthesized by [18F]fluoride-ion displacement of the corresponding tosylate in approximately 40% decay-corrected radiochemical yield within approximately 120 min from end of bombardment.
|
Inhibitory activity against cloned human CA2
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II "selective" inhibitor celecoxib.
Year : 2006
Volume : 16
Issue : 2
First Page : 437
Last Page : 442
Authors : Di Fiore A, Pedone C, D'Ambrosio K, Scozzafava A, De Simone G, Supuran CT.
Abstract : The high resolution X-ray crystal structure of the adduct of human carbonic anhydrase (CA, EC 4.2.1.1) isoform II (hCA II) with the clinically used painkiller valdecoxib, acting as a potent CA II and cyclooxygenase-2 (COX-2) inhibitor, is reported. The ionized sulfonamide moiety of valdecoxib is coordinated to the catalytic Zn(II) ion with a tetrahedral geometry. The phenyl-isoxazole moiety of the inhibitor fills the active site channel and interacts with the side chains of Gln92, Val121, Leu198, Thr200, and Pro202. Its 3-phenyl group is located into a hydrophobic pocket, simultaneously establishing van der Waals interactions with the aliphatic side chain of various hydrophobic residues (Val135, Ile91, Val121, Leu198, and Leu141) and a strong offset face-to-face stacking interaction with the aromatic ring of Phe131 (the chi1 angle of which is rotated about 90 degrees with respect to what was observed in the structure of the native enzyme and those of other sulfonamide complexes). Celecoxib, a structurally related COX-2 inhibitor for which the X-ray crystal structure was reported earlier, binds in a completely different manner to hCA II as compared to valdecoxib. Celecoxib completely fills the entire CA II active site, with its trifluoromethyl group in the hydrophobic part of the active site and the p-tolyl moiety in the hydrophilic one, not establishing any interaction with Phe131. In contrast to celecoxib, valdecoxib was rotated about 90 degrees around the chemical bond connecting the benzensulfonamide and the substituted isoxazole ring allowing for these multiple favorable interactions. These different binding modes allow for the further drug design of various CA inhibitors belonging to the benzenesulfonamide class.
|
Inhibitory activity against CA4 isolated from bovine lung microsomes
|
Bos taurus
|
340.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II "selective" inhibitor celecoxib.
Year : 2006
Volume : 16
Issue : 2
First Page : 437
Last Page : 442
Authors : Di Fiore A, Pedone C, D'Ambrosio K, Scozzafava A, De Simone G, Supuran CT.
Abstract : The high resolution X-ray crystal structure of the adduct of human carbonic anhydrase (CA, EC 4.2.1.1) isoform II (hCA II) with the clinically used painkiller valdecoxib, acting as a potent CA II and cyclooxygenase-2 (COX-2) inhibitor, is reported. The ionized sulfonamide moiety of valdecoxib is coordinated to the catalytic Zn(II) ion with a tetrahedral geometry. The phenyl-isoxazole moiety of the inhibitor fills the active site channel and interacts with the side chains of Gln92, Val121, Leu198, Thr200, and Pro202. Its 3-phenyl group is located into a hydrophobic pocket, simultaneously establishing van der Waals interactions with the aliphatic side chain of various hydrophobic residues (Val135, Ile91, Val121, Leu198, and Leu141) and a strong offset face-to-face stacking interaction with the aromatic ring of Phe131 (the chi1 angle of which is rotated about 90 degrees with respect to what was observed in the structure of the native enzyme and those of other sulfonamide complexes). Celecoxib, a structurally related COX-2 inhibitor for which the X-ray crystal structure was reported earlier, binds in a completely different manner to hCA II as compared to valdecoxib. Celecoxib completely fills the entire CA II active site, with its trifluoromethyl group in the hydrophobic part of the active site and the p-tolyl moiety in the hydrophilic one, not establishing any interaction with Phe131. In contrast to celecoxib, valdecoxib was rotated about 90 degrees around the chemical bond connecting the benzensulfonamide and the substituted isoxazole ring allowing for these multiple favorable interactions. These different binding modes allow for the further drug design of various CA inhibitors belonging to the benzenesulfonamide class.
|
Inhibitory activity against cloned human CA9
|
Homo sapiens
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II "selective" inhibitor celecoxib.
Year : 2006
Volume : 16
Issue : 2
First Page : 437
Last Page : 442
Authors : Di Fiore A, Pedone C, D'Ambrosio K, Scozzafava A, De Simone G, Supuran CT.
Abstract : The high resolution X-ray crystal structure of the adduct of human carbonic anhydrase (CA, EC 4.2.1.1) isoform II (hCA II) with the clinically used painkiller valdecoxib, acting as a potent CA II and cyclooxygenase-2 (COX-2) inhibitor, is reported. The ionized sulfonamide moiety of valdecoxib is coordinated to the catalytic Zn(II) ion with a tetrahedral geometry. The phenyl-isoxazole moiety of the inhibitor fills the active site channel and interacts with the side chains of Gln92, Val121, Leu198, Thr200, and Pro202. Its 3-phenyl group is located into a hydrophobic pocket, simultaneously establishing van der Waals interactions with the aliphatic side chain of various hydrophobic residues (Val135, Ile91, Val121, Leu198, and Leu141) and a strong offset face-to-face stacking interaction with the aromatic ring of Phe131 (the chi1 angle of which is rotated about 90 degrees with respect to what was observed in the structure of the native enzyme and those of other sulfonamide complexes). Celecoxib, a structurally related COX-2 inhibitor for which the X-ray crystal structure was reported earlier, binds in a completely different manner to hCA II as compared to valdecoxib. Celecoxib completely fills the entire CA II active site, with its trifluoromethyl group in the hydrophobic part of the active site and the p-tolyl moiety in the hydrophilic one, not establishing any interaction with Phe131. In contrast to celecoxib, valdecoxib was rotated about 90 degrees around the chemical bond connecting the benzensulfonamide and the substituted isoxazole ring allowing for these multiple favorable interactions. These different binding modes allow for the further drug design of various CA inhibitors belonging to the benzenesulfonamide class.
|
Inhibitory activity against cloned human CA12
|
Homo sapiens
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II "selective" inhibitor celecoxib.
Year : 2006
Volume : 16
Issue : 2
First Page : 437
Last Page : 442
Authors : Di Fiore A, Pedone C, D'Ambrosio K, Scozzafava A, De Simone G, Supuran CT.
Abstract : The high resolution X-ray crystal structure of the adduct of human carbonic anhydrase (CA, EC 4.2.1.1) isoform II (hCA II) with the clinically used painkiller valdecoxib, acting as a potent CA II and cyclooxygenase-2 (COX-2) inhibitor, is reported. The ionized sulfonamide moiety of valdecoxib is coordinated to the catalytic Zn(II) ion with a tetrahedral geometry. The phenyl-isoxazole moiety of the inhibitor fills the active site channel and interacts with the side chains of Gln92, Val121, Leu198, Thr200, and Pro202. Its 3-phenyl group is located into a hydrophobic pocket, simultaneously establishing van der Waals interactions with the aliphatic side chain of various hydrophobic residues (Val135, Ile91, Val121, Leu198, and Leu141) and a strong offset face-to-face stacking interaction with the aromatic ring of Phe131 (the chi1 angle of which is rotated about 90 degrees with respect to what was observed in the structure of the native enzyme and those of other sulfonamide complexes). Celecoxib, a structurally related COX-2 inhibitor for which the X-ray crystal structure was reported earlier, binds in a completely different manner to hCA II as compared to valdecoxib. Celecoxib completely fills the entire CA II active site, with its trifluoromethyl group in the hydrophobic part of the active site and the p-tolyl moiety in the hydrophilic one, not establishing any interaction with Phe131. In contrast to celecoxib, valdecoxib was rotated about 90 degrees around the chemical bond connecting the benzensulfonamide and the substituted isoxazole ring allowing for these multiple favorable interactions. These different binding modes allow for the further drug design of various CA inhibitors belonging to the benzenesulfonamide class.
|
Inhibition of human recombinant COX2
|
Homo sapiens
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : New celecoxib derivatives as anti-inflammatory agents.
Year : 2008
Volume : 51
Issue : 1
First Page : 142
Last Page : 147
Authors : Szabó G, Fischer J, Kis-Varga A, Gyires K.
Abstract : A series of 1,5-diarylpyrazoles with a substituted benzenesulfonamide moiety was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Some compounds, for example, (+/-)-2-[4-(5- p-tolyl-3-trifluoromethyl-pyrazole-1-yl)-benzenesulfonylaminooxy]-propionic acid 16 and its disodium salt 21, had a higher in vivo anti-inflammatory activity compared to celecoxib, despite having no in vitro COX-1 or COX-2 inhibitory activity. Their gastrointestinal side effect profile is essentially more favorable than that of celecoxib.
|
Inhibition of COX2 in human whole blood assessed as effect on thrombin-induced TXB2 production
|
Homo sapiens
|
660.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological evaluation, and enzyme docking simulations of 1,5-diarylpyrrole-3-alkoxyethyl ethers as selective cyclooxygenase-2 inhibitors endowed with anti-inflammatory and antinociceptive activity.
Year : 2008
Volume : 51
Issue : 15
First Page : 4476
Last Page : 4481
Authors : Anzini M, Rovini M, Cappelli A, Vomero S, Manetti F, Botta M, Sautebin L, Rossi A, Pergola C, Ghelardini C, Norcini M, Giordani A, Makovec F, Anzellotti P, Patrignani P, Biava M.
Abstract : A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers (6, 7, and 8) has been synthesized with the aim to assess if in the previously reported 1,5-diarylpyrrole derivatives (5) the replacement of the acetic ester moiety with an alkoxyethyl group still led to new, highly selective and potent COX-2 inhibitors. In the in vitro cell culture assay, all the compounds proved to be potent and selective COX-2 inhibitors. In the human whole blood (HWB) assay, compound 8a had a comparable COX-2 selectivity to valdecoxib, while it was more selective than celecoxib but less selective than rofecoxib. The potential anti-inflammatory and antinociceptive activities of compounds 7a, 8a, and 8d were evaluated in vivo, where they showed a very good activity against both carrageenan-induced hyperalgesia and edema in the rat paw test. In the abdominal constriction test compound 7a, 8a, and 8d were able to reduce the number of writhes in a statistically significant manner. Furthermore, the affinity data of these compounds have been rationalized through enzyme docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site by means of the software package Autodock 3.0.5, GRID 21, and MacroModel 8.5 using the complex between COX-2 and SC-558 (1b), refined at a 3 A resolution (Brookhaven Protein Data Bank entry: 6cox ).
|
Inhibition of human recombinant carbonic anhydrase 2 by stopped flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Carbonic anhydrase inhibitors. Cloning, characterization, and inhibition studies of a new beta-carbonic anhydrase from Mycobacterium tuberculosis.
Year : 2009
Volume : 52
Issue : 9
First Page : 3116
Last Page : 3120
Authors : Nishimori I, Minakuchi T, Vullo D, Scozzafava A, Innocenti A, Supuran CT.
Abstract : The Rv3273 gene product of Mycobacterium tuberculosis, a beta-carbonic anhydrase (CA, EC 4.2.1.1), mtCA 3, shows appreciable catalytic activity for CO(2) hydration (k(cat) of 4.3 x 10(5) s(-1), and k(cat)/K(m) of 4.0 x 10(7) M(-1) x s(-1)). A series of sulfonamides/sulfamates was assayed for their interaction with mtCA 3. Sulfanilyl-sulfonamides, acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and zonisamide, showed effective, submicromolar inhibition (K(I)s of 104-611 nM), the best inhibitor being 2-amino-pyrimidin-4-yl-sulfanilamide (K(I) of 91 nM).
|
Inhibition of human recombinant CA2 by stopped-flow CO2 hydrase assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors: inhibition of the beta-class enzyme from the yeast Saccharomyces cerevisiae with sulfonamides and sulfamates.
Year : 2009
Volume : 17
Issue : 3
First Page : 1158
Last Page : 1163
Authors : Isik S, Kockar F, Aydin M, Arslan O, Guler OO, Innocenti A, Scozzafava A, Supuran CT.
Abstract : The protein encoded by the Nce103 gene of Saccharomyces cerevisiae, a beta-carbonic anhydrase (CA, EC 4.2.1.1) designated as scCA, has been cloned, purified, characterized kinetically and investigated for its inhibition with a series of sulfonamides and one sulfamate. The enzyme showed high CO(2) hydrase activity, with a k(cat) of 9.4x10(5)s(-1), and k(cat)/K(M) of 9.8x10(7)M(-1)s(-1). Simple benzenesulfonamides substituted in 2-, 4- and 3,4-positions of the benzene ring with amino, alkyl, halogeno and hydroxyalkyl moieties were weak scCA inhibitors with K(I)s in the range of 0.976-18.45 microM. Better inhibition (K(I)s in the range of 154-654 nM) was observed for benzenesulfonamides incorporating aminoalkyl/carboxyalkyl moieties or halogenosulfanilamides; benzene-1,3-disulfonamides; simple heterocyclic sulfonamides and sulfanilyl-sulfonamides. The clinically used sulfonamides/sulfamate (acetazolamide, ethoxzolamide, methazolamide, dorzolamide, topiramate, celecoxib, etc.) generally showed effective scCA inhibitory activity, with K(I)s in the range of 82.6-133 nM. The best inhibitor (K(I) of 15.1 nM) was 4-(2-amino-pyrimidin-4-yl)-benzenesulfonamide. These inhibitors may be useful to better understand the physiological role of beta-CAs in yeast and some pathogenic fungi which encode orthologues of the yeast enzyme and eventually for designing novel antifungal therapies.
|
Inhibition of Saccharomyces cerevisiae recombinant CA expressed in Escherichia coli by stopped-flow CO2 hydrase assay
|
Saccharomyces cerevisiae
|
654.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors: inhibition of the beta-class enzyme from the yeast Saccharomyces cerevisiae with sulfonamides and sulfamates.
Year : 2009
Volume : 17
Issue : 3
First Page : 1158
Last Page : 1163
Authors : Isik S, Kockar F, Aydin M, Arslan O, Guler OO, Innocenti A, Scozzafava A, Supuran CT.
Abstract : The protein encoded by the Nce103 gene of Saccharomyces cerevisiae, a beta-carbonic anhydrase (CA, EC 4.2.1.1) designated as scCA, has been cloned, purified, characterized kinetically and investigated for its inhibition with a series of sulfonamides and one sulfamate. The enzyme showed high CO(2) hydrase activity, with a k(cat) of 9.4x10(5)s(-1), and k(cat)/K(M) of 9.8x10(7)M(-1)s(-1). Simple benzenesulfonamides substituted in 2-, 4- and 3,4-positions of the benzene ring with amino, alkyl, halogeno and hydroxyalkyl moieties were weak scCA inhibitors with K(I)s in the range of 0.976-18.45 microM. Better inhibition (K(I)s in the range of 154-654 nM) was observed for benzenesulfonamides incorporating aminoalkyl/carboxyalkyl moieties or halogenosulfanilamides; benzene-1,3-disulfonamides; simple heterocyclic sulfonamides and sulfanilyl-sulfonamides. The clinically used sulfonamides/sulfamate (acetazolamide, ethoxzolamide, methazolamide, dorzolamide, topiramate, celecoxib, etc.) generally showed effective scCA inhibitory activity, with K(I)s in the range of 82.6-133 nM. The best inhibitor (K(I) of 15.1 nM) was 4-(2-amino-pyrimidin-4-yl)-benzenesulfonamide. These inhibitors may be useful to better understand the physiological role of beta-CAs in yeast and some pathogenic fungi which encode orthologues of the yeast enzyme and eventually for designing novel antifungal therapies.
|
Inhibition of human recombinant carbonic anhydrase 2 by stopped flow CO2 hydrase assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Cloning, expression, post-translational modifications and inhibition studies on the latest mammalian carbonic anhydrase isoform, CA XV.
Year : 2009
Volume : 52
Issue : 3
First Page : 646
Last Page : 654
Authors : Hilvo M, Salzano AM, Innocenti A, Kulomaa MS, Scozzafava A, Scaloni A, Parkkila S, Supuran CT.
Abstract : We have cloned and purified to homogeneity the latest member of the mammalian alpha-carbonic anhydrase (CA, EC 4.2.1.1) family, the mouse CA XV (mCA XV) protein. An investigation on the post-translational modifications of the enzyme has also been performed. The enzyme shows a moderate catalytic activity for the physiologic reaction, similarly to the physiologically relevant isoforms CA I, IV, VI, XII, and XIV, and it is susceptible to inhibition by sulfonamides and sulfamates. Best mCA XV inhibitors were celecoxib, sulfanilyl-sulfonamides, methazolamide, ethoxzolamide, dorzolamide, brinzolamide, and sulthiame, with K(I)s in the range of 45-65 nM. Due to the presence of this enzyme in rather high amounts in the rodent kidneys, the contribution of this isoform to the overall drug response should be taken into account when animal models are used to investigate CA inhibitors.
|
Inhibition of human full length recombinant carbonic anhydrase 6 by stopped flow CO2 hydrase assay
|
Homo sapiens
|
572.0
nM
|
|
Journal : J. Med. Chem.
Title : Cloning, expression, post-translational modifications and inhibition studies on the latest mammalian carbonic anhydrase isoform, CA XV.
Year : 2009
Volume : 52
Issue : 3
First Page : 646
Last Page : 654
Authors : Hilvo M, Salzano AM, Innocenti A, Kulomaa MS, Scozzafava A, Scaloni A, Parkkila S, Supuran CT.
Abstract : We have cloned and purified to homogeneity the latest member of the mammalian alpha-carbonic anhydrase (CA, EC 4.2.1.1) family, the mouse CA XV (mCA XV) protein. An investigation on the post-translational modifications of the enzyme has also been performed. The enzyme shows a moderate catalytic activity for the physiologic reaction, similarly to the physiologically relevant isoforms CA I, IV, VI, XII, and XIV, and it is susceptible to inhibition by sulfonamides and sulfamates. Best mCA XV inhibitors were celecoxib, sulfanilyl-sulfonamides, methazolamide, ethoxzolamide, dorzolamide, brinzolamide, and sulthiame, with K(I)s in the range of 45-65 nM. Due to the presence of this enzyme in rather high amounts in the rodent kidneys, the contribution of this isoform to the overall drug response should be taken into account when animal models are used to investigate CA inhibitors.
|
Inhibition of human recombinant carbonic anhydrase 9 catalytic domain by stopped flow CO2 hydrase assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Cloning, expression, post-translational modifications and inhibition studies on the latest mammalian carbonic anhydrase isoform, CA XV.
Year : 2009
Volume : 52
Issue : 3
First Page : 646
Last Page : 654
Authors : Hilvo M, Salzano AM, Innocenti A, Kulomaa MS, Scozzafava A, Scaloni A, Parkkila S, Supuran CT.
Abstract : We have cloned and purified to homogeneity the latest member of the mammalian alpha-carbonic anhydrase (CA, EC 4.2.1.1) family, the mouse CA XV (mCA XV) protein. An investigation on the post-translational modifications of the enzyme has also been performed. The enzyme shows a moderate catalytic activity for the physiologic reaction, similarly to the physiologically relevant isoforms CA I, IV, VI, XII, and XIV, and it is susceptible to inhibition by sulfonamides and sulfamates. Best mCA XV inhibitors were celecoxib, sulfanilyl-sulfonamides, methazolamide, ethoxzolamide, dorzolamide, brinzolamide, and sulthiame, with K(I)s in the range of 45-65 nM. Due to the presence of this enzyme in rather high amounts in the rodent kidneys, the contribution of this isoform to the overall drug response should be taken into account when animal models are used to investigate CA inhibitors.
|
Inhibition of mouse recombinant carbonic anhydrase 15 by stopped flow CO2 hydrase assay
|
Mus musculus
|
66.0
nM
|
|
Journal : J. Med. Chem.
Title : Cloning, expression, post-translational modifications and inhibition studies on the latest mammalian carbonic anhydrase isoform, CA XV.
Year : 2009
Volume : 52
Issue : 3
First Page : 646
Last Page : 654
Authors : Hilvo M, Salzano AM, Innocenti A, Kulomaa MS, Scozzafava A, Scaloni A, Parkkila S, Supuran CT.
Abstract : We have cloned and purified to homogeneity the latest member of the mammalian alpha-carbonic anhydrase (CA, EC 4.2.1.1) family, the mouse CA XV (mCA XV) protein. An investigation on the post-translational modifications of the enzyme has also been performed. The enzyme shows a moderate catalytic activity for the physiologic reaction, similarly to the physiologically relevant isoforms CA I, IV, VI, XII, and XIV, and it is susceptible to inhibition by sulfonamides and sulfamates. Best mCA XV inhibitors were celecoxib, sulfanilyl-sulfonamides, methazolamide, ethoxzolamide, dorzolamide, brinzolamide, and sulthiame, with K(I)s in the range of 45-65 nM. Due to the presence of this enzyme in rather high amounts in the rodent kidneys, the contribution of this isoform to the overall drug response should be taken into account when animal models are used to investigate CA inhibitors.
|
Inhibition of human recombinant carbonic anhydrase 2 by stopped flow CO2 hydration method
|
Homo sapiens
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Molecular cloning, characterization, and inhibition studies of the Rv1284 beta-carbonic anhydrase from Mycobacterium tuberculosis with sulfonamides and a sulfamate.
Year : 2009
Volume : 52
Issue : 8
First Page : 2226
Last Page : 2232
Authors : Minakuchi T, Nishimori I, Vullo D, Scozzafava A, Supuran CT.
Abstract : The beta-carbonic anhydrase (CA, EC 4.2.1.1) encoded by the gene Rv1284 (mtCA 1) of Mycobacterium tuberculosis shows appreciable catalytic activity for CO(2) hydration, with a k(cat) of 3.9 x 10(5) s(-1) and a k(cat)/K(m) of 3.7 x 10(7) M(-1) s(-1). A panel of 36 sulfonamides and one sulfamate, some of which are used clinically, were assayed for their effect on mtCA 1 catalytic activity. Most sulfonamides exhibited K(I) values in the range of 1-10 microM, but several derivatives, including sulfanilyl-sulfonamides acetazolamide, methazolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and the sulfamate topiramate, exhibited submicromolar inhibition (K(I) values of 0.481-0.905 microM). The best inhibitors were 3-bromosulfanilamide and indisulam (K(I) values of 97-186 nM). This study demonstrates that mtCA 1 can be inhibited by sulfonamides and sulfamates and thus has potential for developing antimycobacterial agents with an alternate mechanism of action. This is an important finding to explore further, as many strains exhibit multidrug resistance and extensive multidrug resistance to existing therapeutics.
|
Inhibition of Candida albicans recombinant Nce103 by stopped-flow CO2 hydration assay
|
Candida albicans
|
699.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Inhibition and homology modeling studies of the fungal beta-carbonic anhydrase from Candida albicans with sulfonamides.
Year : 2009
Volume : 17
Issue : 13
First Page : 4503
Last Page : 4509
Authors : Innocenti A, Hall RA, Schlicker C, Scozzafava A, Steegborn C, Mühlschlegel FA, Supuran CT.
Abstract : The beta-carbonic anhydrase (CA, EC 4.2.1.1) from the fungal pathogen Candida albicans (Nce103) is involved in a CO(2) sensing pathway critical for the pathogen life cycle and amenable to drug design studies. Herein we report an inhibition study of Nce103 with a library of sulfonamides and one sulfamate, showing that Nce103, similarly to the related enzyme from Cryptococcus neoformans Can2, is inhibited by these compounds with K(I)s in the range of 132 nM-7.6 microM. The best Nce103 inhibitors were acetazolamide, methazolamide, bromosulfanilamide, and 4-hydroxymethylbenzenesulfonamide (K(I)s<500 nM). A homology model was generated for Nce103 based on the crystal structure of Can2. The model shows that compounds with zinc-binding groups incorporating less polar moieties and compact scaffolds generate stronger Nce103 inhibitors, whereas highly polar zinc-binding groups and bulkier compounds appear more promising for the specific inhibition of Can2. Such compounds may be useful for the design of antifungal agents possessing a new mechanism of action.
|
Inhibition of Cryptococcus neoformans recombinant Can2 by stopped-flow CO2 hydration assay
|
Cryptococcus neoformans
|
704.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Inhibition and homology modeling studies of the fungal beta-carbonic anhydrase from Candida albicans with sulfonamides.
Year : 2009
Volume : 17
Issue : 13
First Page : 4503
Last Page : 4509
Authors : Innocenti A, Hall RA, Schlicker C, Scozzafava A, Steegborn C, Mühlschlegel FA, Supuran CT.
Abstract : The beta-carbonic anhydrase (CA, EC 4.2.1.1) from the fungal pathogen Candida albicans (Nce103) is involved in a CO(2) sensing pathway critical for the pathogen life cycle and amenable to drug design studies. Herein we report an inhibition study of Nce103 with a library of sulfonamides and one sulfamate, showing that Nce103, similarly to the related enzyme from Cryptococcus neoformans Can2, is inhibited by these compounds with K(I)s in the range of 132 nM-7.6 microM. The best Nce103 inhibitors were acetazolamide, methazolamide, bromosulfanilamide, and 4-hydroxymethylbenzenesulfonamide (K(I)s<500 nM). A homology model was generated for Nce103 based on the crystal structure of Can2. The model shows that compounds with zinc-binding groups incorporating less polar moieties and compact scaffolds generate stronger Nce103 inhibitors, whereas highly polar zinc-binding groups and bulkier compounds appear more promising for the specific inhibition of Can2. Such compounds may be useful for the design of antifungal agents possessing a new mechanism of action.
|
Inhibition of Helicobacter pylori beta-carbonic anhydrase by stopped-flow CO2 hydration assay
|
Helicobacter pylori
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Inhibition and homology modeling studies of the fungal beta-carbonic anhydrase from Candida albicans with sulfonamides.
Year : 2009
Volume : 17
Issue : 13
First Page : 4503
Last Page : 4509
Authors : Innocenti A, Hall RA, Schlicker C, Scozzafava A, Steegborn C, Mühlschlegel FA, Supuran CT.
Abstract : The beta-carbonic anhydrase (CA, EC 4.2.1.1) from the fungal pathogen Candida albicans (Nce103) is involved in a CO(2) sensing pathway critical for the pathogen life cycle and amenable to drug design studies. Herein we report an inhibition study of Nce103 with a library of sulfonamides and one sulfamate, showing that Nce103, similarly to the related enzyme from Cryptococcus neoformans Can2, is inhibited by these compounds with K(I)s in the range of 132 nM-7.6 microM. The best Nce103 inhibitors were acetazolamide, methazolamide, bromosulfanilamide, and 4-hydroxymethylbenzenesulfonamide (K(I)s<500 nM). A homology model was generated for Nce103 based on the crystal structure of Can2. The model shows that compounds with zinc-binding groups incorporating less polar moieties and compact scaffolds generate stronger Nce103 inhibitors, whereas highly polar zinc-binding groups and bulkier compounds appear more promising for the specific inhibition of Can2. Such compounds may be useful for the design of antifungal agents possessing a new mechanism of action.
|
Inhibition of human COX2 expressed in african green monkey COS cells assessed as inhibition of arachidonic acid-stimulated PGE2 production treated 1 hr before arachidonic acid challenge by enzyme immunoassay
|
Homo sapiens
|
183.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors.
Year : 2009
Volume : 19
Issue : 15
First Page : 4504
Last Page : 4508
Authors : Swarbrick ME, Beswick PJ, Gleave RJ, Green RH, Bingham S, Bountra C, Carter MC, Chambers LJ, Chessell IP, Clayton NM, Collins SD, Corfield JA, Hartley CD, Kleanthous S, Lambeth PF, Lucas FS, Mathews N, Naylor A, Page LW, Payne JJ, Pegg NA, Price HS, Skidmore J, Stevens AJ, Stocker R, Stratton SC, Stuart AJ, Wiseman JO.
Abstract : A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
|
Inhibition of human recombinant CA2 by stopped-flow CO2 assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Inhibition studies of a coral secretory isoform by sulfonamides.
Year : 2009
Volume : 17
Issue : 14
First Page : 5054
Last Page : 5058
Authors : Bertucci A, Innocenti A, Zoccola D, Scozzafava A, Tambutté S, Supuran CT.
Abstract : The inhibition of a newly cloned coral carbonic anhydrase (CA, EC 4.2.1.1) has been investigated with a series of sulfonamides, including some clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and sulpiride, or indisulam, a compound in clinical development as antitumor drug), as well as the sulfamate antiepileptic topiramate. Some simple amino-/hydrazine-/hydroxy-substituted aromatic/heterocyclic sulfonamides have also been included in the study. All types of activity have been detected, with low potency inhibitors (K(I)s in the range of 163-770nM), or with medium potency inhibitors (K(I)s in the range of 75.1-105nM), whereas ethoxzolamide, several clinically used sulfonamides and heterocyclic compounds showed stronger potency, with K(I)s in the range of 16-48.2nM. These inhibitors may be useful to better understand the physiological role of the Stylophora pistillata CA (STPCA) in corals and its involvement in biomineralisation in this era of global warming.
|
Inhibition of cloned Stylophora pistillata alpha-CA expressed in human HEK293 cells by stopped-flow CO2 assay
|
Stylophora pistillata
|
28.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Inhibition studies of a coral secretory isoform by sulfonamides.
Year : 2009
Volume : 17
Issue : 14
First Page : 5054
Last Page : 5058
Authors : Bertucci A, Innocenti A, Zoccola D, Scozzafava A, Tambutté S, Supuran CT.
Abstract : The inhibition of a newly cloned coral carbonic anhydrase (CA, EC 4.2.1.1) has been investigated with a series of sulfonamides, including some clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and sulpiride, or indisulam, a compound in clinical development as antitumor drug), as well as the sulfamate antiepileptic topiramate. Some simple amino-/hydrazine-/hydroxy-substituted aromatic/heterocyclic sulfonamides have also been included in the study. All types of activity have been detected, with low potency inhibitors (K(I)s in the range of 163-770nM), or with medium potency inhibitors (K(I)s in the range of 75.1-105nM), whereas ethoxzolamide, several clinically used sulfonamides and heterocyclic compounds showed stronger potency, with K(I)s in the range of 16-48.2nM. These inhibitors may be useful to better understand the physiological role of the Stylophora pistillata CA (STPCA) in corals and its involvement in biomineralisation in this era of global warming.
|
Inhibition of human recombinant CA2 by stopped-flow hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Characterization and inhibition studies of the most active beta-carbonic anhydrase from Mycobacterium tuberculosis, Rv3588c.
Year : 2009
Volume : 19
Issue : 23
First Page : 6649
Last Page : 6654
Authors : Carta F, Maresca A, Covarrubias AS, Mowbray SL, Jones TA, Supuran CT.
Abstract : The Rv3588c gene product of Mycobacterium tuberculosis, a beta-carbonic anhydrase (CA, EC 4.2.1.1) denominated here mtCA 2, shows the highest catalytic activity for CO(2) hydration (k(cat) of 9.8 x 10(5)s(-1), and k(cat)/K(m) of 9.3 x 10(7)M(-1)s(-1)) among the three beta-CAs encoded in the genome of this pathogen. A series of sulfonamides/sulfamates was assayed for their interaction with mtCA 2, and some diazenylbenzenesulfonamides were synthesized from sulfanilamide/metanilamide by diazotization followed by coupling with amines or phenols. Several low nanomolar mtCA 2 inhibitors have been detected among which acetazolamide, ethoxzolamide and some 4-diazenylbenzenesulfonamides (K(I)s of 9-59 nM). As the Rv3588c gene was shown to be essential to the growth of M. tuberculosis, inhibition of this enzyme may be relevant for the design of antituberculosis drugs possessing a novel mechanism of action.
|
Inhibition of full length Mycobacterium tuberculosis H37Rv recombinant carbonic anhydrase 2 encoded by RV3588c by stopped flow CO2 hydration assay
|
Mycobacterium tuberculosis
|
682.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Characterization and inhibition studies of the most active beta-carbonic anhydrase from Mycobacterium tuberculosis, Rv3588c.
Year : 2009
Volume : 19
Issue : 23
First Page : 6649
Last Page : 6654
Authors : Carta F, Maresca A, Covarrubias AS, Mowbray SL, Jones TA, Supuran CT.
Abstract : The Rv3588c gene product of Mycobacterium tuberculosis, a beta-carbonic anhydrase (CA, EC 4.2.1.1) denominated here mtCA 2, shows the highest catalytic activity for CO(2) hydration (k(cat) of 9.8 x 10(5)s(-1), and k(cat)/K(m) of 9.3 x 10(7)M(-1)s(-1)) among the three beta-CAs encoded in the genome of this pathogen. A series of sulfonamides/sulfamates was assayed for their interaction with mtCA 2, and some diazenylbenzenesulfonamides were synthesized from sulfanilamide/metanilamide by diazotization followed by coupling with amines or phenols. Several low nanomolar mtCA 2 inhibitors have been detected among which acetazolamide, ethoxzolamide and some 4-diazenylbenzenesulfonamides (K(I)s of 9-59 nM). As the Rv3588c gene was shown to be essential to the growth of M. tuberculosis, inhibition of this enzyme may be relevant for the design of antituberculosis drugs possessing a novel mechanism of action.
|
Inhibition of human recombinant CA2 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Inhibition studies with anions and sulfonamides of a new cytosolic enzyme from the scleractinian coral Stylophora pistillata.
Year : 2011
Volume : 21
Issue : 2
First Page : 710
Last Page : 714
Authors : Bertucci A, Innocenti A, Scozzafava A, Tambutté S, Zoccola D, Supuran CT.
Abstract : The catalytic activity and the inhibition of a new coral carbonic anhydrase (CA, EC 4.2.1.1), from the scleractinian coral Stylophora pistillata, STPCA-2, has been investigated. STPCA-2 has high catalytic activity for the physiological reaction being less sensitive to anion and sulfonamide inhibitors compared to STPCA, a coral enzyme previously described. The best STPCA-2 anion inhibitors were sulfamide, sulfamic acid, phenylboronic acid, and phenylarsonic acid (K(I)s of 5.7-67.2μM) whereas the best sulfonamide inhibitors were acetazolamide and dichlorophenamide (K(I)s of 74-79nM). Because this discriminatory effect between these two coral CAs, sulfonamides may be useful to better understand the physiological role of STPCA and STPCA-2 in corals and biomineralization processes.
|
Inhibition of Stylophora pistillata carbonic anhydrase by stopped-flow CO2 hydration assay
|
Stylophora pistillata
|
28.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors. Inhibition studies with anions and sulfonamides of a new cytosolic enzyme from the scleractinian coral Stylophora pistillata.
Year : 2011
Volume : 21
Issue : 2
First Page : 710
Last Page : 714
Authors : Bertucci A, Innocenti A, Scozzafava A, Tambutté S, Zoccola D, Supuran CT.
Abstract : The catalytic activity and the inhibition of a new coral carbonic anhydrase (CA, EC 4.2.1.1), from the scleractinian coral Stylophora pistillata, STPCA-2, has been investigated. STPCA-2 has high catalytic activity for the physiological reaction being less sensitive to anion and sulfonamide inhibitors compared to STPCA, a coral enzyme previously described. The best STPCA-2 anion inhibitors were sulfamide, sulfamic acid, phenylboronic acid, and phenylarsonic acid (K(I)s of 5.7-67.2μM) whereas the best sulfonamide inhibitors were acetazolamide and dichlorophenamide (K(I)s of 74-79nM). Because this discriminatory effect between these two coral CAs, sulfonamides may be useful to better understand the physiological role of STPCA and STPCA-2 in corals and biomineralization processes.
|
Inhibition of human carbonic anhydrase II by spectrophotometry at pH 7.5
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A new β-carbonic anhydrase from Brucella suis, its cloning, characterization, and inhibition with sulfonamides and sulfamates, leading to impaired pathogen growth.
Year : 2011
Volume : 19
Issue : 3
First Page : 1172
Last Page : 1178
Authors : Joseph P, Ouahrani-Bettache S, Montero JL, Nishimori I, Minakuchi T, Vullo D, Scozzafava A, Winum JY, Köhler S, Supuran CT.
Abstract : A β-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA II, has been cloned, purified, and characterized kinetically. bsCA II showed high catalytic activity for the hydration of CO(2) to bicarbonate, with a k(cat) of 1.1×10(6), and k(cat)/K(m) of 8.9×10(7)M(-1)s(-1). A panel of sulfonamides and sulfamates have been investigated for inhibition of this enzyme. All types of activities, from the low nanomolar to the micromolar, have been detected for these derivatives, which showed inhibition constants in the range of 7.3nM-8.56μM. The best bsCA II inhibitors were some glycosylated sulfanilamides, aliphatic sulfamates, and halogenated sulfanilamides, with inhibition constants of 7.3-87nM. Some of these dual inhibitors of bsCA I and II, also inhibited bacterial growth in vitro, in liquid cultures. These promising data on live bacteria allow us to propose bacterial β-CA inhibition as an approach for obtaining anti-infective agents with a new mechanism of action compared to classical antibiotics.
|
Inhibition of Brucella suis carbonic anhydrase II by spectrophotometry at pH 8.3
|
Brucella suis
|
612.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A new β-carbonic anhydrase from Brucella suis, its cloning, characterization, and inhibition with sulfonamides and sulfamates, leading to impaired pathogen growth.
Year : 2011
Volume : 19
Issue : 3
First Page : 1172
Last Page : 1178
Authors : Joseph P, Ouahrani-Bettache S, Montero JL, Nishimori I, Minakuchi T, Vullo D, Scozzafava A, Winum JY, Köhler S, Supuran CT.
Abstract : A β-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA II, has been cloned, purified, and characterized kinetically. bsCA II showed high catalytic activity for the hydration of CO(2) to bicarbonate, with a k(cat) of 1.1×10(6), and k(cat)/K(m) of 8.9×10(7)M(-1)s(-1). A panel of sulfonamides and sulfamates have been investigated for inhibition of this enzyme. All types of activities, from the low nanomolar to the micromolar, have been detected for these derivatives, which showed inhibition constants in the range of 7.3nM-8.56μM. The best bsCA II inhibitors were some glycosylated sulfanilamides, aliphatic sulfamates, and halogenated sulfanilamides, with inhibition constants of 7.3-87nM. Some of these dual inhibitors of bsCA I and II, also inhibited bacterial growth in vitro, in liquid cultures. These promising data on live bacteria allow us to propose bacterial β-CA inhibition as an approach for obtaining anti-infective agents with a new mechanism of action compared to classical antibiotics.
|
Inhibition of Brucella suis carbonic anhydrase I by spectrophotometry at pH 8.3
|
Brucella suis
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A new β-carbonic anhydrase from Brucella suis, its cloning, characterization, and inhibition with sulfonamides and sulfamates, leading to impaired pathogen growth.
Year : 2011
Volume : 19
Issue : 3
First Page : 1172
Last Page : 1178
Authors : Joseph P, Ouahrani-Bettache S, Montero JL, Nishimori I, Minakuchi T, Vullo D, Scozzafava A, Winum JY, Köhler S, Supuran CT.
Abstract : A β-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA II, has been cloned, purified, and characterized kinetically. bsCA II showed high catalytic activity for the hydration of CO(2) to bicarbonate, with a k(cat) of 1.1×10(6), and k(cat)/K(m) of 8.9×10(7)M(-1)s(-1). A panel of sulfonamides and sulfamates have been investigated for inhibition of this enzyme. All types of activities, from the low nanomolar to the micromolar, have been detected for these derivatives, which showed inhibition constants in the range of 7.3nM-8.56μM. The best bsCA II inhibitors were some glycosylated sulfanilamides, aliphatic sulfamates, and halogenated sulfanilamides, with inhibition constants of 7.3-87nM. Some of these dual inhibitors of bsCA I and II, also inhibited bacterial growth in vitro, in liquid cultures. These promising data on live bacteria allow us to propose bacterial β-CA inhibition as an approach for obtaining anti-infective agents with a new mechanism of action compared to classical antibiotics.
|
Inhibition of human recombinant carbonic anhydrase 2 at pH 7.5 by stopped flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Inhibition studies of the β-carbonic anhydrases from the bacterial pathogen Salmonella enterica serovar Typhimurium with sulfonamides and sulfamates.
Year : 2011
Volume : 19
Issue : 16
First Page : 5023
Last Page : 5030
Authors : Nishimori I, Minakuchi T, Vullo D, Scozzafava A, Supuran CT.
Abstract : The two β-carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Salmonella enterica serovar Typhimurium, stCA 1 and stCA 2, were investigated for their inhibition with a large panel of sulfonamides and sulfamates. Unlike inorganic anions, which are weak, millimolar inhibitors of the two enzymes [Vullo et al., Bioorg. Med. Chem. Lett.2011, 21, 3591], sulfonamides and sulfamates are effective micro-to nanomolar inhibitors of the two enzymes. Various types of inhibitors have been detected among the 38 investigated sulfonamides/sulfamates, with K(I)s in the range of 31 nM-5.87 μM. The best stCA 1 inhibitors were acetazolamide and benzolamide-based compounds, whereas the best stCA 2 inhibitors were sulfonylated benzenesulfonamides and amino-benzolamide derivatives (K(I)s in the range of 31-90 nM). 3-Fluoro-5-chloro-4-aminobenzolamide showed an inhibition constant of 51 nM against stCA 1 and of 38 nM against stCA 2, being the best inhibitor detected so far for these enzymes. As many strains of S. enterica show extensive resistance to classical antibiotics, inhibition of the β-CAs investigated here may be useful for developing novel antibacterials, targeting β-CAs which may be involved in pathogenicity and invasion of some bacteria.
|
Inhibition of human carbonic anhydrase 2-catalyzed CO2 hydration activity by stopped flow assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenylethynylbenzenesulfonamide regioisomers strongly and selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic isoforms I and II.
Year : 2011
Volume : 21
Issue : 19
First Page : 5892
Last Page : 5896
Authors : Knaus EE, Innocenti A, Scozzafava A, Supuran CT.
Abstract : A series of compounds incorporating regioisomeric phenylethynylbenzenesulfonamide moieties has been investigated for the inhibition of four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. Inhibition between the low nanomolar to the milliomolar range has been observed against them, with several low nanomolar and tumor-CA selective inhibitors detected. The position of the sulfamoyl group with respect to the alkyne functionality, and the nature of the moieties substituting the second aromatic ring were the principal structural features influencing CA inhibition. The para-sulfamoyl-substituted derivatives were effective inhibitors of CA IX and XII, the meta-substituted regioisomers of CA I, IX and XII, whereas the ortho-substituted sulfonamides were weak inhibitors of CA I, II and IX, but inhibited significantly CA XII.
|
Inhibition of human carbonic anhydrase 9-catalyzed CO2 hydration activity by stopped flow assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenylethynylbenzenesulfonamide regioisomers strongly and selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic isoforms I and II.
Year : 2011
Volume : 21
Issue : 19
First Page : 5892
Last Page : 5896
Authors : Knaus EE, Innocenti A, Scozzafava A, Supuran CT.
Abstract : A series of compounds incorporating regioisomeric phenylethynylbenzenesulfonamide moieties has been investigated for the inhibition of four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. Inhibition between the low nanomolar to the milliomolar range has been observed against them, with several low nanomolar and tumor-CA selective inhibitors detected. The position of the sulfamoyl group with respect to the alkyne functionality, and the nature of the moieties substituting the second aromatic ring were the principal structural features influencing CA inhibition. The para-sulfamoyl-substituted derivatives were effective inhibitors of CA IX and XII, the meta-substituted regioisomers of CA I, IX and XII, whereas the ortho-substituted sulfonamides were weak inhibitors of CA I, II and IX, but inhibited significantly CA XII.
|
Inhibition of human carbonic anhydrase 12-catalyzed CO2 hydration activity by stopped flow assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenylethynylbenzenesulfonamide regioisomers strongly and selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic isoforms I and II.
Year : 2011
Volume : 21
Issue : 19
First Page : 5892
Last Page : 5896
Authors : Knaus EE, Innocenti A, Scozzafava A, Supuran CT.
Abstract : A series of compounds incorporating regioisomeric phenylethynylbenzenesulfonamide moieties has been investigated for the inhibition of four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. Inhibition between the low nanomolar to the milliomolar range has been observed against them, with several low nanomolar and tumor-CA selective inhibitors detected. The position of the sulfamoyl group with respect to the alkyne functionality, and the nature of the moieties substituting the second aromatic ring were the principal structural features influencing CA inhibition. The para-sulfamoyl-substituted derivatives were effective inhibitors of CA IX and XII, the meta-substituted regioisomers of CA I, IX and XII, whereas the ortho-substituted sulfonamides were weak inhibitors of CA I, II and IX, but inhibited significantly CA XII.
|
DRUGMATRIX: Cyclooxygenase COX-2 enzyme inhibition (substrate: Arachidonic acid)
|
None
|
208.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of GST-tagged astrosclera willeyana Astrosclerin-3 expressed in Escherichia coli after 15 mins preincubation by stopped flow CO2 hydration assay
|
Astrosclera willeyana
|
517.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Cloning, characterization and sulfonamide inhibition studies of an α-carbonic anhydrase from the living fossil sponge Astrosclera willeyana.
Year : 2012
Volume : 20
Issue : 4
First Page : 1403
Last Page : 1410
Authors : Ohradanova A, Vullo D, Pastorekova S, Pastorek J, Jackson DJ, Wörheide G, Supuran CT.
Abstract : The α-carbonic anhydrase (CA, EC 4.2.1.1) Astrosclerin-3 previously isolated from the living fossil sponge Astrosclera willeyana (Jackson et al., Science 2007, 316, 1893), was cloned, kinetically characterized and investigated for its inhibition properties with sulfonamides and sulfamates. Astrosclerin-3 has a high catalytic activity for the CO(2) hydration reaction to bicarbonate and protons (k(cat) of 9.0×10(5) s(-1) and k(cat)/K(m) of 1.1×10(8) M(-1) × s(-1)), and is inhibited by various aromatic/heterocyclic sulfonamides and sulfamates with inhibition constants in the range of 2.9 nM-8.85 μM. Astrosclerin, and the human isoform CA II, display similar kinetic properties and affinities for sulfonamide inhibitors, despite more than 550 million years of independent evolution. Because Astrosclerin-3 is involved in biocalcification, the inhibitors characterized here may be used to gain insights into such processes in other metazoans.
|
Inhibition of human recombinant carbonic anhydrase 2 after 15 mins by stopped flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Cloning, characterization and sulfonamide inhibition studies of an α-carbonic anhydrase from the living fossil sponge Astrosclera willeyana.
Year : 2012
Volume : 20
Issue : 4
First Page : 1403
Last Page : 1410
Authors : Ohradanova A, Vullo D, Pastorekova S, Pastorek J, Jackson DJ, Wörheide G, Supuran CT.
Abstract : The α-carbonic anhydrase (CA, EC 4.2.1.1) Astrosclerin-3 previously isolated from the living fossil sponge Astrosclera willeyana (Jackson et al., Science 2007, 316, 1893), was cloned, kinetically characterized and investigated for its inhibition properties with sulfonamides and sulfamates. Astrosclerin-3 has a high catalytic activity for the CO(2) hydration reaction to bicarbonate and protons (k(cat) of 9.0×10(5) s(-1) and k(cat)/K(m) of 1.1×10(8) M(-1) × s(-1)), and is inhibited by various aromatic/heterocyclic sulfonamides and sulfamates with inhibition constants in the range of 2.9 nM-8.85 μM. Astrosclerin, and the human isoform CA II, display similar kinetic properties and affinities for sulfonamide inhibitors, despite more than 550 million years of independent evolution. Because Astrosclerin-3 is involved in biocalcification, the inhibitors characterized here may be used to gain insights into such processes in other metazoans.
|
Inhibition of human carbonic anhydrase 2 preincubated for 15 mins measured for 10 to 100 sec by stopped-flow method
|
Homo sapiens
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Molecular cloning, characterization, and inhibition studies of a β-carbonic anhydrase from Malassezia globosa, a potential antidandruff target.
Year : 2012
Volume : 55
Issue : 7
First Page : 3513
Last Page : 3520
Authors : Hewitson KS, Vullo D, Scozzafava A, Mastrolorenzo A, Supuran CT.
Abstract : A β-carbonic anhydrase (CA, EC 4.2.1.1) from the fungal pathogen Malassezia globosa has been cloned, characterized, and studied for its inhibition with sulfonamides. This enzyme, designated MG-CA, has significant catalytic activity in the CO(2) hydration reaction and was inhibited by sulfonamides, sulfamates, and sulfamides with K(I) in the nanomolar to micromolar range. Several sulfonamides have also been investigated for the inhibition of growth of M. globosa, M. dermatis, M. pachydermatic, and M. furfur in cultures, whereas a mouse model of dandruff showed that treatment with sulfonamides led to fragmented fungal hyphae, as for the treatment with ketoconazole, a clinically used antifungal agent. These data prompt us to propose MG-CA as a new antidandruff drug target.
|
Inhibition of Cryptococcus neoformans Can2 preincubated for 15 mins measured for 10 to 100 sec by stopped-flow method
|
Cryptococcus neoformans
|
704.0
nM
|
|
Journal : J. Med. Chem.
Title : Molecular cloning, characterization, and inhibition studies of a β-carbonic anhydrase from Malassezia globosa, a potential antidandruff target.
Year : 2012
Volume : 55
Issue : 7
First Page : 3513
Last Page : 3520
Authors : Hewitson KS, Vullo D, Scozzafava A, Mastrolorenzo A, Supuran CT.
Abstract : A β-carbonic anhydrase (CA, EC 4.2.1.1) from the fungal pathogen Malassezia globosa has been cloned, characterized, and studied for its inhibition with sulfonamides. This enzyme, designated MG-CA, has significant catalytic activity in the CO(2) hydration reaction and was inhibited by sulfonamides, sulfamates, and sulfamides with K(I) in the nanomolar to micromolar range. Several sulfonamides have also been investigated for the inhibition of growth of M. globosa, M. dermatis, M. pachydermatic, and M. furfur in cultures, whereas a mouse model of dandruff showed that treatment with sulfonamides led to fragmented fungal hyphae, as for the treatment with ketoconazole, a clinically used antifungal agent. These data prompt us to propose MG-CA as a new antidandruff drug target.
|
Inhibition of Candida albicans CaNce103 preincubated for 15 mins measured for 10 to 100 sec by stopped-flow method
|
Candida albicans
|
699.0
nM
|
|
Journal : J. Med. Chem.
Title : Molecular cloning, characterization, and inhibition studies of a β-carbonic anhydrase from Malassezia globosa, a potential antidandruff target.
Year : 2012
Volume : 55
Issue : 7
First Page : 3513
Last Page : 3520
Authors : Hewitson KS, Vullo D, Scozzafava A, Mastrolorenzo A, Supuran CT.
Abstract : A β-carbonic anhydrase (CA, EC 4.2.1.1) from the fungal pathogen Malassezia globosa has been cloned, characterized, and studied for its inhibition with sulfonamides. This enzyme, designated MG-CA, has significant catalytic activity in the CO(2) hydration reaction and was inhibited by sulfonamides, sulfamates, and sulfamides with K(I) in the nanomolar to micromolar range. Several sulfonamides have also been investigated for the inhibition of growth of M. globosa, M. dermatis, M. pachydermatic, and M. furfur in cultures, whereas a mouse model of dandruff showed that treatment with sulfonamides led to fragmented fungal hyphae, as for the treatment with ketoconazole, a clinically used antifungal agent. These data prompt us to propose MG-CA as a new antidandruff drug target.
|
Inhibition of Mycobacterium tuberculosis recombinant carbonic anhydrase Rv3588c pre-incubated for 15 mins by stopped-flow CO2 hydration method
|
Mycobacterium tuberculosis
|
682.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic sulfonamides incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole effectively inhibit α- and β-carbonic anhydrase: X-ray crystallography and solution investigations on 15 isoforms.
Year : 2012
Volume : 55
Issue : 22
First Page : 9619
Last Page : 9629
Authors : Marini AM, Maresca A, Aggarwal M, Orlandini E, Nencetti S, Da Settimo F, Salerno S, Simorini F, La Motta C, Taliani S, Nuti E, Scozzafava A, McKenna R, Rossello A, Supuran CT.
Abstract : Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.
|
Inhibition of human recombinant CA14 catalytic domain pre-incubated for 15 mins by stopped-flow CO2 hydration method
|
Homo sapiens
|
107.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic sulfonamides incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole effectively inhibit α- and β-carbonic anhydrase: X-ray crystallography and solution investigations on 15 isoforms.
Year : 2012
Volume : 55
Issue : 22
First Page : 9619
Last Page : 9629
Authors : Marini AM, Maresca A, Aggarwal M, Orlandini E, Nencetti S, Da Settimo F, Salerno S, Simorini F, La Motta C, Taliani S, Nuti E, Scozzafava A, McKenna R, Rossello A, Supuran CT.
Abstract : Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.
|
Inhibition of human recombinant CA13 catalytic domain pre-incubated for 15 mins by stopped-flow CO2 hydration method
|
Homo sapiens
|
425.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic sulfonamides incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole effectively inhibit α- and β-carbonic anhydrase: X-ray crystallography and solution investigations on 15 isoforms.
Year : 2012
Volume : 55
Issue : 22
First Page : 9619
Last Page : 9629
Authors : Marini AM, Maresca A, Aggarwal M, Orlandini E, Nencetti S, Da Settimo F, Salerno S, Simorini F, La Motta C, Taliani S, Nuti E, Scozzafava A, McKenna R, Rossello A, Supuran CT.
Abstract : Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.
|
Inhibition of human recombinant CA9 catalytic domain pre-incubated for 15 mins by stopped-flow CO2 hydration method
|
Homo sapiens
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic sulfonamides incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole effectively inhibit α- and β-carbonic anhydrase: X-ray crystallography and solution investigations on 15 isoforms.
Year : 2012
Volume : 55
Issue : 22
First Page : 9619
Last Page : 9629
Authors : Marini AM, Maresca A, Aggarwal M, Orlandini E, Nencetti S, Da Settimo F, Salerno S, Simorini F, La Motta C, Taliani S, Nuti E, Scozzafava A, McKenna R, Rossello A, Supuran CT.
Abstract : Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.
|
Inhibition of human recombinant CA12 catalytic domain pre-incubated for 15 mins by stopped-flow CO2 hydration method
|
Homo sapiens
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic sulfonamides incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole effectively inhibit α- and β-carbonic anhydrase: X-ray crystallography and solution investigations on 15 isoforms.
Year : 2012
Volume : 55
Issue : 22
First Page : 9619
Last Page : 9629
Authors : Marini AM, Maresca A, Aggarwal M, Orlandini E, Nencetti S, Da Settimo F, Salerno S, Simorini F, La Motta C, Taliani S, Nuti E, Scozzafava A, McKenna R, Rossello A, Supuran CT.
Abstract : Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.
|
Inhibition of human recombinant full length CA6 pre-incubated for 15 mins by stopped-flow CO2 hydration method
|
Homo sapiens
|
572.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic sulfonamides incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole effectively inhibit α- and β-carbonic anhydrase: X-ray crystallography and solution investigations on 15 isoforms.
Year : 2012
Volume : 55
Issue : 22
First Page : 9619
Last Page : 9629
Authors : Marini AM, Maresca A, Aggarwal M, Orlandini E, Nencetti S, Da Settimo F, Salerno S, Simorini F, La Motta C, Taliani S, Nuti E, Scozzafava A, McKenna R, Rossello A, Supuran CT.
Abstract : Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.
|
Inhibition of human recombinant full length CA5B pre-incubated for 15 mins by stopped-flow CO2 hydration method
|
Homo sapiens
|
88.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic sulfonamides incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole effectively inhibit α- and β-carbonic anhydrase: X-ray crystallography and solution investigations on 15 isoforms.
Year : 2012
Volume : 55
Issue : 22
First Page : 9619
Last Page : 9629
Authors : Marini AM, Maresca A, Aggarwal M, Orlandini E, Nencetti S, Da Settimo F, Salerno S, Simorini F, La Motta C, Taliani S, Nuti E, Scozzafava A, McKenna R, Rossello A, Supuran CT.
Abstract : Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.
|
Inhibition of human recombinant full length CA5A pre-incubated for 15 mins by stopped-flow CO2 hydration method
|
Homo sapiens
|
912.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic sulfonamides incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole effectively inhibit α- and β-carbonic anhydrase: X-ray crystallography and solution investigations on 15 isoforms.
Year : 2012
Volume : 55
Issue : 22
First Page : 9619
Last Page : 9629
Authors : Marini AM, Maresca A, Aggarwal M, Orlandini E, Nencetti S, Da Settimo F, Salerno S, Simorini F, La Motta C, Taliani S, Nuti E, Scozzafava A, McKenna R, Rossello A, Supuran CT.
Abstract : Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.
|
Inhibition of human recombinant full length CA2 pre-incubated for 15 mins by stopped-flow CO2 hydration method
|
Homo sapiens
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic sulfonamides incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole effectively inhibit α- and β-carbonic anhydrase: X-ray crystallography and solution investigations on 15 isoforms.
Year : 2012
Volume : 55
Issue : 22
First Page : 9619
Last Page : 9629
Authors : Marini AM, Maresca A, Aggarwal M, Orlandini E, Nencetti S, Da Settimo F, Salerno S, Simorini F, La Motta C, Taliani S, Nuti E, Scozzafava A, McKenna R, Rossello A, Supuran CT.
Abstract : Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.
|
Inhibition of recombinant Vibrio cholerae carbonic anhydrase expressed in Escherichia coli (DE3) preincubated for 15 mins by stopped-flow CO2 hydrase assay
|
Vibrio cholerae
|
89.7
nM
|
|
Journal : J. Med. Chem.
Title : DNA cloning, characterization, and inhibition studies of an α-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae.
Year : 2012
Volume : 55
Issue : 23
First Page : 10742
Last Page : 10748
Authors : Del Prete S, Isik S, Vullo D, De Luca V, Carginale V, Scozzafava A, Supuran CT, Capasso C.
Abstract : We have cloned, purified, and characterized an α-carbonic anhydrase (CA, EC 4.2.1.1) from the human pathogenic bacterium Vibrio cholerae, VchCA. The new enzyme has significant catalytic activity, and an inhibition study with sulfonamides and sulfamates led to the detection of a large number of low nanomolar inhibitors, among which are methazolamide, acetazolamide, ethoxzolamide, dorzolamide, brinzolamide, benzolamide, and indisulam (KI values in the range 0.69-8.1 nM). As bicarbonate is a virulence factor of this bacterium and since ethoxzolamide was shown to inhibit the in vivo virulence, we propose that VchCA may be a target for antibiotic development, exploiting a mechanism of action rarely considered until now.
|
Inhibition of human recombinant carbonic anhydrase 2 preincubated for 15 mins by stopped-flow CO2 hydrase assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : DNA cloning, characterization, and inhibition studies of an α-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae.
Year : 2012
Volume : 55
Issue : 23
First Page : 10742
Last Page : 10748
Authors : Del Prete S, Isik S, Vullo D, De Luca V, Carginale V, Scozzafava A, Supuran CT, Capasso C.
Abstract : We have cloned, purified, and characterized an α-carbonic anhydrase (CA, EC 4.2.1.1) from the human pathogenic bacterium Vibrio cholerae, VchCA. The new enzyme has significant catalytic activity, and an inhibition study with sulfonamides and sulfamates led to the detection of a large number of low nanomolar inhibitors, among which are methazolamide, acetazolamide, ethoxzolamide, dorzolamide, brinzolamide, benzolamide, and indisulam (KI values in the range 0.69-8.1 nM). As bicarbonate is a virulence factor of this bacterium and since ethoxzolamide was shown to inhibit the in vivo virulence, we propose that VchCA may be a target for antibiotic development, exploiting a mechanism of action rarely considered until now.
|
Inhibition of human recombinant carbonic anhydrase 2 by stopped flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Cloning, characterization, and sulfonamide and thiol inhibition studies of an α-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease.
Year : 2013
Volume : 56
Issue : 4
First Page : 1761
Last Page : 1771
Authors : Pan P, Vermelho AB, Capaci Rodrigues G, Scozzafava A, Tolvanen ME, Parkkila S, Capasso C, Supuran CT.
Abstract : An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.
|
Inhibition of Trypanosoma cruzi CL Brener recombinant alpha-carbonic anhydrase expressed in insect Sf9 cell Baculovirus system by stopped flow CO2 hydration assay
|
Trypanosoma cruzi
|
82.7
nM
|
|
Journal : J. Med. Chem.
Title : Cloning, characterization, and sulfonamide and thiol inhibition studies of an α-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease.
Year : 2013
Volume : 56
Issue : 4
First Page : 1761
Last Page : 1771
Authors : Pan P, Vermelho AB, Capaci Rodrigues G, Scozzafava A, Tolvanen ME, Parkkila S, Capasso C, Supuran CT.
Abstract : An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.
|
Inhibition of recombinant full length Candida glabrata NCE103 expressed in Escherichia coli BL21 preincubated for 15 mins by stopped-flow CO2 hydrase assay
|
Candida glabrata
|
97.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Carbonic anhydrase inhibitors: inhibition of the β-class enzyme from the pathogenic yeast Candida glabrata with sulfonamides, sulfamates and sulfamides.
Year : 2013
Volume : 23
Issue : 9
First Page : 2647
Last Page : 2652
Authors : Vullo D, Leewattanapasuk W, Mühlschlegel FA, Mastrolorenzo A, Capasso C, Supuran CT.
Abstract : The fungal pathogen Candida glabrata encodes for a β-carbonic anhydrase (CA, EC 4.2.1.1), CgNce103, recently discovered. Only anions have been investigated as CgNce103 inhibitors up until now. Here we report the first sulfonamides inhibition study of this enzyme. Simple sulfonamides showed weak or moderate CgNce103 inhibitory properties, whereas acetazolamide, and a series of 4-substituted ureido-benzene-sulfonamides, sulfamates and sulfamides showed effective CgNce103 inhibitory properties, with KIs in the range of 4.1-115 nM, being also ineffective as human CA II inhibitors. As there is significant resistance of C. glabrata clinical isolates to many classical antifungal agents, inhibition of the β-CA from this organism may allow an interesting means of controlling the pathogen growth, eventually leading to antifungals with a novel mechanism of action.
|
Inhibition of Sulfurihydrogenibium yellowstonense YO3AOP1 recombinant carbonic anhydrase preincubated for 15 mins by CO2 hydration stopped-flow assay
|
Sulfurihydrogenibium yellowstonense
|
5.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The alpha-carbonic anhydrase from the thermophilic bacterium Sulfurihydrogenibium yellowstonense YO3AOP1 is highly susceptible to inhibition by sulfonamides.
Year : 2013
Volume : 21
Issue : 6
First Page : 1534
Last Page : 1538
Authors : Vullo D, Luca VD, Scozzafava A, Carginale V, Rossi M, Supuran CT, Capasso C.
Abstract : The α-carbonic anhydrase (CA, EC 4.2.1.1) from the newly discovered thermophilic bacterium Sulfurihydrogenibium yellowstonense YO3AOP1 (SspCA) was investigated for its inhibition with a large series of sulfonamides and a sulfamate, the classical inhibitors of these zinc enzymes. SspCA showed an inhibition profile with these compounds very similar to that of the predominant human cytosolic isoform hCA II, and not to that of the bacterial α-CA from Helicobacter pylori. Some clinically used drugs such as acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, topiramate, celecoxib and sulthiame were low nanomolar SspCA/hCA II inhibitors (KIs in the range of 4.5-12.3nM) whereas simple aromatic/heterocyclic sulfonamides were less effective, micromolar inhibitors. As this highly catalytically active and thermostable enzyme may show biotechnological applications, its inhibition studies may be relevant for designing on/off systems to control its activity.
|
Inhibition of human recombinant carbonic anhydrase 2 preincubated for 15 mins by CO2 hydration stopped-flow assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The alpha-carbonic anhydrase from the thermophilic bacterium Sulfurihydrogenibium yellowstonense YO3AOP1 is highly susceptible to inhibition by sulfonamides.
Year : 2013
Volume : 21
Issue : 6
First Page : 1534
Last Page : 1538
Authors : Vullo D, Luca VD, Scozzafava A, Carginale V, Rossi M, Supuran CT, Capasso C.
Abstract : The α-carbonic anhydrase (CA, EC 4.2.1.1) from the newly discovered thermophilic bacterium Sulfurihydrogenibium yellowstonense YO3AOP1 (SspCA) was investigated for its inhibition with a large series of sulfonamides and a sulfamate, the classical inhibitors of these zinc enzymes. SspCA showed an inhibition profile with these compounds very similar to that of the predominant human cytosolic isoform hCA II, and not to that of the bacterial α-CA from Helicobacter pylori. Some clinically used drugs such as acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, topiramate, celecoxib and sulthiame were low nanomolar SspCA/hCA II inhibitors (KIs in the range of 4.5-12.3nM) whereas simple aromatic/heterocyclic sulfonamides were less effective, micromolar inhibitors. As this highly catalytically active and thermostable enzyme may show biotechnological applications, its inhibition studies may be relevant for designing on/off systems to control its activity.
|
Inhibition of human cytosolic carbonic anhydrase 2 preincubated for 15 mins by stopped flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors: Synthesis and inhibition of the cytosolic mammalian carbonic anhydrase isoforms I, II and VII with benzene sulfonamides incorporating 4,5,6,7-tetrachlorophthalimide moiety.
Year : 2013
Volume : 21
Issue : 17
First Page : 5168
Last Page : 5174
Authors : Sethi KK, Verma SM, Tanç M, Carta F, Supuran CT.
Abstract : A series of 4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzene sulfonamides incorporating primary amino moieties with 4,5,6,7-tetrachlorophthalic anhydride. These sulfonamides were assayed as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Some of these compounds showed very good in vitro human carbonic anhydrase (hCA) isoforms I, II and VII inhibitory properties, with affinities in the low nanomolar range. Inhibition activities against hCA I were in the range of 159-444nM; against hCA II in the range of 2.4-4515nM, and against hCA VII in the range of 1.3-469nM. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoform being established.
|
Inhibition of human membrane bound carbonic anhydrase 12 preincubated for 15 mins at room temperature followed by 72 hrs at 4 degC by stopped flow CO2 hydration assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, VII, IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety.
Year : 2013
Volume : 21
Issue : 19
First Page : 5973
Last Page : 5982
Authors : Sethi KK, Vullo D, Verma SM, Tanç M, Carta F, Supuran CT.
Abstract : A series of 4,5,6,7-tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzene sulfonamide derivatives with 4,5,6,7-tetrabromophthalic anhydride moiety. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I, II and VII and the transmembrane tumor-associated isoform hCA IX and XII. The new compounds were good hCA I inhibitors (Kis in the range of 143 to >10,000nM), but were moderately effective, as hCA II inhibitors (Kis of 47-190nM) and poor hCA VII inhibitors (Kis in the range of 54-175nM) compared to acetazolamide. The tumor-associated hCA IX was effectively inhibited with Kis ranging between 8.5 and 234nM and hCA XII with inhibition constants in the range of 6.1-197nM with high selectivity ratio. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking study of compounds was performed to rationalize the SAR reported over here.
|
Inhibition of human membrane bound carbonic anhydrase 9 preincubated for 15 mins at room temperature followed by 72 hrs at 4 degC by stopped flow CO2 hydration assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, VII, IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety.
Year : 2013
Volume : 21
Issue : 19
First Page : 5973
Last Page : 5982
Authors : Sethi KK, Vullo D, Verma SM, Tanç M, Carta F, Supuran CT.
Abstract : A series of 4,5,6,7-tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzene sulfonamide derivatives with 4,5,6,7-tetrabromophthalic anhydride moiety. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I, II and VII and the transmembrane tumor-associated isoform hCA IX and XII. The new compounds were good hCA I inhibitors (Kis in the range of 143 to >10,000nM), but were moderately effective, as hCA II inhibitors (Kis of 47-190nM) and poor hCA VII inhibitors (Kis in the range of 54-175nM) compared to acetazolamide. The tumor-associated hCA IX was effectively inhibited with Kis ranging between 8.5 and 234nM and hCA XII with inhibition constants in the range of 6.1-197nM with high selectivity ratio. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking study of compounds was performed to rationalize the SAR reported over here.
|
Inhibition of human cytosolic carbonic anhydrase 2 preincubated for 15 mins at room temperature followed by 72 hrs at 4 degC by stopped flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, VII, IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety.
Year : 2013
Volume : 21
Issue : 19
First Page : 5973
Last Page : 5982
Authors : Sethi KK, Vullo D, Verma SM, Tanç M, Carta F, Supuran CT.
Abstract : A series of 4,5,6,7-tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzene sulfonamide derivatives with 4,5,6,7-tetrabromophthalic anhydride moiety. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I, II and VII and the transmembrane tumor-associated isoform hCA IX and XII. The new compounds were good hCA I inhibitors (Kis in the range of 143 to >10,000nM), but were moderately effective, as hCA II inhibitors (Kis of 47-190nM) and poor hCA VII inhibitors (Kis in the range of 54-175nM) compared to acetazolamide. The tumor-associated hCA IX was effectively inhibited with Kis ranging between 8.5 and 234nM and hCA XII with inhibition constants in the range of 6.1-197nM with high selectivity ratio. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking study of compounds was performed to rationalize the SAR reported over here.
|
Inhibition of recombinant Leishmania donovani chagasi beta-carbonic anhydrase expressed in baculovirus infected insect Sf9 cells incubated for 15 mins prior to testing by stopped flow CO2 hydrase assay
|
Leishmania donovani chagasi
|
338.0
nM
|
|
Journal : J. Med. Chem.
Title : Cloning, characterization, and inhibition studies of a β-carbonic anhydrase from Leishmania donovani chagasi, the protozoan parasite responsible for leishmaniasis.
Year : 2013
Volume : 56
Issue : 18
First Page : 7372
Last Page : 7381
Authors : Syrjänen L, Vermelho AB, Rodrigues Ide A, Corte-Real S, Salonen T, Pan P, Vullo D, Parkkila S, Capasso C, Supuran CT.
Abstract : Leishmaniasis is an infection provoked by protozoans belonging to the genus Leishmania. Among the many species and subsepecies of such protozoa, Leishmania donovani chagasi causes visceral leishmaniasis. A β-carbonic anhydrase (CA, EC 4.2.1.1) was cloned and characterized from this organism, denominated here LdcCA. LdcCA possesses effective catalytic activity for the CO2 hydration reaction, with kcat of 9.35 × 10(5) s(-1) and kcat/KM of 5.9 × 10(7) M(-1) s(-1). A large number of aromatic/heterocyclic sulfonamides and 5-mercapto-1,3,4-thiadiazoles were investigated as LdcCA inhibitors. The sulfonamides were medium potency to weak inhibitors (KI values of 50.2 nM-9.25 μM), whereas some heterocyclic thiols inhibited the enzyme with KIs in the range of 13.4-152 nM. Some of the investigated thiols efficiently inhibited the in vivo growth of Leishmania chagasi and Leishmania amazonensis promastigotes, by impairing the flagellar pocket and movement of the parasites and causing their death. The β-CA from Leishmania spp. is proposed here as a new antileishmanial drug target.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
120.37
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
94.41
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of Thalassiosira weissflogii delta carbonic anhydrase preincubated for 15 mins by stopped flow CO2 hydration assay
|
Thalassiosira weissflogii
|
378.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the δ-carbonic anhydrase from the diatom Thalassiosira weissflogii.
Year : 2014
Volume : 24
Issue : 1
First Page : 275
Last Page : 279
Authors : Vullo D, Del Prete S, Osman SM, De Luca V, Scozzafava A, Alothman Z, Supuran CT, Capasso C.
Abstract : The δ-carbonic anhydrase (CA, EC 4.2.1.1) TweCA from the marine diatom Thalassiosira weissflogii has recently been cloned, purified and its activity/inhibition with anions investigated. Here we report the first sulfonamide/sulfamate inhibition study of a δ-class CA. Among the 40 such compounds investigated so far, 3-bromosulfanilamide, acetazolamide, ethoxzolamide, dorzolamide and brinzolamide were the most effective TweCA inhibitors detected, with KIs of 49.6-118nM. Many simple aromatic sulfonamides as well as dichlorophenamide, benzolamide, topiramate, zonisamide, indisulam and valdecoxib were medium potency inhibitors, (KIs of 375-897nM). Saccharin and hydrochlorothiazide were ineffective inhibitors of the δ-class enzyme, with KIs of 4.27-9.20μM. The inhibition profile of the δ-CA is very different from that of α-, β- and γ-CAs from different organisms. Although no X-ray crystal structure of this enzyme is available, we hypothesize that as for other CA classes, the sulfonamides inhibit the enzymatic activity by binding to the Zn(II) ion from the δ-CA active site.
|
Inhibition of Porphyromonas gingivalis recombinant gamma-carbonic anhydrase preincubated for 15 mins by stopped flow CO2 hydration assay
|
Porphyromonas gingivalis
|
755.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the δ-carbonic anhydrase from the diatom Thalassiosira weissflogii.
Year : 2014
Volume : 24
Issue : 1
First Page : 275
Last Page : 279
Authors : Vullo D, Del Prete S, Osman SM, De Luca V, Scozzafava A, Alothman Z, Supuran CT, Capasso C.
Abstract : The δ-carbonic anhydrase (CA, EC 4.2.1.1) TweCA from the marine diatom Thalassiosira weissflogii has recently been cloned, purified and its activity/inhibition with anions investigated. Here we report the first sulfonamide/sulfamate inhibition study of a δ-class CA. Among the 40 such compounds investigated so far, 3-bromosulfanilamide, acetazolamide, ethoxzolamide, dorzolamide and brinzolamide were the most effective TweCA inhibitors detected, with KIs of 49.6-118nM. Many simple aromatic sulfonamides as well as dichlorophenamide, benzolamide, topiramate, zonisamide, indisulam and valdecoxib were medium potency inhibitors, (KIs of 375-897nM). Saccharin and hydrochlorothiazide were ineffective inhibitors of the δ-class enzyme, with KIs of 4.27-9.20μM. The inhibition profile of the δ-CA is very different from that of α-, β- and γ-CAs from different organisms. Although no X-ray crystal structure of this enzyme is available, we hypothesize that as for other CA classes, the sulfonamides inhibit the enzymatic activity by binding to the Zn(II) ion from the δ-CA active site.
|
Inhibition of Leishmania donovani chagasi recombinant beta-carbonic anhydrase preincubated for 15 mins by stopped flow CO2 hydration assay
|
Leishmania chagasi
|
338.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the δ-carbonic anhydrase from the diatom Thalassiosira weissflogii.
Year : 2014
Volume : 24
Issue : 1
First Page : 275
Last Page : 279
Authors : Vullo D, Del Prete S, Osman SM, De Luca V, Scozzafava A, Alothman Z, Supuran CT, Capasso C.
Abstract : The δ-carbonic anhydrase (CA, EC 4.2.1.1) TweCA from the marine diatom Thalassiosira weissflogii has recently been cloned, purified and its activity/inhibition with anions investigated. Here we report the first sulfonamide/sulfamate inhibition study of a δ-class CA. Among the 40 such compounds investigated so far, 3-bromosulfanilamide, acetazolamide, ethoxzolamide, dorzolamide and brinzolamide were the most effective TweCA inhibitors detected, with KIs of 49.6-118nM. Many simple aromatic sulfonamides as well as dichlorophenamide, benzolamide, topiramate, zonisamide, indisulam and valdecoxib were medium potency inhibitors, (KIs of 375-897nM). Saccharin and hydrochlorothiazide were ineffective inhibitors of the δ-class enzyme, with KIs of 4.27-9.20μM. The inhibition profile of the δ-CA is very different from that of α-, β- and γ-CAs from different organisms. Although no X-ray crystal structure of this enzyme is available, we hypothesize that as for other CA classes, the sulfonamides inhibit the enzymatic activity by binding to the Zn(II) ion from the δ-CA active site.
|
Inhibition of human recombinant carbonic anhydrase 2 preincubated for 15 mins by stopped flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the δ-carbonic anhydrase from the diatom Thalassiosira weissflogii.
Year : 2014
Volume : 24
Issue : 1
First Page : 275
Last Page : 279
Authors : Vullo D, Del Prete S, Osman SM, De Luca V, Scozzafava A, Alothman Z, Supuran CT, Capasso C.
Abstract : The δ-carbonic anhydrase (CA, EC 4.2.1.1) TweCA from the marine diatom Thalassiosira weissflogii has recently been cloned, purified and its activity/inhibition with anions investigated. Here we report the first sulfonamide/sulfamate inhibition study of a δ-class CA. Among the 40 such compounds investigated so far, 3-bromosulfanilamide, acetazolamide, ethoxzolamide, dorzolamide and brinzolamide were the most effective TweCA inhibitors detected, with KIs of 49.6-118nM. Many simple aromatic sulfonamides as well as dichlorophenamide, benzolamide, topiramate, zonisamide, indisulam and valdecoxib were medium potency inhibitors, (KIs of 375-897nM). Saccharin and hydrochlorothiazide were ineffective inhibitors of the δ-class enzyme, with KIs of 4.27-9.20μM. The inhibition profile of the δ-CA is very different from that of α-, β- and γ-CAs from different organisms. Although no X-ray crystal structure of this enzyme is available, we hypothesize that as for other CA classes, the sulfonamides inhibit the enzymatic activity by binding to the Zn(II) ion from the δ-CA active site.
|
Inhibition of recombinant Methanosarcina thermophila gamma-CA CAM by stopped flow CO2 hydration assay
|
Leishmania donovani chagasi
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the oral pathogen Porphyromonas gingivalis.
Year : 2014
Volume : 24
Issue : 1
First Page : 240
Last Page : 244
Authors : Vullo D, Del Prete S, Osman SM, De Luca V, Scozzafava A, Alothman Z, Supuran CT, Capasso C.
Abstract : A carbonic anhydrase (CA, EC 4.2.1.1) denominated PgiCA, belonging to the γ-class, from the oral pathogenic bacteria Porphyromonas gingivalis, the main causative agent of periodontitis, was investigated for its inhibition profile with sulfonamides and one sulfamate. Dichlorophenamide, topiramate and many simple aromatic/heterocyclic sulfonamides were ineffective as PgiCA inhibitors whereas the best inhibition was observed with halogenosulfanilamides incorporating heavy halogens, 4-hydroxy- and 4-hydroxyalkyl-benzenesulfonamides, acetazolamide, methazolamide, zonisamide, indisulam, celecoxib, saccharin and hydrochlorothiazide (KIs in the range of 131-380nM). The inhibition profile of PgiCA was very different from that of CAM, hCA I and II or the β-CA from a protozoan parasite (Leishmania donovani chagasii). Identification of potent and possibly selective inhibitors of PgiCA may lead to pharmacological tools useful for understanding the physiological role(s) of this enzyme.
|
Inhibition of Porphyromonas gingivalis gamma-carbonic anhydrase expressed in Escherichia coli preincubated for 15 mins by stopped flow CO2 hydration assay
|
Porphyromonas gingivalis
|
755.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the oral pathogen Porphyromonas gingivalis.
Year : 2014
Volume : 24
Issue : 1
First Page : 240
Last Page : 244
Authors : Vullo D, Del Prete S, Osman SM, De Luca V, Scozzafava A, Alothman Z, Supuran CT, Capasso C.
Abstract : A carbonic anhydrase (CA, EC 4.2.1.1) denominated PgiCA, belonging to the γ-class, from the oral pathogenic bacteria Porphyromonas gingivalis, the main causative agent of periodontitis, was investigated for its inhibition profile with sulfonamides and one sulfamate. Dichlorophenamide, topiramate and many simple aromatic/heterocyclic sulfonamides were ineffective as PgiCA inhibitors whereas the best inhibition was observed with halogenosulfanilamides incorporating heavy halogens, 4-hydroxy- and 4-hydroxyalkyl-benzenesulfonamides, acetazolamide, methazolamide, zonisamide, indisulam, celecoxib, saccharin and hydrochlorothiazide (KIs in the range of 131-380nM). The inhibition profile of PgiCA was very different from that of CAM, hCA I and II or the β-CA from a protozoan parasite (Leishmania donovani chagasii). Identification of potent and possibly selective inhibitors of PgiCA may lead to pharmacological tools useful for understanding the physiological role(s) of this enzyme.
|
Inhibition of human transmembrane carbonic anhydrase 12 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, IX and XII with benzene sulfonamides incorporating 4- and 3-nitrophthalimide moieties.
Year : 2014
Volume : 22
Issue : 5
First Page : 1586
Last Page : 1595
Authors : Sethi KK, Verma SM, Tanç M, Purper G, Calafato G, Carta F, Supuran CT.
Abstract : A series of 4 and 5 nitro-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzenesulfonamide derivatives with 4 and 3-nitrophthalic anhydrides. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated hCA IX and XII. Most of the novel compounds were medium potency-weak hCA I inhibitors (Kis in the range of 295-10,000 nM), but were more effective hCA II inhibitors (Kis of 1.7-887 nM). The tumor-associated hCA IX was also inhibited, with Kis in the micromolar range, whereas against hCA XII the inhibition constants were in the range of 90-3,746 nM. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking studies was performed in order to rationalize the activities reported and binding mode to different hCA as inhibitors.
|
Inhibition of human transmembrane carbonic anhydrase 9 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, IX and XII with benzene sulfonamides incorporating 4- and 3-nitrophthalimide moieties.
Year : 2014
Volume : 22
Issue : 5
First Page : 1586
Last Page : 1595
Authors : Sethi KK, Verma SM, Tanç M, Purper G, Calafato G, Carta F, Supuran CT.
Abstract : A series of 4 and 5 nitro-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzenesulfonamide derivatives with 4 and 3-nitrophthalic anhydrides. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated hCA IX and XII. Most of the novel compounds were medium potency-weak hCA I inhibitors (Kis in the range of 295-10,000 nM), but were more effective hCA II inhibitors (Kis of 1.7-887 nM). The tumor-associated hCA IX was also inhibited, with Kis in the micromolar range, whereas against hCA XII the inhibition constants were in the range of 90-3,746 nM. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking studies was performed in order to rationalize the activities reported and binding mode to different hCA as inhibitors.
|
Inhibition of human cytosolic carbonic anhydrase 2 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, IX and XII with benzene sulfonamides incorporating 4- and 3-nitrophthalimide moieties.
Year : 2014
Volume : 22
Issue : 5
First Page : 1586
Last Page : 1595
Authors : Sethi KK, Verma SM, Tanç M, Purper G, Calafato G, Carta F, Supuran CT.
Abstract : A series of 4 and 5 nitro-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzenesulfonamide derivatives with 4 and 3-nitrophthalic anhydrides. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated hCA IX and XII. Most of the novel compounds were medium potency-weak hCA I inhibitors (Kis in the range of 295-10,000 nM), but were more effective hCA II inhibitors (Kis of 1.7-887 nM). The tumor-associated hCA IX was also inhibited, with Kis in the micromolar range, whereas against hCA XII the inhibition constants were in the range of 90-3,746 nM. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking studies was performed in order to rationalize the activities reported and binding mode to different hCA as inhibitors.
|
Inhibition of human carbonic anhydrase-2 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of two β-carbonic anhydrases from the bacterial pathogen Legionella pneumophila.
Year : 2014
Volume : 22
Issue : 11
First Page : 2939
Last Page : 2946
Authors : Nishimori I, Vullo D, Minakuchi T, Scozzafava A, Capasso C, Supuran CT.
Abstract : Two β-carbonic anhydrases (CAs, EC 4.2.1.1) were identified, cloned and purified in the pathogenic bacterium Legionella pneumophila, denominated LpCA1 and LpCA2. They efficiently catalyze CO2 hydration to bicarbonate and protons, with kcat in the range of (3.4-8.3) × 10(5)s(-1) and kcat/Km of (4.7-8.5) × 10(7)M(-1)s(-1), and are inhibited by sulfonamides and sulfamates. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide(KIs in the range of 40.3-90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide and dichlorophenamide (KIs in the range of 25.2-88.5 nM). As these enzymes may be involved in pH regulation in the phagosome during Legionella infection, their inhibition may lead to antibacterials with a novel mechanism of action.
|
Inhibition of Legionella pneumophilia subsp. Pneumophila strain Philadelphia-1 carbonic anhydrase-1 assessed as CO2 hydrase activity by stopped-flow assay
|
Legionella pneumophila subsp. pneumophila str. Philadelphia 1
|
536.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of two β-carbonic anhydrases from the bacterial pathogen Legionella pneumophila.
Year : 2014
Volume : 22
Issue : 11
First Page : 2939
Last Page : 2946
Authors : Nishimori I, Vullo D, Minakuchi T, Scozzafava A, Capasso C, Supuran CT.
Abstract : Two β-carbonic anhydrases (CAs, EC 4.2.1.1) were identified, cloned and purified in the pathogenic bacterium Legionella pneumophila, denominated LpCA1 and LpCA2. They efficiently catalyze CO2 hydration to bicarbonate and protons, with kcat in the range of (3.4-8.3) × 10(5)s(-1) and kcat/Km of (4.7-8.5) × 10(7)M(-1)s(-1), and are inhibited by sulfonamides and sulfamates. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide(KIs in the range of 40.3-90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide and dichlorophenamide (KIs in the range of 25.2-88.5 nM). As these enzymes may be involved in pH regulation in the phagosome during Legionella infection, their inhibition may lead to antibacterials with a novel mechanism of action.
|
Inhibition of Legionella pneumophilia subsp. Pneumophila strain Philadelphia-1 carbonic anhydrase-2 assessed as CO2 hydrase activity by stopped-flow assay
|
Legionella pneumophila subsp. pneumophila str. Philadelphia 1
|
879.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of two β-carbonic anhydrases from the bacterial pathogen Legionella pneumophila.
Year : 2014
Volume : 22
Issue : 11
First Page : 2939
Last Page : 2946
Authors : Nishimori I, Vullo D, Minakuchi T, Scozzafava A, Capasso C, Supuran CT.
Abstract : Two β-carbonic anhydrases (CAs, EC 4.2.1.1) were identified, cloned and purified in the pathogenic bacterium Legionella pneumophila, denominated LpCA1 and LpCA2. They efficiently catalyze CO2 hydration to bicarbonate and protons, with kcat in the range of (3.4-8.3) × 10(5)s(-1) and kcat/Km of (4.7-8.5) × 10(7)M(-1)s(-1), and are inhibited by sulfonamides and sulfamates. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide(KIs in the range of 40.3-90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide and dichlorophenamide (KIs in the range of 25.2-88.5 nM). As these enzymes may be involved in pH regulation in the phagosome during Legionella infection, their inhibition may lead to antibacterials with a novel mechanism of action.
|
Inhibition of human recombinant Carbonic anhydrase 2 compound preincubated for 15 mins by stopped flow CO2 hydrase assay method
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition study of the carbonic anhydrases from the bacterial pathogen Porphyromonas gingivalis: the β-class (PgiCAb) versus the γ-class (PgiCA) enzymes.
Year : 2014
Volume : 22
Issue : 17
First Page : 4537
Last Page : 4543
Authors : Prete SD, Vullo D, Osman SM, Scozzafava A, AlOthman Z, Capasso C, Supuran CT.
Abstract : The oral pathogenic bacterium Porphyromonas gingivalis, encodes for two carbonic anhydrases (CAs, EC 4.2.1.1) one belonging to the γ-class (PgiCA) and another one to the β-class (PgiCAb). This last enzyme has been cloned and characterized here for its inhibition profile with the main class of CA inhibitors, the sulfonamides. Many of the clinically used sulfonamides as well as simple aromatic/heterocyclic sulfonamides were ineffective as PgiCAb inhibitors whereas better inhibition was observed with simple derivatives such as sulfanilamide, metanilamide, 4-aminoalkylbenzenesulfonamides (KIs of 364-475nM). The halogenosulfanilamides incorporating heavy halogens, 4-hydroxy- and 4-hydroxyalkyl-benzenesulfonamides, were also micromolar, ineffective PgiCAb inhibitors. The best inhibitors of the β-class enzyme were acetazolamide and ethoxzolamide, with KIs of 214-280nM. Interestingly, the γ-class enzyme was much more sensitive to sulfonamide inhibitors compared to the β-class one, PgiCAb. Identification of potent and possibly selective inhibitors of PgiCAb/PgiCA may lead to pharmacological tools useful for understanding the physiological role(s) of these enzymes, since this bacterium is the main causative agent of periodontitis and few treatment options are presently available.
|
Inhibition of Porphyromonas gingivalis Gamma-carbonic anhydrase compound preincubated for 15 mins by stopped flow CO2 hydrase assay method
|
Porphyromonas gingivalis
|
755.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition study of the carbonic anhydrases from the bacterial pathogen Porphyromonas gingivalis: the β-class (PgiCAb) versus the γ-class (PgiCA) enzymes.
Year : 2014
Volume : 22
Issue : 17
First Page : 4537
Last Page : 4543
Authors : Prete SD, Vullo D, Osman SM, Scozzafava A, AlOthman Z, Capasso C, Supuran CT.
Abstract : The oral pathogenic bacterium Porphyromonas gingivalis, encodes for two carbonic anhydrases (CAs, EC 4.2.1.1) one belonging to the γ-class (PgiCA) and another one to the β-class (PgiCAb). This last enzyme has been cloned and characterized here for its inhibition profile with the main class of CA inhibitors, the sulfonamides. Many of the clinically used sulfonamides as well as simple aromatic/heterocyclic sulfonamides were ineffective as PgiCAb inhibitors whereas better inhibition was observed with simple derivatives such as sulfanilamide, metanilamide, 4-aminoalkylbenzenesulfonamides (KIs of 364-475nM). The halogenosulfanilamides incorporating heavy halogens, 4-hydroxy- and 4-hydroxyalkyl-benzenesulfonamides, were also micromolar, ineffective PgiCAb inhibitors. The best inhibitors of the β-class enzyme were acetazolamide and ethoxzolamide, with KIs of 214-280nM. Interestingly, the γ-class enzyme was much more sensitive to sulfonamide inhibitors compared to the β-class one, PgiCAb. Identification of potent and possibly selective inhibitors of PgiCAb/PgiCA may lead to pharmacological tools useful for understanding the physiological role(s) of these enzymes, since this bacterium is the main causative agent of periodontitis and few treatment options are presently available.
|
Inhibition of human recombinant carbonic anhydrase 2 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of the η-class carbonic anhydrase from the malaria pathogen Plasmodium falciparum.
Year : 2015
Volume : 23
Issue : 3
First Page : 526
Last Page : 531
Authors : Vullo D, Del Prete S, Fisher GM, Andrews KT, Poulsen SA, Capasso C, Supuran CT.
Abstract : The η-carbonic anhydrases (CAs, EC 4.2.1.1) were recently discovered as the sixth genetic class of this metalloenzyme superfamily, and are so far known only in protozoa, including various Plasmodium species, the causative agents of malaria. We report here an inhibition study of the η-CA from Plasmodium falciparum (PfCA) against a panel of sulfonamides and one sulfamate compound, some of which are clinically used. The strongest inhibitors identified were ethoxzolamide and sulthiame, with KIs of 131-132 nM, followed by acetazolamide, methazolamide and hydrochlorothiazide (KIs of 153-198 nM). Brinzolamide, topiramate, zonisamide, indisulam, valdecoxib and celecoxib also showed significant inhibitory action against PfCA, with KIs ranging from 217 to 308 nM. An interesting observation was that the more efficient PfCA inhibitors are representative of several scaffolds and chemical classes, including benzene sulfonamides, monocyclic/bicyclic heterocyclic sulfonamides and compounds with a more complex scaffold (i.e., the sugar sulfamate derivative, topiramate, and the coxibs, celecoxib and valdecoxib). A comprehensive inhibition study of small molecules for η-CAs is needed as a first step towards assessing PfCA as a druggable target. The present work identifies the first known η-CA inhibitors and provides a platform for the development of next generation novel PfCA inhibitors.
|
Inhibition of Plasmodium falciparum Eta-carbonic anhydrase pre-incubated for 15 mins before CO2 substrate addition by stopped-flow CO2 hydration assay
|
Plasmodium falciparum
|
226.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of the η-class carbonic anhydrase from the malaria pathogen Plasmodium falciparum.
Year : 2015
Volume : 23
Issue : 3
First Page : 526
Last Page : 531
Authors : Vullo D, Del Prete S, Fisher GM, Andrews KT, Poulsen SA, Capasso C, Supuran CT.
Abstract : The η-carbonic anhydrases (CAs, EC 4.2.1.1) were recently discovered as the sixth genetic class of this metalloenzyme superfamily, and are so far known only in protozoa, including various Plasmodium species, the causative agents of malaria. We report here an inhibition study of the η-CA from Plasmodium falciparum (PfCA) against a panel of sulfonamides and one sulfamate compound, some of which are clinically used. The strongest inhibitors identified were ethoxzolamide and sulthiame, with KIs of 131-132 nM, followed by acetazolamide, methazolamide and hydrochlorothiazide (KIs of 153-198 nM). Brinzolamide, topiramate, zonisamide, indisulam, valdecoxib and celecoxib also showed significant inhibitory action against PfCA, with KIs ranging from 217 to 308 nM. An interesting observation was that the more efficient PfCA inhibitors are representative of several scaffolds and chemical classes, including benzene sulfonamides, monocyclic/bicyclic heterocyclic sulfonamides and compounds with a more complex scaffold (i.e., the sugar sulfamate derivative, topiramate, and the coxibs, celecoxib and valdecoxib). A comprehensive inhibition study of small molecules for η-CAs is needed as a first step towards assessing PfCA as a druggable target. The present work identifies the first known η-CA inhibitors and provides a platform for the development of next generation novel PfCA inhibitors.
|
Inhibition of human recombinant carbonic anhydrase 2 by stopped flow CO2 hydrase assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic cyanobacterium Nostoc commune.
Year : 2015
Volume : 23
Issue : 8
First Page : 1728
Last Page : 1734
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Capasso C, Supuran CT.
Abstract : A carbonic anhydrase (CA, EC 4.2.1.1) belonging to the γ-class has been cloned, purified and characterized from the Antarctic cyanobacterium Nostoc commune. The enzyme showed a good catalytic activity for the physiologic reaction (hydration of carbon dioxide to bicarbonate and a proton) with the following kinetic parameters, kcat of 9.5×10(5)s(-1) and kcat/KM of 8.3×10(7)M(-1)s(-1), being the γ-CA with the highest catalytic activity described so far. A range of aromatic/heterocyclic sulfonamides and one sulfamate were investigated as inhibitors of the new enzyme, denominated here NcoCA. The best NcoCA inhibitors were some sulfonylated sulfanilamide derivatives possessing elongated molecules, aminobenzolamide, acetazolamide, benzolamide, dorzolamide, brinzolamide and topiramate, which showed inhibition constants in the range of 40.3-92.3nM. As 1,5-bisphosphate carboxylase/oxygenase (RubisCO) and γ-CAs are closely associated in carboxysomes of cyanobacteria for enhancing the affinity of RubisCO for CO2 and the efficiency of photosynthesis, investigation of this new enzyme and its affinity for modulators of its activity may bring new insights in these crucial processes.
|
Inhibition of recombinant Methanosarcina thermophila gamma-carbonic anhydrase by stopped flow CO2 hydrase assay
|
Methanosarcina thermophila
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic cyanobacterium Nostoc commune.
Year : 2015
Volume : 23
Issue : 8
First Page : 1728
Last Page : 1734
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Capasso C, Supuran CT.
Abstract : A carbonic anhydrase (CA, EC 4.2.1.1) belonging to the γ-class has been cloned, purified and characterized from the Antarctic cyanobacterium Nostoc commune. The enzyme showed a good catalytic activity for the physiologic reaction (hydration of carbon dioxide to bicarbonate and a proton) with the following kinetic parameters, kcat of 9.5×10(5)s(-1) and kcat/KM of 8.3×10(7)M(-1)s(-1), being the γ-CA with the highest catalytic activity described so far. A range of aromatic/heterocyclic sulfonamides and one sulfamate were investigated as inhibitors of the new enzyme, denominated here NcoCA. The best NcoCA inhibitors were some sulfonylated sulfanilamide derivatives possessing elongated molecules, aminobenzolamide, acetazolamide, benzolamide, dorzolamide, brinzolamide and topiramate, which showed inhibition constants in the range of 40.3-92.3nM. As 1,5-bisphosphate carboxylase/oxygenase (RubisCO) and γ-CAs are closely associated in carboxysomes of cyanobacteria for enhancing the affinity of RubisCO for CO2 and the efficiency of photosynthesis, investigation of this new enzyme and its affinity for modulators of its activity may bring new insights in these crucial processes.
|
Inhibition of recombinant Porphyromonas gingivalis gamma-carbonic anhydrase by stopped flow CO2 hydrase assay
|
Porphyromonas gingivalis
|
755.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic cyanobacterium Nostoc commune.
Year : 2015
Volume : 23
Issue : 8
First Page : 1728
Last Page : 1734
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Capasso C, Supuran CT.
Abstract : A carbonic anhydrase (CA, EC 4.2.1.1) belonging to the γ-class has been cloned, purified and characterized from the Antarctic cyanobacterium Nostoc commune. The enzyme showed a good catalytic activity for the physiologic reaction (hydration of carbon dioxide to bicarbonate and a proton) with the following kinetic parameters, kcat of 9.5×10(5)s(-1) and kcat/KM of 8.3×10(7)M(-1)s(-1), being the γ-CA with the highest catalytic activity described so far. A range of aromatic/heterocyclic sulfonamides and one sulfamate were investigated as inhibitors of the new enzyme, denominated here NcoCA. The best NcoCA inhibitors were some sulfonylated sulfanilamide derivatives possessing elongated molecules, aminobenzolamide, acetazolamide, benzolamide, dorzolamide, brinzolamide and topiramate, which showed inhibition constants in the range of 40.3-92.3nM. As 1,5-bisphosphate carboxylase/oxygenase (RubisCO) and γ-CAs are closely associated in carboxysomes of cyanobacteria for enhancing the affinity of RubisCO for CO2 and the efficiency of photosynthesis, investigation of this new enzyme and its affinity for modulators of its activity may bring new insights in these crucial processes.
|
Inhibition of recombinant Nostoc commune gamma-carbonic anhydrase preincubated for 15 mins by stopped flow CO2 hydrase assay
|
Nostoc commune
|
53.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic cyanobacterium Nostoc commune.
Year : 2015
Volume : 23
Issue : 8
First Page : 1728
Last Page : 1734
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Capasso C, Supuran CT.
Abstract : A carbonic anhydrase (CA, EC 4.2.1.1) belonging to the γ-class has been cloned, purified and characterized from the Antarctic cyanobacterium Nostoc commune. The enzyme showed a good catalytic activity for the physiologic reaction (hydration of carbon dioxide to bicarbonate and a proton) with the following kinetic parameters, kcat of 9.5×10(5)s(-1) and kcat/KM of 8.3×10(7)M(-1)s(-1), being the γ-CA with the highest catalytic activity described so far. A range of aromatic/heterocyclic sulfonamides and one sulfamate were investigated as inhibitors of the new enzyme, denominated here NcoCA. The best NcoCA inhibitors were some sulfonylated sulfanilamide derivatives possessing elongated molecules, aminobenzolamide, acetazolamide, benzolamide, dorzolamide, brinzolamide and topiramate, which showed inhibition constants in the range of 40.3-92.3nM. As 1,5-bisphosphate carboxylase/oxygenase (RubisCO) and γ-CAs are closely associated in carboxysomes of cyanobacteria for enhancing the affinity of RubisCO for CO2 and the efficiency of photosynthesis, investigation of this new enzyme and its affinity for modulators of its activity may bring new insights in these crucial processes.
|
Inhibition of human carbonic anhydrase 2 pre-incubated for 15 mins by stopped-flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The β-carbonic anhydrase from the malaria mosquito Anopheles gambiae is highly inhibited by sulfonamides.
Year : 2015
Volume : 23
Issue : 10
First Page : 2303
Last Page : 2309
Authors : Syrjänen L, Kuuslahti M, Tolvanen M, Vullo D, Parkkila S, Supuran CT.
Abstract : A β-carbonic anhydrase (CA, EC 4.2.1.1) was cloned, purified and characterized from Anopheles gambiae, the mosquito species mainly involved in the transmission of malaria. The new enzyme, AgaCA, showed a significant catalytic activity for the physiologic reaction, CO2 hydration to bicarbonate and protons, with a kcat of 7.2×10(5)s(-1) and kcat/Km of 5.6×10(7)M(-1)s(-1), being thus similar to parasite β-CAs which were discovered earlier as drug targets for antifungal or anti-protozoan agents. An inhibition study of AgaCA with a panel of aromatic, aliphatic and heterocyclic sulfonamides allowed us to identify several low nanomolar inhibitors of the enzyme. Benzolamide and aminobenzolamide showed inhibition constants of 6.8-9.8nM, whereas a structurally related aromatic derivative, 4-(2-hydroxymethyl-4-nitrophenyl-sulfonamidoethyl)-benzenesulfonamide was the strongest inhibitor with a KI of 6.1nM. As β-CAs are not present in mammals, including humans, finding effective and selective A. gambiae CA inhibitors may lead to alternative procedures for controlling malaria by impairing the growth of its transmission vector, the mosquito.
|
Inhibition of Anopheles gambiae carbonic anhydrase pre-incubated for 15 mins by stopped-flow CO2 hydration assay
|
Anopheles gambiae
|
164.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The β-carbonic anhydrase from the malaria mosquito Anopheles gambiae is highly inhibited by sulfonamides.
Year : 2015
Volume : 23
Issue : 10
First Page : 2303
Last Page : 2309
Authors : Syrjänen L, Kuuslahti M, Tolvanen M, Vullo D, Parkkila S, Supuran CT.
Abstract : A β-carbonic anhydrase (CA, EC 4.2.1.1) was cloned, purified and characterized from Anopheles gambiae, the mosquito species mainly involved in the transmission of malaria. The new enzyme, AgaCA, showed a significant catalytic activity for the physiologic reaction, CO2 hydration to bicarbonate and protons, with a kcat of 7.2×10(5)s(-1) and kcat/Km of 5.6×10(7)M(-1)s(-1), being thus similar to parasite β-CAs which were discovered earlier as drug targets for antifungal or anti-protozoan agents. An inhibition study of AgaCA with a panel of aromatic, aliphatic and heterocyclic sulfonamides allowed us to identify several low nanomolar inhibitors of the enzyme. Benzolamide and aminobenzolamide showed inhibition constants of 6.8-9.8nM, whereas a structurally related aromatic derivative, 4-(2-hydroxymethyl-4-nitrophenyl-sulfonamidoethyl)-benzenesulfonamide was the strongest inhibitor with a KI of 6.1nM. As β-CAs are not present in mammals, including humans, finding effective and selective A. gambiae CA inhibitors may lead to alternative procedures for controlling malaria by impairing the growth of its transmission vector, the mosquito.
|
Inhibition of recombinant Streptococcus mutans UA159 beta-carbonic anhydrase expressed in Escherichia coli Arctic cells preincubated for 15 mins by stopped flow CO2 hydrase assay
|
Streptococcus mutans UA159
|
444.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition study of the β-class carbonic anhydrase from the caries producing pathogen Streptococcus mutans.
Year : 2015
Volume : 25
Issue : 11
First Page : 2291
Last Page : 2297
Authors : Dedeoglu N, DeLuca V, Isik S, Yildirim H, Kockar F, Capasso C, Supuran CT.
Abstract : Streptococcus mutans, the oral pathogenic bacterium provoking dental caries formation, encodes for a β-class carbonic anhydrase (CA, EC 4.2.1.1), SmuCA. This enzyme was cloned, characterized and investigated for its inhibition profile with the major class of CA inhibitors, the primary sulfonamides. SmuCA has a good catalytic activity for the CO2 hydration reaction, with a kcat of 4.2×10(5) s(-1) and kcat/Km of 5.8×10(7) M(-1)×s(-1), and is efficiently inhibited by most sulfonamides (KIs of 246 nM-13.5 μM). The best SmuCA inhibitors were bromosulfanilamide, deacetylated acetazolamide, 4-hydroxymethylbenzenesulfonamide, a pyrimidine-substituted sulfanilamide derivative, aminobenzolamide and compounds structurally similar to it, as well as acetazolamide, methazolamide, indisulam and valdecoxib. These compounds showed inhibition constants ranging between 246 and 468 nM. Identification of effective inhibitors of this enzyme may lead to pharmacological tools useful for understanding the role of S. mutans CAs in dental caries formation, and eventually the development of pharmacological agents with a new mechanism of antibacterial action.
|
Inhibition of Nostoc commune gamma carbonic anhydrase by CO2 hydration assay
|
Nostoc commune
|
53.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis.
Year : 2015
Volume : 25
Issue : 17
First Page : 3550
Last Page : 3555
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Capasso C, Supuran CT.
Abstract : The Antarctic bacterium Pseudoalteromonas haloplanktis encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (PhaCAγ) has a good catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) of 1.4×10(5) s(-1) and a k(cat)/K(m) of 1.9×10(6) M(-1)×s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. Methazolamide and indisulam showed the best inhibitory properties (K(I)s of 86.7-94.7 nM). This contribution shed new light on γ-CAs inhibition profiles with a relevant class of pharmacologic agents.
|
Inhibition of Pseudoalteromonas haloplanktis gamma carbonic anhydrase by CO2 hydration assay
|
Pseudoalteromonas haloplanktis
|
735.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis.
Year : 2015
Volume : 25
Issue : 17
First Page : 3550
Last Page : 3555
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Capasso C, Supuran CT.
Abstract : The Antarctic bacterium Pseudoalteromonas haloplanktis encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (PhaCAγ) has a good catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) of 1.4×10(5) s(-1) and a k(cat)/K(m) of 1.9×10(6) M(-1)×s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. Methazolamide and indisulam showed the best inhibitory properties (K(I)s of 86.7-94.7 nM). This contribution shed new light on γ-CAs inhibition profiles with a relevant class of pharmacologic agents.
|
Inhibition of Methanosarcina thermophila recombinant gamma carbonic anhydrase by stopped flow CO2 hydrase assay method
|
Methanosarcina thermophila
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis.
Year : 2015
Volume : 25
Issue : 17
First Page : 3550
Last Page : 3555
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Capasso C, Supuran CT.
Abstract : The Antarctic bacterium Pseudoalteromonas haloplanktis encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (PhaCAγ) has a good catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) of 1.4×10(5) s(-1) and a k(cat)/K(m) of 1.9×10(6) M(-1)×s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. Methazolamide and indisulam showed the best inhibitory properties (K(I)s of 86.7-94.7 nM). This contribution shed new light on γ-CAs inhibition profiles with a relevant class of pharmacologic agents.
|
Inhibition of human recombinant carbonic anhydrase-2 by stopped flow CO2 hydrase assay method
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis.
Year : 2015
Volume : 25
Issue : 17
First Page : 3550
Last Page : 3555
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Capasso C, Supuran CT.
Abstract : The Antarctic bacterium Pseudoalteromonas haloplanktis encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (PhaCAγ) has a good catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) of 1.4×10(5) s(-1) and a k(cat)/K(m) of 1.9×10(6) M(-1)×s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. Methazolamide and indisulam showed the best inhibitory properties (K(I)s of 86.7-94.7 nM). This contribution shed new light on γ-CAs inhibition profiles with a relevant class of pharmacologic agents.
|
Inhibition of human CA2 incubated for 15 mins prior to testing by stopped flow CO2 hydrase assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anion and sulfonamide inhibition studies of an α-carbonic anhydrase from the Antarctic hemoglobinless fish Chionodraco hamatus.
Year : 2015
Volume : 25
Issue : 23
First Page : 5485
Last Page : 5489
Authors : Cincinelli A, Martellini T, Vullo D, Supuran CT.
Abstract : An α-carbonic anhydrase (CA, EC 4.2.1.1) has been purified from the Antarctic hemoglobinless fish Chionodraco hamatus (icefish). The new enzyme, denominated ChaCA, has a good catalytic activity for the physiologic CO2 hydration to bicarbonate reaction, similar to that of the low activity human isoform hCA I, with a kcat of 5.3×10(5) s(-1), and a kcat/Km of 3.7×10(7) M(-1) s(-1). The enzyme was inhibited in the submillimolar range by most inorganic anions (cyanate, thiocyanate, cyanide, bicarbonate, halides), whereas sulfamide, sulfamate, phenylboronic/phenylarsonic acids were micromolar inhibitors, with KIs in the range of 9-77 μM. Many clinically used drugs, such as acetazolamide, methazolamide, dorzolamide, brinzolamide, topiramate and benzolamide were low nanomolar inhibitors, with KIs in the range of 39.1-77.6 nM. As the physiology of CO2/bicarbonate transport or the Root effect in this Antarctic fish are poorly understood at this moment, such inhibition data may give a more detailed insight in the role that CAs play in these phenomena, by the use of inhibitors described here as physiologic tools.
|
Inhibition of Chionodraco hamatus alphaCA incubated for 15 mins prior to testing by stopped flow CO2 hydrase assay
|
Chionodraco hamatus
|
726.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anion and sulfonamide inhibition studies of an α-carbonic anhydrase from the Antarctic hemoglobinless fish Chionodraco hamatus.
Year : 2015
Volume : 25
Issue : 23
First Page : 5485
Last Page : 5489
Authors : Cincinelli A, Martellini T, Vullo D, Supuran CT.
Abstract : An α-carbonic anhydrase (CA, EC 4.2.1.1) has been purified from the Antarctic hemoglobinless fish Chionodraco hamatus (icefish). The new enzyme, denominated ChaCA, has a good catalytic activity for the physiologic CO2 hydration to bicarbonate reaction, similar to that of the low activity human isoform hCA I, with a kcat of 5.3×10(5) s(-1), and a kcat/Km of 3.7×10(7) M(-1) s(-1). The enzyme was inhibited in the submillimolar range by most inorganic anions (cyanate, thiocyanate, cyanide, bicarbonate, halides), whereas sulfamide, sulfamate, phenylboronic/phenylarsonic acids were micromolar inhibitors, with KIs in the range of 9-77 μM. Many clinically used drugs, such as acetazolamide, methazolamide, dorzolamide, brinzolamide, topiramate and benzolamide were low nanomolar inhibitors, with KIs in the range of 39.1-77.6 nM. As the physiology of CO2/bicarbonate transport or the Root effect in this Antarctic fish are poorly understood at this moment, such inhibition data may give a more detailed insight in the role that CAs play in these phenomena, by the use of inhibitors described here as physiologic tools.
|
Inhibition of recombinant human carbonic anhydrase-2 by stopped flow CO2 hydrase assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the α-carbonic anhydrase from the gammaproteobacterium Thiomicrospira crunogena XCL-2, TcruCA.
Year : 2016
Volume : 26
Issue : 2
First Page : 401
Last Page : 405
Authors : Vullo D, Bhatt A, Mahon BP, McKenna R, Supuran CT.
Abstract : We report a sulfonamide/sulfamate inhibition study of the α-carbonic anhydrase (CA, EC 4.2.1.1) present in the gammaproteobacterium Thiomicrospira crunogena XCL-2, a mesophilic hydrothermal vent-isolate organism, TcruCA. As Thiomicrospira crunogena is one of thousands of marine organisms that uses CA for metabolic regulation, the effect of sulfonamide inhibition has been considered. Sulfonamide-based drugs have been widely used in a variety of antibiotics, and bioelimination of these compounds results in exposure of these compounds to marine life. The enzyme was highly inhibited, with Ki values ranging from 2.5 to 40.7nM by a variety of sulfonamides including acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide and benzenesulfonamides incorporating 4-hydroxyalkyl moieties. Less effective inhibitors were topiramate, zonisamide, celecoxib, saccharin and hydrochlorothiazide as well as simple benzenesulfonamides incorporating amino, halogeno, alkyl, aminoalkyl and other moieties in the ortho- or para-positions of the aromatic ring (Kis of 202-933nM). The active site interactions between TcruCA and three clinically-used CA inhibitors, acetazolamide (Diamox®), dorzolamide (Trusopt®), and brinzolamide (Azopt®) are studied using molecular docking to provide insight into the reported Ki values. Comparison between various enzymes belonging to this family may also bring interesting hints in these fascinating phenomena.
|
Inhibition of recombinant Sulfurihydrogenibium yellowstonense YO3AOP1 carbonic anhydrase by stopped flow CO2 hydrase assay
|
Sulfurihydrogenibium yellowstonense
|
5.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the α-carbonic anhydrase from the gammaproteobacterium Thiomicrospira crunogena XCL-2, TcruCA.
Year : 2016
Volume : 26
Issue : 2
First Page : 401
Last Page : 405
Authors : Vullo D, Bhatt A, Mahon BP, McKenna R, Supuran CT.
Abstract : We report a sulfonamide/sulfamate inhibition study of the α-carbonic anhydrase (CA, EC 4.2.1.1) present in the gammaproteobacterium Thiomicrospira crunogena XCL-2, a mesophilic hydrothermal vent-isolate organism, TcruCA. As Thiomicrospira crunogena is one of thousands of marine organisms that uses CA for metabolic regulation, the effect of sulfonamide inhibition has been considered. Sulfonamide-based drugs have been widely used in a variety of antibiotics, and bioelimination of these compounds results in exposure of these compounds to marine life. The enzyme was highly inhibited, with Ki values ranging from 2.5 to 40.7nM by a variety of sulfonamides including acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide and benzenesulfonamides incorporating 4-hydroxyalkyl moieties. Less effective inhibitors were topiramate, zonisamide, celecoxib, saccharin and hydrochlorothiazide as well as simple benzenesulfonamides incorporating amino, halogeno, alkyl, aminoalkyl and other moieties in the ortho- or para-positions of the aromatic ring (Kis of 202-933nM). The active site interactions between TcruCA and three clinically-used CA inhibitors, acetazolamide (Diamox®), dorzolamide (Trusopt®), and brinzolamide (Azopt®) are studied using molecular docking to provide insight into the reported Ki values. Comparison between various enzymes belonging to this family may also bring interesting hints in these fascinating phenomena.
|
Inhibition of recombinant Thiomicrospira crunogena XCL-2 carbonic anhydrase by stopped flow CO2 hydrase assay
|
Thiomicrospira crunogena XCL-2
|
529.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the α-carbonic anhydrase from the gammaproteobacterium Thiomicrospira crunogena XCL-2, TcruCA.
Year : 2016
Volume : 26
Issue : 2
First Page : 401
Last Page : 405
Authors : Vullo D, Bhatt A, Mahon BP, McKenna R, Supuran CT.
Abstract : We report a sulfonamide/sulfamate inhibition study of the α-carbonic anhydrase (CA, EC 4.2.1.1) present in the gammaproteobacterium Thiomicrospira crunogena XCL-2, a mesophilic hydrothermal vent-isolate organism, TcruCA. As Thiomicrospira crunogena is one of thousands of marine organisms that uses CA for metabolic regulation, the effect of sulfonamide inhibition has been considered. Sulfonamide-based drugs have been widely used in a variety of antibiotics, and bioelimination of these compounds results in exposure of these compounds to marine life. The enzyme was highly inhibited, with Ki values ranging from 2.5 to 40.7nM by a variety of sulfonamides including acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide and benzenesulfonamides incorporating 4-hydroxyalkyl moieties. Less effective inhibitors were topiramate, zonisamide, celecoxib, saccharin and hydrochlorothiazide as well as simple benzenesulfonamides incorporating amino, halogeno, alkyl, aminoalkyl and other moieties in the ortho- or para-positions of the aromatic ring (Kis of 202-933nM). The active site interactions between TcruCA and three clinically-used CA inhibitors, acetazolamide (Diamox®), dorzolamide (Trusopt®), and brinzolamide (Azopt®) are studied using molecular docking to provide insight into the reported Ki values. Comparison between various enzymes belonging to this family may also bring interesting hints in these fascinating phenomena.
|
Inhibition of Vibrio cholerae alpha-carbonic anhydrase using CO2 as substrate preincubated for 15 mins by stopped-flow CO2 hydration assay
|
Vibrio cholerae
|
89.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of the β-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae.
Year : 2016
Volume : 24
Issue : 5
First Page : 1115
Last Page : 1120
Authors : Del Prete S, Vullo D, De Luca V, Carginale V, Ferraroni M, Osman SM, AlOthman Z, Supuran CT, Capasso C.
Abstract : The genome of the pathogenic bacterium Vibrio cholerae encodes for three carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the α-, β- and γ-classes. VchCA, the α-CA from this species was investigated earlier, whereas the β-class enzyme, VchCAβ was recently cloned, characterized kinetically and its X-ray crystal structure reported by this group. Here we report an inhibition study with sulfonamides and one sulfamate of this enzyme. The best VchCAβ inhibitors were deacetylated acetazolamide and methazolamide and hydrochlorothiazide, which showed inhibition constants of 68.2-87.0nM. Other compounds, with medium potency against VchCAβ, (KIs in the range of 275-463nM), were sulfanilamide, metanilamide, sulthiame and saccharin whereas the clinically used agents such as acetazolamide, methazolamide, ethoxzolamide, dorzolamide, zonisamide and celecoxib were micromolar inhibitors (KIs in the range of 4.51-8.57μM). Identification of potent and possibly selective inhibitors of VchCA and VchCAβ over the human CA isoforms, may lead to pharmacological tools useful for understanding the physiological role(s) of this under-investigated enzymes.
|
Inhibition of human Carbonic anhydrase2 using CO2 as substrate preincubated for 15 mins by stopped-flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Sulfonamide inhibition studies of the β-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae.
Year : 2016
Volume : 24
Issue : 5
First Page : 1115
Last Page : 1120
Authors : Del Prete S, Vullo D, De Luca V, Carginale V, Ferraroni M, Osman SM, AlOthman Z, Supuran CT, Capasso C.
Abstract : The genome of the pathogenic bacterium Vibrio cholerae encodes for three carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the α-, β- and γ-classes. VchCA, the α-CA from this species was investigated earlier, whereas the β-class enzyme, VchCAβ was recently cloned, characterized kinetically and its X-ray crystal structure reported by this group. Here we report an inhibition study with sulfonamides and one sulfamate of this enzyme. The best VchCAβ inhibitors were deacetylated acetazolamide and methazolamide and hydrochlorothiazide, which showed inhibition constants of 68.2-87.0nM. Other compounds, with medium potency against VchCAβ, (KIs in the range of 275-463nM), were sulfanilamide, metanilamide, sulthiame and saccharin whereas the clinically used agents such as acetazolamide, methazolamide, ethoxzolamide, dorzolamide, zonisamide and celecoxib were micromolar inhibitors (KIs in the range of 4.51-8.57μM). Identification of potent and possibly selective inhibitors of VchCA and VchCAβ over the human CA isoforms, may lead to pharmacological tools useful for understanding the physiological role(s) of this under-investigated enzymes.
|
Inhibition of human carbonic anhydrase 2 preincubated for 15 mins by CO2 hydrase stopped flow assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Colwellia psychrerythraea.
Year : 2016
Volume : 26
Issue : 4
First Page : 1253
Last Page : 1259
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Osman SM, AlOthman Z, Capasso C, Supuran CT.
Abstract : The Antarctic bacterium Colwellia psychrerythraea encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (CpsCAγ) has a moderate catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) 6.0×10(5) s(-1) and a k(cat)/K(m) of 4.7×10(6) M(-1) s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. The best inhibitor was metanilamide (K(I) of 83.5 nM) followed by indisulam, valdecoxib, celecoxib, sulthiame and hydrochlorothiazide (K(I)s ranging between 343 and 491 nM). Acetazolamide, methazolamide as well as other aromatic/heterocyclic derivatives showed inhibition constants between 502 and 7660 nM. The present study may shed some more light regarding the role that γ-CAs play in the life cycle of psychrophilic bacteria as the Antarctic one investigated here, by allowing the identification of inhibitors which may be useful as pharmacologic tools.
|
Inhibition of Porphyromonas gingivalis gamma carbonic anhydrase preincubated for 15 mins by stopped flow CO2 hydration assay
|
Porphyromonas gingivalis
|
755.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Colwellia psychrerythraea.
Year : 2016
Volume : 26
Issue : 4
First Page : 1253
Last Page : 1259
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Osman SM, AlOthman Z, Capasso C, Supuran CT.
Abstract : The Antarctic bacterium Colwellia psychrerythraea encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (CpsCAγ) has a moderate catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) 6.0×10(5) s(-1) and a k(cat)/K(m) of 4.7×10(6) M(-1) s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. The best inhibitor was metanilamide (K(I) of 83.5 nM) followed by indisulam, valdecoxib, celecoxib, sulthiame and hydrochlorothiazide (K(I)s ranging between 343 and 491 nM). Acetazolamide, methazolamide as well as other aromatic/heterocyclic derivatives showed inhibition constants between 502 and 7660 nM. The present study may shed some more light regarding the role that γ-CAs play in the life cycle of psychrophilic bacteria as the Antarctic one investigated here, by allowing the identification of inhibitors which may be useful as pharmacologic tools.
|
Inhibition of Nostoc commune gamma carbonic anhydrase preincubated for 15 mins by stopped flow CO2 hydration assay
|
Nostoc commune
|
53.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Colwellia psychrerythraea.
Year : 2016
Volume : 26
Issue : 4
First Page : 1253
Last Page : 1259
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Osman SM, AlOthman Z, Capasso C, Supuran CT.
Abstract : The Antarctic bacterium Colwellia psychrerythraea encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (CpsCAγ) has a moderate catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) 6.0×10(5) s(-1) and a k(cat)/K(m) of 4.7×10(6) M(-1) s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. The best inhibitor was metanilamide (K(I) of 83.5 nM) followed by indisulam, valdecoxib, celecoxib, sulthiame and hydrochlorothiazide (K(I)s ranging between 343 and 491 nM). Acetazolamide, methazolamide as well as other aromatic/heterocyclic derivatives showed inhibition constants between 502 and 7660 nM. The present study may shed some more light regarding the role that γ-CAs play in the life cycle of psychrophilic bacteria as the Antarctic one investigated here, by allowing the identification of inhibitors which may be useful as pharmacologic tools.
|
Inhibition of Pseudoalteromonas haloplanktis gamma carbonic anhydrase preincubated for 15 mins by stopped flow CO2 hydration assay
|
Pseudoalteromonas haloplanktis
|
735.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Colwellia psychrerythraea.
Year : 2016
Volume : 26
Issue : 4
First Page : 1253
Last Page : 1259
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Osman SM, AlOthman Z, Capasso C, Supuran CT.
Abstract : The Antarctic bacterium Colwellia psychrerythraea encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (CpsCAγ) has a moderate catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) 6.0×10(5) s(-1) and a k(cat)/K(m) of 4.7×10(6) M(-1) s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. The best inhibitor was metanilamide (K(I) of 83.5 nM) followed by indisulam, valdecoxib, celecoxib, sulthiame and hydrochlorothiazide (K(I)s ranging between 343 and 491 nM). Acetazolamide, methazolamide as well as other aromatic/heterocyclic derivatives showed inhibition constants between 502 and 7660 nM. The present study may shed some more light regarding the role that γ-CAs play in the life cycle of psychrophilic bacteria as the Antarctic one investigated here, by allowing the identification of inhibitors which may be useful as pharmacologic tools.
|
Inhibition of recombinant Colwellia psychrerythraea gamma carbonic anhydrase preincubated for 15 mins by stopped flow CO2 hydration assay
|
Colwellia psychrerythraea
|
343.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Colwellia psychrerythraea.
Year : 2016
Volume : 26
Issue : 4
First Page : 1253
Last Page : 1259
Authors : Vullo D, De Luca V, Del Prete S, Carginale V, Scozzafava A, Osman SM, AlOthman Z, Capasso C, Supuran CT.
Abstract : The Antarctic bacterium Colwellia psychrerythraea encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (CpsCAγ) has a moderate catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k(cat) 6.0×10(5) s(-1) and a k(cat)/K(m) of 4.7×10(6) M(-1) s(-1). A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. The best inhibitor was metanilamide (K(I) of 83.5 nM) followed by indisulam, valdecoxib, celecoxib, sulthiame and hydrochlorothiazide (K(I)s ranging between 343 and 491 nM). Acetazolamide, methazolamide as well as other aromatic/heterocyclic derivatives showed inhibition constants between 502 and 7660 nM. The present study may shed some more light regarding the role that γ-CAs play in the life cycle of psychrophilic bacteria as the Antarctic one investigated here, by allowing the identification of inhibitors which may be useful as pharmacologic tools.
|
Inhibition of human carbonic anhydrase 2 incubated for 15 mins by stopped-flow CO2 hydration assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the β-carbonic anhydrase from the newly discovered bacterium Enterobacter sp. B13.
Year : 2016
Volume : 26
Issue : 7
First Page : 1821
Last Page : 1826
Authors : Eminoğlu A, Vullo D, Aşık A, Çolak DN, Çanakçı S, Beldüz AO, Supuran CT.
Abstract : The genome of the newly identified bacterium Enterobacter sp. B13 encodes for a β-class carbonic anhydrases (CAs, EC 4.2.1.1), EspCA. This enzyme was recently cloned, and characterized kinetically by this group (J. Enzyme Inhib. Med. Chem. 2016, 31). Here we report an inhibition study with sulfonamides and sulfamates of this enzyme. The best EspCA inhibitors were some sulfanylated sulfonamides with elongated molecules, metanilamide, 4-aminoalkyl-benzenesulfonamides, acetazolamide, and deacetylated methazolamide (KIs in the range of 58.7-96.5nM). Clinically used agents such as methazolamide, ethoxzolamide, dorzolamide, brinzolamide, benzolamide, zonisamide, sulthiame, sulpiride, topiramate and valdecoxib were slightly less effective inhibitors (KIs in the range of 103-138nM). Saccharin, celecoxib, dichlorophenamide and many simple benzenesulfonamides were even less effective as EspCA inhibitors, with KIs in the range of 384-938nM. Identification of effective inhibitors of this bacterial enzyme may lead to pharmacological tools useful for understanding the physiological role(s) of the β-class CAs in bacterial pathogenicity/virulence.
|
Inhibition of recombinant Enterobacter sp. B13 beta carbonic anhydrase incubated for 15 mins by stopped-flow CO2 hydration assay
|
Enterobacter sp.
|
133.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamide inhibition studies of the β-carbonic anhydrase from the newly discovered bacterium Enterobacter sp. B13.
Year : 2016
Volume : 26
Issue : 7
First Page : 1821
Last Page : 1826
Authors : Eminoğlu A, Vullo D, Aşık A, Çolak DN, Çanakçı S, Beldüz AO, Supuran CT.
Abstract : The genome of the newly identified bacterium Enterobacter sp. B13 encodes for a β-class carbonic anhydrases (CAs, EC 4.2.1.1), EspCA. This enzyme was recently cloned, and characterized kinetically by this group (J. Enzyme Inhib. Med. Chem. 2016, 31). Here we report an inhibition study with sulfonamides and sulfamates of this enzyme. The best EspCA inhibitors were some sulfanylated sulfonamides with elongated molecules, metanilamide, 4-aminoalkyl-benzenesulfonamides, acetazolamide, and deacetylated methazolamide (KIs in the range of 58.7-96.5nM). Clinically used agents such as methazolamide, ethoxzolamide, dorzolamide, brinzolamide, benzolamide, zonisamide, sulthiame, sulpiride, topiramate and valdecoxib were slightly less effective inhibitors (KIs in the range of 103-138nM). Saccharin, celecoxib, dichlorophenamide and many simple benzenesulfonamides were even less effective as EspCA inhibitors, with KIs in the range of 384-938nM. Identification of effective inhibitors of this bacterial enzyme may lead to pharmacological tools useful for understanding the physiological role(s) of the β-class CAs in bacterial pathogenicity/virulence.
|
Inhibition of recombinant Vibrio cholerae gamma-carbonic anhydrase preincubated for 15 mins by stopped-flow CO2 hydration assay
|
Vibrio cholerae
|
817.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Comparison of the sulfonamide inhibition profiles of the α-, β- and γ-carbonic anhydrases from the pathogenic bacterium Vibrio cholerae.
Year : 2016
Volume : 26
Issue : 8
First Page : 1941
Last Page : 1946
Authors : Del Prete S, Vullo D, De Luca V, Carginale V, Osman SM, AlOthman Z, Supuran CT, Capasso C.
Abstract : Carbonic anhydrases (CA, EC 4.2.1.1) are ubiquitous metalloenzymes, which catalyze the conversion of carbon dioxide (CO2) to bicarbonate (HCO3(-)) and protons (H(+)). In prokaryotes, the existence of genes encoding for α-, β- and γ-classes suggests that these enzymes play an important role in the prokaryotic physiology. It has been demonstrated, in fact, that their inhibition in vivo leads to growth impairment or growth defects of the microorganism. Ultimately, we started to investigate the biochemical properties and the inhibitory profiles of the α- and β-CAs identified in the genome of Vibrio cholerae, which is the causative agent of cholera. The genome of this pathogen encodes for CAs belonging to α, β and γ classes. Here, we report a sulfonamide inhibition study of the γ-CA (named VchCAγ) comparing it with data obtained for the α- and β-CA enzymes. VchCAγ activity (kcat=7.39 × 10(5)s(-1)) was significantly higher than the other γ-CAs. The inhibition study with a panel of sulfonamides and one sulfamate led to the detection of a large number of nanomolar VchCAγ inhibitors, including simple aromatic/heterocyclic sulfonamides (compounds 2-9, 11, 13-15, 24) as well as EZA, DZA, BRZ, BZA, TPM, ZNS, SLP, IND (KIs in the range of 66.2-95.3 nM). As it was proven that bicarbonate is a virulence factor of this bacterium and since ethoxzolamide was shown to inhibit this virulence in vivo, we propose that VchCA, VchCAβ and VchCAγ may be a target for antibiotic development, exploiting a mechanism of action rarely considered up until now, i.e., interference with bicarbonate supply as a virulence factor.
|
Inhibition of human carbonic anhydrase 2 assessed as reduction in CO2 hydration preincubated for 15 mins followed by CO2 addition measured for 10 to 100 sec by Line-Weaver Burk plot analysis
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Sulfonamide inhibition profile of the γ-carbonic anhydrase identified in the genome of the pathogenic bacterium Burkholderia pseudomallei the etiological agent responsible of melioidosis.
Year : 2017
Volume : 27
Issue : 3
First Page : 490
Last Page : 495
Authors : Del Prete S, Vullo D, Di Fonzo P, Osman SM, AlOthman Z, Donald WA, Supuran CT, Capasso C.
Abstract : A new γ-carbonic anhydrase (CA, EC 4.1.1.1) was cloned and characterized kinetically in the genome of the bacterial pathogen Burkholderia pseudomallei, the etiological agent of melioidosis, an endemic disease of tropical and sub-tropical regions of the world. The catalytic activity of this new enzyme, BpsCAγ, is significant with a kcat of 5.3×105s-1 and kcat/Km of 2.5×107M-1×s-1 for the physiologic CO2 hydration reaction. The inhibition constant value for this enzyme for 39 sulfonamide inhibitors was obtained. Acetazolamide, benzolamide and metanilamide were the most effective (KIs of 149-653nM) inhibitors of BpsCAγ activity, whereas other sulfonamides/sulfamates such as ethoxzolamide, topiramate, sulpiride, indisulam, sulthiame and saccharin were active in the micromolar range (KIs of 1.27-9.56μM). As Burkholderia pseudomallei is resistant to many classical antibiotics, identifying compounds that interfere with crucial enzymes in the B. pseudomallei life cycle may lead to antibiotics with novel mechanisms of action.
|
Inhibition of Vibrio cholerae Gamma-carbonic anhydrase assessed as reduction in CO2 hydration preincubated for 15 mins followed by CO2 addition measured for 10 to 100 sec by Line-Weaver Burk plot analysis
|
Vibrio cholerae
|
817.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Sulfonamide inhibition profile of the γ-carbonic anhydrase identified in the genome of the pathogenic bacterium Burkholderia pseudomallei the etiological agent responsible of melioidosis.
Year : 2017
Volume : 27
Issue : 3
First Page : 490
Last Page : 495
Authors : Del Prete S, Vullo D, Di Fonzo P, Osman SM, AlOthman Z, Donald WA, Supuran CT, Capasso C.
Abstract : A new γ-carbonic anhydrase (CA, EC 4.1.1.1) was cloned and characterized kinetically in the genome of the bacterial pathogen Burkholderia pseudomallei, the etiological agent of melioidosis, an endemic disease of tropical and sub-tropical regions of the world. The catalytic activity of this new enzyme, BpsCAγ, is significant with a kcat of 5.3×105s-1 and kcat/Km of 2.5×107M-1×s-1 for the physiologic CO2 hydration reaction. The inhibition constant value for this enzyme for 39 sulfonamide inhibitors was obtained. Acetazolamide, benzolamide and metanilamide were the most effective (KIs of 149-653nM) inhibitors of BpsCAγ activity, whereas other sulfonamides/sulfamates such as ethoxzolamide, topiramate, sulpiride, indisulam, sulthiame and saccharin were active in the micromolar range (KIs of 1.27-9.56μM). As Burkholderia pseudomallei is resistant to many classical antibiotics, identifying compounds that interfere with crucial enzymes in the B. pseudomallei life cycle may lead to antibiotics with novel mechanisms of action.
|
Inhibition of human carbonic anhydrase-2 assessed as reduction in CO2 hydration preincubated for 15 mins followed by CO2 addition measured for 10 to 100 secs by stopped-flow assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg Med Chem
Title : Sulfonamide inhibition profiles of the β-carbonic anhydrase from the pathogenic bacterium Francisella tularensis responsible of the febrile illness tularemia.
Year : 2017
Volume : 25
Issue : 13
First Page : 3555
Last Page : 3561
Authors : Del Prete S, Vullo D, Osman SM, AlOthman Z, Supuran CT, Capasso C.
Abstract : A new β-class carbonic anhydrase (CA, EC 4.2.1.1) has been cloned, purified and characterized in the genome of the pathogenic bacterium Francisella tularensis responsible of the febrile illness tularemia. This enzyme, FtuβCA, showed a kcat of 9.8 ×105s-1 and a kcat/KM of 8.9 ×107M-1s-1 for the CO2 hydration, physiological reaction, being one of the most effective β-CAs known to date, with a catalytic activity only 1.68-times lower than that of the human(h) isoform hCA II. A panel of 39 simple aromatic and heterocyclic sulfonamides, as well as clinically used drugs incorporating sulfonamide/sulfamate zinc-binding groups, was used to investigate the inhibition profile of FtuβCA with these classes of derivatives. The enzyme generally showed a weaker affinity for these inhibitors compared to other α- and β-CAs investigated earlier, with only acetazolamide and its deacetylated precursor having inhibition constant <1µM. Indeed, the two compounds acetazolamide AAZ and its deacetylated precursor 13 (KIs of 655-770nM), as well as metanilamide and methazolamide (KIs of 2.53-2.92µM), were the best FtuβCA inhibitors detected so far. As the physiological role of bacterial β-CAs is poorly understood for the virulence/life cycle of these pathogens, the present study may constitute a starting point for the design of effective pathogenic bacteria CA inhibitors with potential use as antiinfectives.
|
Inhibition of recombinant human COX-2 assessed as reduction of prostaglandin-G2 to prostaglandin-H2 by measuring oxidation of 10-acetyl-3,7-dihydroxyphenoxazine to resorufin after 5 mins by fluorescence based assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : MedChemComm
Title : Novel valdecoxib derivatives by ruthenium(ii)-promoted 1,3-dipolar cycloaddition of nitrile oxides with alkynes - synthesis and COX-2 inhibition activity.
Year : 2018
Volume : 9
Issue : 3
First Page : 534
Last Page : 544
Authors : Roscales S, Bechmann N, Weiss DH, Köckerling M, Pietzsch J, Kniess T.
Abstract : Novel valdecoxib-based cyclooxygenase-2 inhibitors were synthesized in one step <i>via</i> 1,3-dipolar cycloaddition of nitrile oxides with a series of eleven aryl alkynes, six of them described for the first time. Application of Ru(ii)-catalysis leads preferably to the formation of the 3,4-diaryl-substituted isoxazoles, while under thermal heating with base the 3,5-diaryl substitution pattern is favoured. The new the 3,4-diaryl-substituted isoxazoles possessing a small substituent (H and Me) displayed high COX-2 inhibition affinity (IC<sub>50</sub> = 0.042-0.073 μM) and excellent selectivity (COX-2 SI > 2000). In contrast, the 3,5-diaryl substituted compounds displayed almost no COX activity. The introduction of a 4-fluorophenyl substituent resulted in retained high COX-2 affinity, making these compounds together with the feasible one step reaction promising candidates for the development of fluorine-18 labelled radiotracers.
|
Inhibition of recombinant human COX-2 by radioligand displacement assay
|
Homo sapiens
|
5.0
nM
|
|
Journal : MedChemComm
Title : Novel valdecoxib derivatives by ruthenium(ii)-promoted 1,3-dipolar cycloaddition of nitrile oxides with alkynes - synthesis and COX-2 inhibition activity.
Year : 2018
Volume : 9
Issue : 3
First Page : 534
Last Page : 544
Authors : Roscales S, Bechmann N, Weiss DH, Köckerling M, Pietzsch J, Kniess T.
Abstract : Novel valdecoxib-based cyclooxygenase-2 inhibitors were synthesized in one step <i>via</i> 1,3-dipolar cycloaddition of nitrile oxides with a series of eleven aryl alkynes, six of them described for the first time. Application of Ru(ii)-catalysis leads preferably to the formation of the 3,4-diaryl-substituted isoxazoles, while under thermal heating with base the 3,5-diaryl substitution pattern is favoured. The new the 3,4-diaryl-substituted isoxazoles possessing a small substituent (H and Me) displayed high COX-2 inhibition affinity (IC<sub>50</sub> = 0.042-0.073 μM) and excellent selectivity (COX-2 SI > 2000). In contrast, the 3,5-diaryl substituted compounds displayed almost no COX activity. The introduction of a 4-fluorophenyl substituent resulted in retained high COX-2 affinity, making these compounds together with the feasible one step reaction promising candidates for the development of fluorine-18 labelled radiotracers.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
10.74
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
4.49
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
13.38
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
8.96
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
22.84
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
1.13
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
0.76
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
38.66
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of recombinant human COX-2 expressed in Baculovirus infected sf9 cells using arachidonic acid as substrate preincubated for 10 mins followed by substrate addition measured after 10 mins by ELISA
|
Homo sapiens
|
5.0
nM
|
|
Journal : Eur J Med Chem
Title : Medicinal chemistry of vicinal diaryl scaffold: A mini review.
Year : 2019
Volume : 162
First Page : 1
Last Page : 17
Authors : Ramajayam R.
Abstract : The privileged structures have been widely used as a valuable template in new drug discovery. 1,2-Diaryl or vicinal diaryl is a simple scaffold found in many drugs and naturally occurring compounds. From synthetic point of view, the vicinal diaryl derivatives are easily accessible due to their facile and expedient syntheses. These scaffolds have shown numerous interesting pharmacological activities against various diseases with lot of clinical potentials. This review aims to highlight the evidence of vicinal diaryl motif as a privileged scaffold in COX-2 inhibitors and CA-4 analogs.
|
Inhibition of human cytosolic carbonic anhydrase 2 preincubated for 15 mins by stop flow CO2 hydrase assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Cloning, expression, purification and sulfonamide inhibition profile of the complete domain of the η-carbonic anhydrase from Plasmodium falciparum.
Year : 2016
Volume : 26
Issue : 17
First Page : 4184
Last Page : 4190
Authors : Del Prete S, Vullo D, De Luca V, Carginale V, Osman SM, AlOthman Z, Supuran CT, Capasso C.
Abstract : We report the cloning, purification and characterization of the full domain of carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, which incorporates 358 amino acid residues (from 181 to 538, in the sequence of this 600 amino acid long protein), called PfCAdom. The enzyme, which belongs to the η-CA class showed the following kinetic parameters: kcat of 3.8×10(5)s(-1) and kcat/Km of 7.2×10(7)M(-1)×s(-1), being 13.3 times more effective as a catalyst compared to the truncated form PfCA. PfCAdom is more effective than the human (h) isoform hCA I, being around 50% less effective compared to hCA II, one of the most catalytically efficient enzymes known so far. Intriguingly, the sulfonamides CA inhibitors generally showed much weaker inhibitory activity against PfCAdom compared to PfCA, prompting us to hypothesize that the 69 amino acid residues insertion present in the active site of this η-CA is crucial for the active site architecture. The best sulfonamide inhibitors for PfCAdom were acetazolamide, methazolamide, metanilamide and sulfanilamide, with KIs in the range of 366-808nM.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
26.26
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
6.971
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.07
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.07
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
