|
Inhibition of human recombinant carbonic anhydrase 1 by stopped flow CO2 hydration assay
|
Homo sapiens
|
374.0
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 carbonic anhydrase 2 by stopped flow CO2 hydration assay
|
Homo sapiens
|
9.0
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 CA1 by stopped-flow CO2 hydrase assay
|
Homo sapiens
|
374.0
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 CA2 by stopped-flow CO2 hydrase assay
|
Homo sapiens
|
9.0
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 1 by stopped flow CO2 hydrase assay
|
Homo sapiens
|
374.0
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 hydrase assay
|
Homo sapiens
|
9.0
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
|
134.0
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
|
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 mouse recombinant carbonic anhydrase 15 by stopped flow CO2 hydrase assay
|
Mus musculus
|
65.0
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 1 by stopped flow CO2 hydration method
|
Homo sapiens
|
374.0
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 human recombinant carbonic anhydrase 2 by stopped flow CO2 hydration method
|
Homo sapiens
|
9.0
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 Cryptococcus neoformans recombinant Can2 by stopped-flow CO2 hydration assay
|
Cryptococcus neoformans
|
890.0
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
|
9.0
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 recombinant carbonic anhydrase 1 by stopped-flow CO2 hydrase method
|
Homo sapiens
|
374.0
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 recombinant CA1 by stopped-flow CO2 assay
|
Homo sapiens
|
374.0
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 human recombinant CA2 by stopped-flow CO2 assay
|
Homo sapiens
|
9.0
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
|
45.2
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
|
9.0
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
|
664.0
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 CA1 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
374.0
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 human recombinant CA2 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
9.0
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
|
45.2
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 2 by stopped-flow CO2 hydration assay
|
Stylophora pistillata
|
123.0
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 human recombinant carbonic anhydrase 1 at pH 7.5 by stopped flow CO2 hydration assay
|
Homo sapiens
|
374.0
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 recombinant carbonic anhydrase 2 at pH 7.5 by stopped flow CO2 hydration assay
|
Homo sapiens
|
9.0
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 GST-tagged astrosclera willeyana Astrosclerin-3 expressed in Escherichia coli after 15 mins preincubation by stopped flow CO2 hydration assay
|
Astrosclera willeyana
|
276.0
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 1 after 15 mins by stopped flow CO2 hydration assay
|
Homo sapiens
|
374.0
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
|
9.0
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 recombinant Vibrio cholerae carbonic anhydrase expressed in Escherichia coli (DE3) preincubated for 15 mins by stopped-flow CO2 hydrase assay
|
Vibrio cholerae
|
88.4
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
|
9.0
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 1 preincubated for 15 mins by stopped-flow CO2 hydrase assay
|
Homo sapiens
|
374.0
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 1 by stopped flow CO2 hydration assay
|
Homo sapiens
|
374.0
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 human recombinant carbonic anhydrase 2 by stopped flow CO2 hydration assay
|
Homo sapiens
|
9.0
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
|
71.9
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 Sulfurihydrogenibium yellowstonense YO3AOP1 recombinant carbonic anhydrase preincubated for 15 mins by CO2 hydration stopped-flow assay
|
Sulfurihydrogenibium yellowstonense
|
7.8
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
|
9.0
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 recombinant carbonic anhydrase 1 preincubated for 15 mins by CO2 hydration stopped-flow assay
|
Homo sapiens
|
374.0
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 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
|
834.0
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 Thalassiosira weissflogii delta carbonic anhydrase preincubated for 15 mins by stopped flow CO2 hydration assay
|
Thalassiosira weissflogii
|
169.0
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
|
424.0
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
|
834.0
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
|
9.0
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 gamma-carbonic anhydrase expressed in Escherichia coli preincubated for 15 mins by stopped flow CO2 hydration assay
|
Porphyromonas gingivalis
|
424.0
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 carbonic anhydrase-1 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
374.0
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 carbonic anhydrase-2 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
9.0
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
|
485.0
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
|
463.0
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 1 compound preincubated for 15 mins by stopped flow CO2 hydrase assay method
|
Homo sapiens
|
374.0
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 compound preincubated for 15 mins by stopped flow CO2 hydrase assay method
|
Homo sapiens
|
9.0
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
|
424.0
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 1 by stopped-flow CO2 hydration assay
|
Homo sapiens
|
374.0
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 hydration assay
|
Homo sapiens
|
9.0
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
|
132.0
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 1 by stopped flow CO2 hydrase assay
|
Homo sapiens
|
374.0
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 human recombinant carbonic anhydrase 2 by stopped flow CO2 hydrase assay
|
Homo sapiens
|
9.0
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
|
424.0
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
|
82.4
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 1 pre-incubated for 15 mins by stopped-flow CO2 hydration assay
|
Homo sapiens
|
374.0
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 human carbonic anhydrase 2 pre-incubated for 15 mins by stopped-flow CO2 hydration assay
|
Homo sapiens
|
9.0
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
|
265.0
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 Nostoc commune gamma carbonic anhydrase by CO2 hydration assay
|
Nostoc commune
|
82.4
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
|
898.0
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
|
9.0
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 CA1 incubated for 15 mins prior to testing by stopped flow CO2 hydrase assay
|
Homo sapiens
|
374.0
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 human CA2 incubated for 15 mins prior to testing by stopped flow CO2 hydrase assay
|
Homo sapiens
|
9.0
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
|
49.5
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-1 by stopped flow CO2 hydrase assay
|
Homo sapiens
|
374.0
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 human carbonic anhydrase-2 by stopped flow CO2 hydrase assay
|
Homo sapiens
|
9.0
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
|
7.8
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
|
432.0
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 beta-carbonic anhydrase using CO2 as substrate preincubated for 15 mins by stopped-flow CO2 hydration assay
|
Vibrio cholerae
|
455.0
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 Vibrio cholerae alpha-carbonic anhydrase using CO2 as substrate preincubated for 15 mins by stopped-flow CO2 hydration assay
|
Vibrio cholerae
|
88.4
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
|
9.0
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 anhydrase1 using CO2 as substrate preincubated for 15 mins by stopped-flow CO2 hydration assay
|
Homo sapiens
|
374.0
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
|
9.0
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
|
424.0
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
|
82.4
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
|
898.0
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
|
380.0
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 1 incubated for 15 mins by stopped-flow CO2 hydration assay
|
Homo sapiens
|
374.0
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 human carbonic anhydrase 2 incubated for 15 mins by stopped-flow CO2 hydration assay
|
Homo sapiens
|
9.0
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 Vibrio cholerae beta carbonic anhydrase incubated for 15 mins by stopped-flow CO2 hydration assay
|
Vibrio cholerae
|
455.0
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.
|
138.0
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
|
464.0
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 recombinant human carbonic anhydrase 1 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
|
374.0
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 sec by Line-Weaver Burk plot analysis
|
Homo sapiens
|
9.0
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
|
464.0
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-1 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
|
374.0
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 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
|
9.0
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 full length human cytosolic carbonic anhydrase 1 preincubated for 15 mins by stop flow CO2 hydrase assay
|
Homo sapiens
|
374.0
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.
|
Inhibition of human cytosolic carbonic anhydrase 2 preincubated for 15 mins by stop flow CO2 hydrase assay
|
Homo sapiens
|
9.0
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
|
21.61
%
|
|
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
|
-0.31
%
|
|
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
|
-0.31
%
|
|
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.
|
Inhibition of Vibrio cholerae beta carbonic anhydrase pre-incubated for 15 mins prior to testing by phenol red-based stopped-flow CO2 hydration assay
|
Vibrio cholerae
|
68.0
nM
|
|
Journal : ACS Med Chem Lett
Title : In Silico-Guided Identification of New Potent Inhibitors of Carbonic Anhydrases Expressed in Vibrio cholerae.
Year : 2020
Volume : 11
Issue : 11
First Page : 2294
Last Page : 2299
Authors : Mancuso F,De Luca L,Angeli A,Berrino E,Del Prete S,Capasso C,Supuran CT,Gitto R
Abstract : Carbonic anhydrases from Vibrio cholerae (VchCAs) play a significant role in bacterial pathophysiological processes. Therefore, their inhibition leads to a reduction of gene expression virulence and bacterial growth impairment. Herein, we report the first ligand-based pharmacophore model as a computational tool to study selective inhibitors of the β-class of VchCA. By a virtual screening on a collection of sulfonamides, we retrieved 9 compounds that were synthesized and evaluated for their inhibitory effects against VchCAβ as well as α- and γ-classes of VchCAs and selectivity over human ubiquitous isoforms hCA I and II. Notably, all tested compounds were active inhibitors of VchCAs. The N-(4-sulfamoylbenzyl)-[1,1'-biphenyl]-4-carboxamide (20e) stood out as the most exciting inhibitor toward the β-class (K = 95.6 nM), also showing a low affinity against the tested human isoforms. By applying docking procedures, we described the binding mode of the inhibitor 20e within the catalytic cavity of the modeled open conformation of VchCAβ.
|
Inhibition of recombinant human carbonic anhydrase 2 preincubated with enzyme for 15 mins by phenol red dye based stopped flow CO2 hydration assay
|
Homo sapiens
|
7.0
nM
|
|
|
Inhibition of Vibrio cholerae alpha carbonic anhydrase preincubated with enzyme for 15 mins by phenol red-based stopped-flow CO2 hydration assay
|
Vibrio cholerae
|
88.4
nM
|
|
|
Inhibition of Vibrio cholerae beta carbonic anhydrase preincubated with enzyme for 15 mins by phenol red-based stopped-flow CO2 hydration assay
|
Vibrio cholerae
|
455.0
nM
|
|
|
Inhibition of recombinant human carbonic anhydrase 1 preincubated with enzyme for 15 mins by phenol red dye based stopped flow CO2 hydration assay
|
Homo sapiens
|
374.0
nM
|
|
