|
In vitro inhibition of rabbit lens aldose reductase at 10e-4 M.
|
Oryctolagus cuniculus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids.
Year : 1986
Volume : 29
Issue : 11
First Page : 2347
Last Page : 2351
Authors : Cerelli MJ, Curtis DL, Dunn JP, Nelson PH, Peak TM, Waterbury LD.
Abstract : A number of dibenztropone, dibenzsuberone, dibenzoxepin, and dibenzthiepin acetic acids were synthesized and tested for antiinflammatory/analgesic activity and also for their ability to inhibit rabbit lens aldose reductase (AR). It was found that the structural requirements for antiinflammatory/analgesic activity, believed to be mediated by inhibition of cyclooxygenase, were much more stringent than were those for AR inhibition. For example, the introduction of a hydroxyl group into positions 1, 4, 6, 7, or 8 on dibenzsuberone-2-acetic acid (1a) had relatively little effect on AR inhibition, but caused wide variations in antiinflammatory/analgesic activity.
|
In vitro inhibition of rabbit lens aldose reductase at 10e-5 M.
|
Oryctolagus cuniculus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids.
Year : 1986
Volume : 29
Issue : 11
First Page : 2347
Last Page : 2351
Authors : Cerelli MJ, Curtis DL, Dunn JP, Nelson PH, Peak TM, Waterbury LD.
Abstract : A number of dibenztropone, dibenzsuberone, dibenzoxepin, and dibenzthiepin acetic acids were synthesized and tested for antiinflammatory/analgesic activity and also for their ability to inhibit rabbit lens aldose reductase (AR). It was found that the structural requirements for antiinflammatory/analgesic activity, believed to be mediated by inhibition of cyclooxygenase, were much more stringent than were those for AR inhibition. For example, the introduction of a hydroxyl group into positions 1, 4, 6, 7, or 8 on dibenzsuberone-2-acetic acid (1a) had relatively little effect on AR inhibition, but caused wide variations in antiinflammatory/analgesic activity.
|
In vitro inhibition of rabbit lens aldose reductase at 10e-6 M.
|
Oryctolagus cuniculus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids.
Year : 1986
Volume : 29
Issue : 11
First Page : 2347
Last Page : 2351
Authors : Cerelli MJ, Curtis DL, Dunn JP, Nelson PH, Peak TM, Waterbury LD.
Abstract : A number of dibenztropone, dibenzsuberone, dibenzoxepin, and dibenzthiepin acetic acids were synthesized and tested for antiinflammatory/analgesic activity and also for their ability to inhibit rabbit lens aldose reductase (AR). It was found that the structural requirements for antiinflammatory/analgesic activity, believed to be mediated by inhibition of cyclooxygenase, were much more stringent than were those for AR inhibition. For example, the introduction of a hydroxyl group into positions 1, 4, 6, 7, or 8 on dibenzsuberone-2-acetic acid (1a) had relatively little effect on AR inhibition, but caused wide variations in antiinflammatory/analgesic activity.
|
Inhibition of mushroom tyrosinase assessed as oxidation of L-DOPA at 0.8 mM
|
Agaricus bisporus
|
23.0
%
|
|
Journal : J. Nat. Prod.
Title : Tyrosinase inhibitors from Anacardium occidentale fruits.
Year : 1994
Volume : 57
Issue : 4
First Page : 545
Last Page : 551
Authors : Kubo I, Kinst-Hori I, Yokokawa Y.
Abstract : Anacardic acids, 2-methylcardols, and cardols isolated from various parts of the cashew [Anacardium occidentale] (Anacardiaceae) fruit have been found to exhibit tyrosinase inhibitory activity. Kinetic studies with the two principal active compounds, 6-[8(Z),11(Z),14-pentadecatrienyl]salicylic acid and 5-[8(Z),11(Z),14-pentadecatrienyl]resorcinol, have indicated that both of these phenolic compounds exhibit characteristic competitive inhibition of the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) by mushroom tyrosinase.
|
Inhibition of soybean 15-lipoxygenase
|
Glycine max
|
48.4
%
|
|
Journal : Bioorg. Med. Chem.
Title : Inhibition of 15-lipoxygenase-catalysed oxygenation of arachidonic acid by substituted benzoic acids.
Year : 2008
Volume : 16
Issue : 8
First Page : 4589
Last Page : 4593
Authors : Russell WR, Scobbie L, Duthie GG, Chesson A.
Abstract : Elevated levels of phospholipases, prostaglandin synthases and lipoxygenases in colonic cells at various stages of malignancy indicate a strong link between dietary lipids and colon cancer. Lipoxygenase-catalysed arachidonic acid metabolism plays a key role in colorectal carcinogenesis and has the potential to be modulated by phenolic compounds. Plant-based foods are rich sources of phenolic compounds and in the human colon they are predominantly available as simple phenolics such as the benzoic acids. Benzoic acids were determined in faecal waters from four volunteers consuming a western-style diet. Structure-activity relationships were established for the lipoxygenase-catalysed oxygenation of arachidonic acid using an oxygen electrode. All compounds studied inhibited this reaction (21-73%; p<0.001) and many of the structural features could be rationalised by computational modelling. No correlation was observed with the ability to act as reductants, supporting the hypothesis that their mode of inhibition may not be by a direct redox effect on the non-haem iron.
|
Inhibition of bovine brain PI-PLCgamma1
|
Bos taurus
|
120.63
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Phospholipase Cgamma1 inhibitory principles from the sarcotestas of Ginkgo biloba.
Year : 1998
Volume : 61
Issue : 7
First Page : 867
Last Page : 871
Authors : Lee JS, Cho YS, Park EJ, Kim J, Oh WK, Lee HS, Ahn JS.
Abstract : Ten phenolic compounds were isolated from the CHCl3 extract of Ginkgo biloba sarcotestas (Ginkgoaceae) as a new class of phosphatidylinositol-specific phospholipase Cgamma1 (PI-PLCgamma1) inhibitors. The substances without the long chain were ineffective. On the other hand, the activities of these compounds were dramatically decreased by acetylation of aromatic hydroxyl groups of cardanol, phenolic acid, and bilobol and by methylation of the aromatic carboxyl group of phenolic acid. The unsaturated long chain as well as the aromatic hydroxyl and carboxyl groups might play a key role for the PI-PLCgamma1 inhibitory activity. These compounds also inhibited the growth of a number of human cancer cell lines, but were less cytotoxic against a human normal colon cell line.
|
Inhibition of trypsin at 10 uM
|
None
|
89.24
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of nitrogen-containing chalcones as possible anti-inflammatory and antioxidant agents.
Year : 2010
Volume : 20
Issue : 2
First Page : 730
Last Page : 733
Authors : Bandgar BP, Patil SA, Gacche RN, Korbad BL, Hote BS, Kinkar SN, Jalde SS.
Abstract : A novel series of nitrogen-containing chalcones were synthesized by Mannich reaction and were screened for anti-inflammatory related activities such as inhibition of cyclooxygenase-2 (COX-2), trypsin and beta-glucuronidase. The antioxidant potential was demonstrated using 1,1-diphenyl-2-picryl hydrazine (DPPH) radical scavenging activity. The results of the above studies shows that the compounds synthesized were found to be effective inhibitors of above pro-inflammatory enzymes, and were found to be possess moderate radical scavenging potential. Overall, the results of the studies reveal that the chalcones with N-methyl piperazine methyl and piperidine methyl substitution (4c, 3b, 4d, 6b) seems to be important for inhibition of beta-glucuronidase. Whereas the chalcones with piperidine methyl substitution (8b, 7b, 7c, 6c, 4b, 3c, 3b) were observed as effective inhibitors of COX-2, while the same compounds were found to be less reactive against COX-1 as compared to COX-2.
|
Inhibition of beta-glucuronidase at 10 uM
|
None
|
23.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of nitrogen-containing chalcones as possible anti-inflammatory and antioxidant agents.
Year : 2010
Volume : 20
Issue : 2
First Page : 730
Last Page : 733
Authors : Bandgar BP, Patil SA, Gacche RN, Korbad BL, Hote BS, Kinkar SN, Jalde SS.
Abstract : A novel series of nitrogen-containing chalcones were synthesized by Mannich reaction and were screened for anti-inflammatory related activities such as inhibition of cyclooxygenase-2 (COX-2), trypsin and beta-glucuronidase. The antioxidant potential was demonstrated using 1,1-diphenyl-2-picryl hydrazine (DPPH) radical scavenging activity. The results of the above studies shows that the compounds synthesized were found to be effective inhibitors of above pro-inflammatory enzymes, and were found to be possess moderate radical scavenging potential. Overall, the results of the studies reveal that the chalcones with N-methyl piperazine methyl and piperidine methyl substitution (4c, 3b, 4d, 6b) seems to be important for inhibition of beta-glucuronidase. Whereas the chalcones with piperidine methyl substitution (8b, 7b, 7c, 6c, 4b, 3c, 3b) were observed as effective inhibitors of COX-2, while the same compounds were found to be less reactive against COX-1 as compared to COX-2.
|
Induction of toxin TSST-1 production in Staphylococcus aureus MN8 at 0.10 % after 24 hrs relative to control
|
Staphylococcus aureus
|
26.3
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Surfactants, aromatic and isoprenoid compounds, and fatty acid biosynthesis inhibitors suppress Staphylococcus aureus production of toxic shock syndrome toxin 1.
Year : 2009
Volume : 53
Issue : 5
First Page : 1898
Last Page : 1906
Authors : McNamara PJ, Syverson RE, Milligan-Myhre K, Frolova O, Schroeder S, Kidder J, Hoang T, Proctor RA.
Abstract : Menstrual toxic shock syndrome is a rare but potentially life-threatening illness manifest through the actions of Staphylococcus aureus toxic shock syndrome toxin 1 (TSST-1). Previous studies have shown that tampon additives can influence staphylococcal TSST-1 production. We report here on the TSST-1-suppressing activity of 34 compounds that are commonly used additives in the pharmaceutical, food, and perfume industries. Many of the tested chemicals had a minimal impact on the growth of S. aureus and yet were potent inhibitors of TSST-1 production. The TSST-1-reducing compounds included surfactants with an ether, amide, or amine linkage to their fatty acid moiety (e.g., myreth-3-myristate, Laureth-3, disodium lauroamphodiacetate, disodium lauramido monoethanolamido, sodium lauriminodipropionic acid, and triethanolamine laureth sulfate); aromatic compounds (e.g. phenylethyl and benzyl alcohols); and several isoprenoids and related compounds (e.g., terpineol and menthol). The membrane-targeting and -altering effects of the TSST-1-suppressing compounds led us to assess the activity of molecules that are known to inhibit fatty acid biosynthesis (e.g., cerulenin, triclosan, and hexachlorophene). These compounds also reduced S. aureus TSST-1 production. This study suggests that more additives than previously recognized inhibit the production of TSST-1.
|
Inhibition of mushroom tyrosinase at 1 mM after 10 mins
|
Agaricus bisporus
|
97.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant 5-lipoxygenase at 1 mM after 10 mins by fluorescence assay
|
Homo sapiens
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of recombinant anthrax lethal factor at 1 mM after 30 mins by fluorescence assay
|
Bacillus anthracis
|
6.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant MMP1 at 1 mM after 30 mins
|
Homo sapiens
|
-1.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant MMP2 at 1 mM after 30 mins
|
Homo sapiens
|
12.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant MMP3 at 1 mM after 30 mins
|
Homo sapiens
|
-2.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant MMP8 at 1 mM after 30 mins
|
Homo sapiens
|
14.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of human recombinant MMP9 at 1 mM after 30 mins
|
Homo sapiens
|
12.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Inhibition of mouse recombinant iNOS at 1 mM after 40 mins by colorimetric assay
|
Mus musculus
|
13.0
%
|
|
Journal : J. Med. Chem.
Title : Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Year : 2011
Volume : 54
Issue : 2
First Page : 591
Last Page : 602
Authors : Jacobsen JA, Fullagar JL, Miller MT, Cohen SM.
Abstract : Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at dose equimolar to 120 mg/kg aspirin, administered intragastrically immediately after carrageenan challenge measured after 3 hrs by water plethysmometer relative to control
|
Rattus norvegicus
|
36.8
%
|
|
Journal : Bioorg. Med. Chem.
Title : Searching for new NO-donor aspirin-like molecules: Furoxanylacyl derivatives of salicylic acid and related furazans.
Year : 2011
Volume : 19
Issue : 19
First Page : 5852
Last Page : 5860
Authors : Lazzarato L, Cena C, Rolando B, Marini E, Lolli ML, Guglielmo S, Guaita E, Morini G, Coruzzi G, Fruttero R, Gasco A.
Abstract : A new group of derivatives of salicylic acid containing NO-donor furoxans, and the related des-NO-furazans, were synthesized and evaluated as new aspirin-like molecules. Their stability was assessed in acid (pH 1) and physiological solutions (pH 7.4), and in human serum. No compound exhibited COX-inhibitory activity against COX-1 and COX-2 isoforms, when tested up to 100μM, respectively, on isolated platelets and on monocytes. Phenylsulfonyl- and cyano-substituted furoxans inhibited platelet aggregation induced by collagen in human platelet-rich plasma, through a cGMP dependent mechanism. Furoxan derivatives displayed cGMP-dependent vasodilator activities, tested on rat aorta strips precontracted with phenylephrine. All products showed anti-inflammatory activity similar to that of ASA, tested on rats by the carrageenan-induced paw edema assay. Unlike ASA, all products showed markedly reduced gastrotoxicity in a rat lesion model.
|
Antihemorrhagic activity in ddY mouse assessed as inhibition of Protobothrops flavoviridis venom-induced hemorrhagic lesion formation compound incubated with venom for 10 mins and administered subcutaneously measured after 24 hrs
|
Mus musculus
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzenepolycarboxylic acids with potential anti-hemorrhagic properties and structure-activity relationships.
Year : 2011
Volume : 19
Issue : 23
First Page : 7000
Last Page : 7002
Authors : Aung HT, Nikai T, Niwa M, Takaya Y.
Abstract : Previously, we reported the structural requirements of the cinnamic acid relatives for inhibition of snake venom hemorrhagic action. In the present study, we examined the effect of benzenepolycarboxylic acids and substituted benzoic acids against Protobothropsflavoviridis venom-induced hemorrhage. Pyromellitic acid (1,2,4,5-benzenetetracarboxylic acid) was found to be a potent inhibitor of hemorrhage, with an IC(50) value of 0.035 μM. In addition, most of the antihemorrhagic activity of compounds tested in this experiment showed good correlation to acidity.
|
Nematotoxic activity against freshly hatched Meloidogyne incognita J2 (root-knot nematode) isolated from tomato roots assessed as induction of nematode paralysis measured 24 hr after immersion in compound test solutions
|
Meloidogyne incognita
|
379.0
ug.mL-1
|
|
Journal : J Agric Food Chem
Title : Nematotoxic phenolic compounds from Melia azedarach against Meloidogyne incognita.
Year : 2012
Volume : 60
Issue : 47
First Page : 11675
Last Page : 11680
Authors : Aoudia H, Ntalli N, Aissani N, Yahiaoui-Zaidi R, Caboni P.
Abstract : In the present study, evaluated was the paralysis activity of whole Italian and Algerian Melia azedarach, commonly known as chinaberry, fruits and parts (seeds, wood, and kernels) against Meloidogyne incognita second stage juveniles (J(2)). The paralysis activity was evaluated in vitro after 1 h and 1 day immersion periods of nematodes in test solutions. Phenolic constituent components of the extracts were identified and quantified by high-performance liquid chromatography-mass spectrometry, while confirmation was performed by high-performance liquid chromatography-diode array. The water extract of the Italian M. azedarach fruit pulp (IPWE) showed significant nematicidal activity (EC(50/48h) = 955 μg/mL) and among its active ingredient components were p-coumaric acid and p-hydroxybenzoic acid (EC(50/48h) = 840 and 871 μg/mL, respectively). This is the first report of the nematicidal activity of M. azedarach pulp water extract and phenolic acids against the root knot nematode M. incognita.
|
Inhibition of beta-glucuronidase (unknown origin) using p-nitrophenyl-beta-D-glucopyranosiduronic acid as substrate at 1 mM after 30 min
|
Homo sapiens
|
26.48
%
|
|
Journal : Med Chem Res
Title : Synthesis and biological evaluation of novel series of chalcone derivatives as inhibitors of cyclooxygenase and LPS-induced TNF- with potent antioxidant properties
Year : 2012
Volume : 21
Issue : 9
First Page : 2292
Last Page : 2299
Authors : Bandgar BP, Hote BS, Dhole NA, Gacche RN
|
Inhibition of trypsin (unknown origin) assessed as hydrolysis of bovine serum albumin at 1 mM after 20 min
|
Homo sapiens
|
86.64
%
|
|
Journal : Med Chem Res
Title : Synthesis and biological evaluation of novel series of chalcone derivatives as inhibitors of cyclooxygenase and LPS-induced TNF- with potent antioxidant properties
Year : 2012
Volume : 21
Issue : 9
First Page : 2292
Last Page : 2299
Authors : Bandgar BP, Hote BS, Dhole NA, Gacche RN
|
Inhibition of beta-glucuronidase (unknown origin) using p-nitrophenyl-beta-D-glucopyranosiduronic acid as substrate at 1 uM after 30 min by spectrophotometric analysis
|
Homo sapiens
|
24.77
%
|
|
Journal : Med Chem Res
Title : Synthesis and biological evaluation of novel curcumin analogues as anti-inflammatory, anti-cancer and anti-oxidant agents
Year : 2012
Volume : 21
Issue : 10
First Page : 3006
Last Page : 3014
Authors : Bandgar BP, Hote BS, Jalde SS, Gacche RN
|
Inhibition of trypsin (unknown origin) using bovine serum albumin as substrate at 1 uM incubated for 20 min prior to substrate addition measured after 25 min by Lowry method
|
Homo sapiens
|
84.99
%
|
|
Journal : Med Chem Res
Title : Synthesis and biological evaluation of novel curcumin analogues as anti-inflammatory, anti-cancer and anti-oxidant agents
Year : 2012
Volume : 21
Issue : 10
First Page : 3006
Last Page : 3014
Authors : Bandgar BP, Hote BS, Jalde SS, Gacche RN
|
Decrease in Lasiodiplodia theobromae ligninolytic enzyme production assessed as pectinase activity using pectin as substrate at 25 mM measured at 28 degC after 4 days
|
Lasiodiplodia theobromae
|
57.0
%
|
|
Journal : Crop Protection
Title : Effect of phenolic compounds on growth and ligninolytic enzyme production in Botryosphaeria isolates
Year : 2013
Volume : 43
First Page : 146
Last Page : 156
Authors : Srivastava P, David L. Wright, James J. Marois, Mrittunjai Srivastava, Peter C. Andersen, Philip F. Harmon.
Abstract : Botryosphaeria spp. are ligninolytic ascomyceteous fungi that incite many diseases in economically important woody plant species. Four Botryosphaeria isolates, Botryosphaeria rhodina (Lasiodiplodia theobromae), Botryosphaeria obtusa, Botryosphaeria dothidea and Botryosphaeria ribis (Neofusicoccum ribis) were used in this study. Ten naturally occurring phenolic compounds from plants were tested to evaluate their effect on mycelium growth and the production of ligninolytic and pectinolytic enzymes. The effect of phenolic compounds in vitro varied with the Botryosphaeria isolates. Inhibition of mycelium growth was dose-dependent, and varied from 2 to 100% inhibition in the ten phenolic compounds tested except syringic acid, which has no toxic effect on mycelium of Botryosphaeria isolates. A significant decrease in laccase production occurred when Botryosphaeria isolates were grown on phenolic compounds. Benzoic acid significantly inhibited pectinase activity in all isolates. The percent inhibition of pectinase activity in B. dothidea and B. obtusa was significantly increased in the presence of salicylic acid and syringic acid, respectively.
|
Decrease in Lasiodiplodia theobromae ligninolytic enzyme production assessed as laccase activity using ABTS as substrate at 1 mM measured at 28 degC after 4 days
|
Lasiodiplodia theobromae
|
58.0
%
|
|
Journal : Crop Protection
Title : Effect of phenolic compounds on growth and ligninolytic enzyme production in Botryosphaeria isolates
Year : 2013
Volume : 43
First Page : 146
Last Page : 156
Authors : Srivastava P, David L. Wright, James J. Marois, Mrittunjai Srivastava, Peter C. Andersen, Philip F. Harmon.
Abstract : Botryosphaeria spp. are ligninolytic ascomyceteous fungi that incite many diseases in economically important woody plant species. Four Botryosphaeria isolates, Botryosphaeria rhodina (Lasiodiplodia theobromae), Botryosphaeria obtusa, Botryosphaeria dothidea and Botryosphaeria ribis (Neofusicoccum ribis) were used in this study. Ten naturally occurring phenolic compounds from plants were tested to evaluate their effect on mycelium growth and the production of ligninolytic and pectinolytic enzymes. The effect of phenolic compounds in vitro varied with the Botryosphaeria isolates. Inhibition of mycelium growth was dose-dependent, and varied from 2 to 100% inhibition in the ten phenolic compounds tested except syringic acid, which has no toxic effect on mycelium of Botryosphaeria isolates. A significant decrease in laccase production occurred when Botryosphaeria isolates were grown on phenolic compounds. Benzoic acid significantly inhibited pectinase activity in all isolates. The percent inhibition of pectinase activity in B. dothidea and B. obtusa was significantly increased in the presence of salicylic acid and syringic acid, respectively.
|
Decrease in Lasiodiplodia theobromae mycelium biomass production measured at 28 degC after 4 days by gravimetric analysis
|
Lasiodiplodia theobromae
|
58.0
%
|
|
Journal : Crop Protection
Title : Effect of phenolic compounds on growth and ligninolytic enzyme production in Botryosphaeria isolates
Year : 2013
Volume : 43
First Page : 146
Last Page : 156
Authors : Srivastava P, David L. Wright, James J. Marois, Mrittunjai Srivastava, Peter C. Andersen, Philip F. Harmon.
Abstract : Botryosphaeria spp. are ligninolytic ascomyceteous fungi that incite many diseases in economically important woody plant species. Four Botryosphaeria isolates, Botryosphaeria rhodina (Lasiodiplodia theobromae), Botryosphaeria obtusa, Botryosphaeria dothidea and Botryosphaeria ribis (Neofusicoccum ribis) were used in this study. Ten naturally occurring phenolic compounds from plants were tested to evaluate their effect on mycelium growth and the production of ligninolytic and pectinolytic enzymes. The effect of phenolic compounds in vitro varied with the Botryosphaeria isolates. Inhibition of mycelium growth was dose-dependent, and varied from 2 to 100% inhibition in the ten phenolic compounds tested except syringic acid, which has no toxic effect on mycelium of Botryosphaeria isolates. A significant decrease in laccase production occurred when Botryosphaeria isolates were grown on phenolic compounds. Benzoic acid significantly inhibited pectinase activity in all isolates. The percent inhibition of pectinase activity in B. dothidea and B. obtusa was significantly increased in the presence of salicylic acid and syringic acid, respectively.
|
Decrease in Diplodia seriata (Schwein.) Shoemaker mycelium biomass production measured at 28 degC after 4 days by gravimetric analysis
|
Diplodia seriata
|
58.0
%
|
|
Journal : Crop Protection
Title : Effect of phenolic compounds on growth and ligninolytic enzyme production in Botryosphaeria isolates
Year : 2013
Volume : 43
First Page : 146
Last Page : 156
Authors : Srivastava P, David L. Wright, James J. Marois, Mrittunjai Srivastava, Peter C. Andersen, Philip F. Harmon.
Abstract : Botryosphaeria spp. are ligninolytic ascomyceteous fungi that incite many diseases in economically important woody plant species. Four Botryosphaeria isolates, Botryosphaeria rhodina (Lasiodiplodia theobromae), Botryosphaeria obtusa, Botryosphaeria dothidea and Botryosphaeria ribis (Neofusicoccum ribis) were used in this study. Ten naturally occurring phenolic compounds from plants were tested to evaluate their effect on mycelium growth and the production of ligninolytic and pectinolytic enzymes. The effect of phenolic compounds in vitro varied with the Botryosphaeria isolates. Inhibition of mycelium growth was dose-dependent, and varied from 2 to 100% inhibition in the ten phenolic compounds tested except syringic acid, which has no toxic effect on mycelium of Botryosphaeria isolates. A significant decrease in laccase production occurred when Botryosphaeria isolates were grown on phenolic compounds. Benzoic acid significantly inhibited pectinase activity in all isolates. The percent inhibition of pectinase activity in B. dothidea and B. obtusa was significantly increased in the presence of salicylic acid and syringic acid, respectively.
|
Decrease in Neofusicoccum ribis mycelium biomass production at 25 mM measured at 28 degC after 4 days by gravimetric analysis
|
Neofusicoccum ribis
|
50.0
%
|
|
Journal : Crop Protection
Title : Effect of phenolic compounds on growth and ligninolytic enzyme production in Botryosphaeria isolates
Year : 2013
Volume : 43
First Page : 146
Last Page : 156
Authors : Srivastava P, David L. Wright, James J. Marois, Mrittunjai Srivastava, Peter C. Andersen, Philip F. Harmon.
Abstract : Botryosphaeria spp. are ligninolytic ascomyceteous fungi that incite many diseases in economically important woody plant species. Four Botryosphaeria isolates, Botryosphaeria rhodina (Lasiodiplodia theobromae), Botryosphaeria obtusa, Botryosphaeria dothidea and Botryosphaeria ribis (Neofusicoccum ribis) were used in this study. Ten naturally occurring phenolic compounds from plants were tested to evaluate their effect on mycelium growth and the production of ligninolytic and pectinolytic enzymes. The effect of phenolic compounds in vitro varied with the Botryosphaeria isolates. Inhibition of mycelium growth was dose-dependent, and varied from 2 to 100% inhibition in the ten phenolic compounds tested except syringic acid, which has no toxic effect on mycelium of Botryosphaeria isolates. A significant decrease in laccase production occurred when Botryosphaeria isolates were grown on phenolic compounds. Benzoic acid significantly inhibited pectinase activity in all isolates. The percent inhibition of pectinase activity in B. dothidea and B. obtusa was significantly increased in the presence of salicylic acid and syringic acid, respectively.
|
Inhibition of quorum sensing system in Pseudomonas aeruginosa ATCC 27853 assessed as inhibition of biofilm formation at 4 mM after 24 hrs by crystal violet staining method relative to control
|
Pseudomonas aeruginosa
|
48.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of (R)-norbgugaine and its potential as quorum sensing inhibitor against Pseudomonas aeruginosa.
Year : 2013
Volume : 23
Issue : 8
First Page : 2353
Last Page : 2356
Authors : Majik MS, Naik D, Bhat C, Tilve S, Tilvi S, D'Souza L.
Abstract : (R)-Bgugaine is a natural pyrrolidine alkaloid from Arisarum vulgare, which shows antifungal and antibacterial activity. In this Letter, we have accomplished the simple synthesis of norbgugaine (demethylated form of natural bgugaine) employing Wittig olefination and cat. hydrogenation as the key steps and its biological studies are reported for the first time. The synthesized norbgugaine was evaluated for inhibition of quorum sensing mediated virulence factors (motility, biofilm formation, pyocyanin pigmentation, rhamnolipid production and LasA protease) in Pseudomonas aeruginosa wherein swarming motility is reduced by 95%, and biofilm formation by 83%.
|
Inhibition of quorum sensing system in Pseudomonas aeruginosa ATCC 27853 assessed as inhibition of twitching motility at 0.1 to 0.5 mM after 24 hrs relative to control
|
Pseudomonas aeruginosa
|
35.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of (R)-norbgugaine and its potential as quorum sensing inhibitor against Pseudomonas aeruginosa.
Year : 2013
Volume : 23
Issue : 8
First Page : 2353
Last Page : 2356
Authors : Majik MS, Naik D, Bhat C, Tilve S, Tilvi S, D'Souza L.
Abstract : (R)-Bgugaine is a natural pyrrolidine alkaloid from Arisarum vulgare, which shows antifungal and antibacterial activity. In this Letter, we have accomplished the simple synthesis of norbgugaine (demethylated form of natural bgugaine) employing Wittig olefination and cat. hydrogenation as the key steps and its biological studies are reported for the first time. The synthesized norbgugaine was evaluated for inhibition of quorum sensing mediated virulence factors (motility, biofilm formation, pyocyanin pigmentation, rhamnolipid production and LasA protease) in Pseudomonas aeruginosa wherein swarming motility is reduced by 95%, and biofilm formation by 83%.
|
Inhibition of quorum sensing system in Pseudomonas aeruginosa ATCC 27853 assessed as inhibition of swimming motility at 0.1 to 0.5 mM after 24 hrs relative to control
|
Pseudomonas aeruginosa
|
40.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of (R)-norbgugaine and its potential as quorum sensing inhibitor against Pseudomonas aeruginosa.
Year : 2013
Volume : 23
Issue : 8
First Page : 2353
Last Page : 2356
Authors : Majik MS, Naik D, Bhat C, Tilve S, Tilvi S, D'Souza L.
Abstract : (R)-Bgugaine is a natural pyrrolidine alkaloid from Arisarum vulgare, which shows antifungal and antibacterial activity. In this Letter, we have accomplished the simple synthesis of norbgugaine (demethylated form of natural bgugaine) employing Wittig olefination and cat. hydrogenation as the key steps and its biological studies are reported for the first time. The synthesized norbgugaine was evaluated for inhibition of quorum sensing mediated virulence factors (motility, biofilm formation, pyocyanin pigmentation, rhamnolipid production and LasA protease) in Pseudomonas aeruginosa wherein swarming motility is reduced by 95%, and biofilm formation by 83%.
|
Inhibition of quorum sensing system in Pseudomonas aeruginosa ATCC 27853 assessed as inhibition of swarming motility at 0.1 to 0.5 mM after 24 hrs relative to control
|
Pseudomonas aeruginosa
|
60.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of (R)-norbgugaine and its potential as quorum sensing inhibitor against Pseudomonas aeruginosa.
Year : 2013
Volume : 23
Issue : 8
First Page : 2353
Last Page : 2356
Authors : Majik MS, Naik D, Bhat C, Tilve S, Tilvi S, D'Souza L.
Abstract : (R)-Bgugaine is a natural pyrrolidine alkaloid from Arisarum vulgare, which shows antifungal and antibacterial activity. In this Letter, we have accomplished the simple synthesis of norbgugaine (demethylated form of natural bgugaine) employing Wittig olefination and cat. hydrogenation as the key steps and its biological studies are reported for the first time. The synthesized norbgugaine was evaluated for inhibition of quorum sensing mediated virulence factors (motility, biofilm formation, pyocyanin pigmentation, rhamnolipid production and LasA protease) in Pseudomonas aeruginosa wherein swarming motility is reduced by 95%, and biofilm formation by 83%.
|
Inhibition of recombinant human IDO1 expressed in Escherichia coli EC538 using L-tryptophan as substrate at 1 mM after 1 hr relative to control
|
Homo sapiens
|
2.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1).
Year : 2013
Volume : 21
Issue : 24
First Page : 7595
Last Page : 7603
Authors : Fung SP, Wang H, Tomek P, Squire CJ, Flanagan JU, Palmer BD, Bridewell DJ, Tijono SM, Jamie JF, Ching LM.
Abstract : Screening of a fragment library identified 2-hydrazinobenzothiazole as a potent inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme expressed by tumours that suppresses the immune system. Spectroscopic studies indicated that 2-hydrazinobenzothiazole interacted with the IDO1 haem and in silico docking predicted that the interaction was through hydrazine. Subsequent studies of hydrazine derivatives identified phenylhydrazine (IC50=0.25 ± 0.07 μM) to be 32-fold more potent than 2-hydrazinobenzothiazole (IC50=8.0 ± 2.3 μM) in inhibiting rhIDO1 and that it inhibited cellular IDO1 at concentrations that were noncytotoxic to cells. Here, phenylhydrazine is shown to inhibit IDO1 through binding to haem.
|
Inhibition of wild type PI3K p110alpha/p85alpha niSH2 (unknown origin) expressed in baculovirus infected sf9 cells assessed as reduction in PIP3 formation at 100 uM using PIP2 as substrate after 45 mins by fluorescence polarization assay relative to control
|
Homo sapiens
|
25.0
%
|
|
Journal : Bioorg Med Chem
Title : Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design.
Year : 2017
Volume : 25
Issue : 4
First Page : 1481
Last Page : 1486
Authors : Miller MS, Maheshwari S, McRobb FM, Kinzler KW, Amzel LM, Vogelstein B, Gabelli SB.
Abstract : PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kα could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW<300Da) for binding to PI3Kα by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains.
|
Inhibition of full length PI3Kalpha (unknown origin) assessed as reduction in PIP3 formation at 100 uM using PIP2 as substrate after 45 mins by fluorescence polarization assay relative to control
|
Homo sapiens
|
25.0
%
|
|
Journal : Bioorg Med Chem
Title : Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design.
Year : 2017
Volume : 25
Issue : 4
First Page : 1481
Last Page : 1486
Authors : Miller MS, Maheshwari S, McRobb FM, Kinzler KW, Amzel LM, Vogelstein B, Gabelli SB.
Abstract : PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kα could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW<300Da) for binding to PI3Kα by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains.
|
Inhibition of mouse recombinant glycolate oxidase expressed in Escherichia coli at 25 uM using glycolate as substrate after 1 min by sulfonated DCIP dye-based assay relative to control
|
Mus musculus
|
18.5
%
|
|
Journal : J Med Chem
Title : Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1.
Year : 2018
Volume : 61
Issue : 16
First Page : 7144
Last Page : 7167
Authors : Moya-Garzón MD, Martín Higueras C, Peñalver P, Romera M, Fernandes MX, Franco-Montalbán F, Gómez-Vidal JA, Salido E, Díaz-Gavilán M.
Abstract : Primary hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease related to glyoxylate metabolism and characterized by accumulation of calcium oxalate crystals. Current therapies involve hepatic and/or renal transplantation, procedures that have significant morbidity and mortality and require long-term immunosuppression. Thus, a pharmacological treatment is urgently needed. We introduce here an unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range, which means a potential use in the treatment of PH1. Though correlation of this phenotypic activity with glycolate oxidase (GO) inhibition is still to be verified, most of the salicylic acids described here are GO inhibitors with IC50 values down to 3 μM. Binding mode of salicylic acids inside GO has been studied using in silico methods, and preliminary structure-activity relationships have been established. The drug-like structure and ease of synthesis of our compounds make them promising hits for structural optimization.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
71.31
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of NAPRT (unknown origin)
|
Homo sapiens
|
0.16
nM
|
|
Title : Sensitization of cancer cells to nampt inhibitors by nicotinic acid phosphoribosyltransferase neutralization
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
32.4
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.84
%
|
|
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
|
0.04
%
|
|
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
|
0.04
%
|
|
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
|
0.04
%
|
|
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
|
0.04
%
|
|
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 beta-glucuronidase (unknown origin) at 10 mg/ml relative to control
|
Homo sapiens
|
92.9
%
|
|
Journal : Eur J Med Chem
Title : Therapeutic significance of β-glucuronidase activity and its inhibitors: A review.
Year : 2020
Volume : 187
First Page : 111921
Last Page : 111921
Authors : Awolade P, Cele N, Kerru N, Gummidi L, Oluwakemi E, Singh P.
Abstract : The emergence of disease and dearth of effective pharmacological agents on most therapeutic fronts, constitutes a major threat to global public health and man's existence. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. To this end, accumulating empirical evidence supports molecular target therapy as a plausible egress and, β-glucuronidase (βGLU) - a lysosomal acid hydrolase responsible for the catalytic deconjugation of β-d-glucuronides has emerged as a viable molecular target for several therapeutic applications. The enzyme's activity level in body fluids is also deemed a potential biomarker for the diagnosis of some pathological conditions. Moreover, due to its role in colon carcinogenesis and certain drug-induced dose-limiting toxicities, the development of potent inhibitors of βGLU in human intestinal microbiota has aroused increased attention over the years. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. Hence, in this review we present a compendium of exploits in the present millennium directed towards the inhibition of βGLU. The aim is to proffer a platform on which new scaffolds can be modelled for improved βGLU inhibitory potency and the development of new therapeutic agents in consequential.
|
Inhibition of beta-glucuronidase (unknown origin) at 1 mM relative to control
|
Homo sapiens
|
82.0
%
|
|
Journal : Eur J Med Chem
Title : Therapeutic significance of β-glucuronidase activity and its inhibitors: A review.
Year : 2020
Volume : 187
First Page : 111921
Last Page : 111921
Authors : Awolade P, Cele N, Kerru N, Gummidi L, Oluwakemi E, Singh P.
Abstract : The emergence of disease and dearth of effective pharmacological agents on most therapeutic fronts, constitutes a major threat to global public health and man's existence. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. To this end, accumulating empirical evidence supports molecular target therapy as a plausible egress and, β-glucuronidase (βGLU) - a lysosomal acid hydrolase responsible for the catalytic deconjugation of β-d-glucuronides has emerged as a viable molecular target for several therapeutic applications. The enzyme's activity level in body fluids is also deemed a potential biomarker for the diagnosis of some pathological conditions. Moreover, due to its role in colon carcinogenesis and certain drug-induced dose-limiting toxicities, the development of potent inhibitors of βGLU in human intestinal microbiota has aroused increased attention over the years. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. Hence, in this review we present a compendium of exploits in the present millennium directed towards the inhibition of βGLU. The aim is to proffer a platform on which new scaffolds can be modelled for improved βGLU inhibitory potency and the development of new therapeutic agents in consequential.
|
Inhibition of recombinant bovine liver ARGI at 500 uM using L-arginine as substrate incubated for 60 mins by spectroscopic analysis relative to control
|
Bos taurus
|
6.0
%
|
|
Journal : RSC Med Chem
Title : Synthesis, evaluation and molecular modelling of piceatannol analogues as arginase inhibitors
Year : 2020
Volume : 11
Issue : 5
First Page : 559
Last Page : 568
Authors : Muller, J., Cardey, B., Zedet, A., Desingle, C., Grzybowski, M., Pomper, P., Foley, S., Harakat, D., Ramseyer, C., Girard, C., Pudlo, M.
Abstract : Arginase is involved in a wide range of pathologies including cardiovascular diseases and infectious diseases whilst it is also a promising target to improve cancer immunotherapy. To date, only a limited number of inhibitors of arginase have been reported. Natural polyphenols, among them piceatannol, are moderate inhibitors of arginase. Herein, we report our efforts to investigate catechol binding by quantum chemistry and generate analogues of piceatannol. In this work, we synthesized a novel series of amino-polyphenols which were then evaluated as arginase inhibitors. Their structure-activity relationships were elucidated by deep quantum chemistry modelling. 4-((3,4-Dihydroxybenzyl)amino)benzene-1,2-diol 3t displays a mixed inhibition activity on bovine and human arginase I with IC50 (Ki) values of 76 (82) microM and 89 microM, respectively.
