|
Inhibitory activity was evaluated against human Prostaglandin G/H synthase 2 was determined
|
None
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a new cyclooxygenase-2 lead compound through 3-D database searching and combinatorial chemistry.
Year : 1998
Volume : 8
Issue : 5
First Page : 529
Last Page : 534
Authors : Stewart KD, Loren S, Frey L, Otis E, Klinghofer V, Hulkower KI.
Abstract : Using a combination of computational and combinatorial chemistry methodologies, a phenothiazine compound was discovered that is a selective inhibitor of cyclooxygenase-2 and serves as a lead compound for a potentially novel series of anti-inflammatory compounds.
|
Percent inhibition of edema in carrageenan-induced rat paw edema was determined by comparing with vehicle control group when tested on 5 rats at peroral dose of 100 umol/Kg
|
Rattus norvegicus
|
61.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of new flosulide analogues, synthesized from natural safrole.
Year : 1998
Volume : 8
Issue : 2
First Page : 183
Last Page : 188
Authors : Lages AS, Silva KC, Miranda AL, Fraga CA, Barreiro EJ.
Abstract : Four new aryl-sulfonamide derivatives (3a, 4a, 5a-b), having methylenedioxy group attached to phenyl ring, were prepared from natural safrole and evaluated as anti-inflammatory agents. The N-methylsulfonamide 3a and corresponding retrosulfonamide derivative 5a were more active than standards indomethacin and nimesulide, at the same molar concentration, in carrageenan-induced pleurisy assay.
|
Percent inhibition of pleural inflammation in carrageenan-induced rat model was determined by comparing with vehicle control group when tested on 8 rats at peroral dose of 100 umol/Kg
|
Rattus norvegicus
|
29.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of new flosulide analogues, synthesized from natural safrole.
Year : 1998
Volume : 8
Issue : 2
First Page : 183
Last Page : 188
Authors : Lages AS, Silva KC, Miranda AL, Fraga CA, Barreiro EJ.
Abstract : Four new aryl-sulfonamide derivatives (3a, 4a, 5a-b), having methylenedioxy group attached to phenyl ring, were prepared from natural safrole and evaluated as anti-inflammatory agents. The N-methylsulfonamide 3a and corresponding retrosulfonamide derivative 5a were more active than standards indomethacin and nimesulide, at the same molar concentration, in carrageenan-induced pleurisy assay.
|
In vitro inhibition activity against cyclooxygenase 2 with the compound dissolved in DMSO
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro antiproliferative activity against human colon cancer cell lines of representative 4-thiazolidinones. Part I.
Year : 2005
Volume : 15
Issue : 17
First Page : 3930
Last Page : 3933
Authors : Ottanà R, Carotti S, Maccari R, Landini I, Chiricosta G, Caciagli B, Vigorita MG, Mini E.
Abstract : The characterization of two cyclooxygenase isoforms (COX), the rate-limiting enzyme for the synthesis of prostaglandins (PGs) from arachidonic acid, has allowed the development of COX-2 selective inhibitors as non-steroidal anti-inflammatory drugs (NSAIDs) with significant gastric tolerability. However, PGs are also important in cancer pathogenesis. Thus, there is an increasing interest in studying COX-2 inhibitors as potential drugs aimed at the prevention and treatment of cancer, especially colorectal cancer. The purpose of this study was to determine the inhibitory effects of some representative 4-thiazolidinones, already widely investigated as potential NSAIDs, on the growth of five human colon carcinoma cell lines with a different COX-2 expression, and to correlate them with COX-2 inhibitory properties. Our results preliminarily revealed that 2-phenylimino derivative 3 and 2,4-thiazolidindione 4 were the most active compounds. In particular, 3 mainly inhibited the HT29 cell line characterized by a high COX-2 expression, whereas 4 showed antiproliferative properties on all tested cell lines, suggesting molecular targets other than COX-2 inhibition.
|
Inhibition of COX2 in human whole blood assessed as inhibition of LPS-stimulated PGE2 production
|
Homo sapiens
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of pyridinic analogues of nimesulide as cyclooxygenase-2 selective inhibitors.
Year : 2004
Volume : 47
Issue : 27
First Page : 6749
Last Page : 6759
Authors : Julémont F, de Leval X, Michaux C, Renard JF, Winum JY, Montero JL, Damas J, Dogné JM, Pirotte B.
Abstract : In this study, we report the synthesis and pharmacological evaluation of original pyridinic sulfonamides related to nimesulide, a cyclooxygenase-2 (COX-2) preferential inhibitor widely used as an anti-inflammatory agent. These original pyridinic derivatives were synthesized in three steps starting from the condensation of 3-bromo-4-nitropyridine N-oxide with appropriately substituted phenols, thiophenols, or anilines followed by a reduction of the nitro moiety into the corresponding aminopyridine, which was finally condensed with alkane- or trifluoromethanesulfonyl chloride to obtain the corresponding sulfonamides. The pK(a) determinations demonstrated that the major ionic form present in solution at physiological pH depends on the nature of the sulfonamide moiety subsituent. Indeed, alkanesulfonamides were mainly present as zwitterionic molecules while trifluoromethanesulfonamides, more acidic derivatives, were mainly present as anionic molecules. The in vitro pharmacological evaluation of the synthesized compounds against COX-1 and COX-2 was performed in a human whole blood model. Results obtained demonstrated that most of alkanesulfonamide derivatives displayed a COX-2 preferential inhibition with selectivity ratio values (IC(50)(COX-1)/IC(50)(COX-2)) up to 7.92 (celecoxib displaying a ratio value of 7.46 in the same test). On the other hand, trifluoromethanesulfonamide derivatives displayed weaker selectivity ratios although they exhibited IC(50) values against COX-2 up to 0.09 microM (celecoxib IC(50) against COX-2: 0.35 microM). Finally, in vivo evaluation of selected compounds showed that they exhibited anti-inflammatory properties similar to that of nimesulide when tested in a carrageenan-induced rat paw oedema model.
|
Antiinflammatory activity against carrageenan-induced oedema in Wistar rat paw at 3 mg/kg, ip after 3 hrs relative to control
|
Rattus norvegicus
|
23.71
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of pyridinic analogues of nimesulide as cyclooxygenase-2 selective inhibitors.
Year : 2004
Volume : 47
Issue : 27
First Page : 6749
Last Page : 6759
Authors : Julémont F, de Leval X, Michaux C, Renard JF, Winum JY, Montero JL, Damas J, Dogné JM, Pirotte B.
Abstract : In this study, we report the synthesis and pharmacological evaluation of original pyridinic sulfonamides related to nimesulide, a cyclooxygenase-2 (COX-2) preferential inhibitor widely used as an anti-inflammatory agent. These original pyridinic derivatives were synthesized in three steps starting from the condensation of 3-bromo-4-nitropyridine N-oxide with appropriately substituted phenols, thiophenols, or anilines followed by a reduction of the nitro moiety into the corresponding aminopyridine, which was finally condensed with alkane- or trifluoromethanesulfonyl chloride to obtain the corresponding sulfonamides. The pK(a) determinations demonstrated that the major ionic form present in solution at physiological pH depends on the nature of the sulfonamide moiety subsituent. Indeed, alkanesulfonamides were mainly present as zwitterionic molecules while trifluoromethanesulfonamides, more acidic derivatives, were mainly present as anionic molecules. The in vitro pharmacological evaluation of the synthesized compounds against COX-1 and COX-2 was performed in a human whole blood model. Results obtained demonstrated that most of alkanesulfonamide derivatives displayed a COX-2 preferential inhibition with selectivity ratio values (IC(50)(COX-1)/IC(50)(COX-2)) up to 7.92 (celecoxib displaying a ratio value of 7.46 in the same test). On the other hand, trifluoromethanesulfonamide derivatives displayed weaker selectivity ratios although they exhibited IC(50) values against COX-2 up to 0.09 microM (celecoxib IC(50) against COX-2: 0.35 microM). Finally, in vivo evaluation of selected compounds showed that they exhibited anti-inflammatory properties similar to that of nimesulide when tested in a carrageenan-induced rat paw oedema model.
|
Antiinflammatory activity against carrageenan-induced oedema in Wistar rat paw at 10 mg/kg, ip after 3 hrs relative to control
|
Rattus norvegicus
|
40.2
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of pyridinic analogues of nimesulide as cyclooxygenase-2 selective inhibitors.
Year : 2004
Volume : 47
Issue : 27
First Page : 6749
Last Page : 6759
Authors : Julémont F, de Leval X, Michaux C, Renard JF, Winum JY, Montero JL, Damas J, Dogné JM, Pirotte B.
Abstract : In this study, we report the synthesis and pharmacological evaluation of original pyridinic sulfonamides related to nimesulide, a cyclooxygenase-2 (COX-2) preferential inhibitor widely used as an anti-inflammatory agent. These original pyridinic derivatives were synthesized in three steps starting from the condensation of 3-bromo-4-nitropyridine N-oxide with appropriately substituted phenols, thiophenols, or anilines followed by a reduction of the nitro moiety into the corresponding aminopyridine, which was finally condensed with alkane- or trifluoromethanesulfonyl chloride to obtain the corresponding sulfonamides. The pK(a) determinations demonstrated that the major ionic form present in solution at physiological pH depends on the nature of the sulfonamide moiety subsituent. Indeed, alkanesulfonamides were mainly present as zwitterionic molecules while trifluoromethanesulfonamides, more acidic derivatives, were mainly present as anionic molecules. The in vitro pharmacological evaluation of the synthesized compounds against COX-1 and COX-2 was performed in a human whole blood model. Results obtained demonstrated that most of alkanesulfonamide derivatives displayed a COX-2 preferential inhibition with selectivity ratio values (IC(50)(COX-1)/IC(50)(COX-2)) up to 7.92 (celecoxib displaying a ratio value of 7.46 in the same test). On the other hand, trifluoromethanesulfonamide derivatives displayed weaker selectivity ratios although they exhibited IC(50) values against COX-2 up to 0.09 microM (celecoxib IC(50) against COX-2: 0.35 microM). Finally, in vivo evaluation of selected compounds showed that they exhibited anti-inflammatory properties similar to that of nimesulide when tested in a carrageenan-induced rat paw oedema model.
|
Antiinflammatory activity against carrageenan-induced oedema in Wistar rat paw at 30 mg/kg, ip after 3 hrs relative to control
|
Rattus norvegicus
|
44.32
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of pyridinic analogues of nimesulide as cyclooxygenase-2 selective inhibitors.
Year : 2004
Volume : 47
Issue : 27
First Page : 6749
Last Page : 6759
Authors : Julémont F, de Leval X, Michaux C, Renard JF, Winum JY, Montero JL, Damas J, Dogné JM, Pirotte B.
Abstract : In this study, we report the synthesis and pharmacological evaluation of original pyridinic sulfonamides related to nimesulide, a cyclooxygenase-2 (COX-2) preferential inhibitor widely used as an anti-inflammatory agent. These original pyridinic derivatives were synthesized in three steps starting from the condensation of 3-bromo-4-nitropyridine N-oxide with appropriately substituted phenols, thiophenols, or anilines followed by a reduction of the nitro moiety into the corresponding aminopyridine, which was finally condensed with alkane- or trifluoromethanesulfonyl chloride to obtain the corresponding sulfonamides. The pK(a) determinations demonstrated that the major ionic form present in solution at physiological pH depends on the nature of the sulfonamide moiety subsituent. Indeed, alkanesulfonamides were mainly present as zwitterionic molecules while trifluoromethanesulfonamides, more acidic derivatives, were mainly present as anionic molecules. The in vitro pharmacological evaluation of the synthesized compounds against COX-1 and COX-2 was performed in a human whole blood model. Results obtained demonstrated that most of alkanesulfonamide derivatives displayed a COX-2 preferential inhibition with selectivity ratio values (IC(50)(COX-1)/IC(50)(COX-2)) up to 7.92 (celecoxib displaying a ratio value of 7.46 in the same test). On the other hand, trifluoromethanesulfonamide derivatives displayed weaker selectivity ratios although they exhibited IC(50) values against COX-2 up to 0.09 microM (celecoxib IC(50) against COX-2: 0.35 microM). Finally, in vivo evaluation of selected compounds showed that they exhibited anti-inflammatory properties similar to that of nimesulide when tested in a carrageenan-induced rat paw oedema model.
|
Antiinflammatory activity against carrageenan-induced paw edema in Wistar rat at 300 umol/kg, po after 3 hrs
|
Rattus norvegicus
|
57.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives: Discovery of LASSBio-881, a new ligand of cannabinoid receptors.
Year : 2007
Volume : 15
Issue : 6
First Page : 2421
Last Page : 2433
Authors : Duarte CD, Tributino JL, Lacerda DI, Martins MV, Alexandre-Moreira MS, Dutra F, Bechara EJ, De-Paula FS, Goulart MO, Ferreira J, Calixto JB, Nunes MP, Bertho AL, Miranda AL, Barreiro EJ, Fraga CA.
Abstract : We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity.
|
Antiinflammatory activity against TPA-induced ear edema in Swiss mouse at 300 umol/kg, po after 6 hrs
|
Mus musculus
|
-10.6
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives: Discovery of LASSBio-881, a new ligand of cannabinoid receptors.
Year : 2007
Volume : 15
Issue : 6
First Page : 2421
Last Page : 2433
Authors : Duarte CD, Tributino JL, Lacerda DI, Martins MV, Alexandre-Moreira MS, Dutra F, Bechara EJ, De-Paula FS, Goulart MO, Ferreira J, Calixto JB, Nunes MP, Bertho AL, Miranda AL, Barreiro EJ, Fraga CA.
Abstract : We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity.
|
Antiinflammatory activity against AA-induced ear edema in Swiss mouse at 300 umol/kg, po after 1 hr
|
Mus musculus
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives: Discovery of LASSBio-881, a new ligand of cannabinoid receptors.
Year : 2007
Volume : 15
Issue : 6
First Page : 2421
Last Page : 2433
Authors : Duarte CD, Tributino JL, Lacerda DI, Martins MV, Alexandre-Moreira MS, Dutra F, Bechara EJ, De-Paula FS, Goulart MO, Ferreira J, Calixto JB, Nunes MP, Bertho AL, Miranda AL, Barreiro EJ, Fraga CA.
Abstract : We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity.
|
Antihyperalgesic effect against formalin-induced pain in mouse at 100 umol/kg, po assessed as licking activity in neurogenic phase
|
Mus musculus
|
9.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives: Discovery of LASSBio-881, a new ligand of cannabinoid receptors.
Year : 2007
Volume : 15
Issue : 6
First Page : 2421
Last Page : 2433
Authors : Duarte CD, Tributino JL, Lacerda DI, Martins MV, Alexandre-Moreira MS, Dutra F, Bechara EJ, De-Paula FS, Goulart MO, Ferreira J, Calixto JB, Nunes MP, Bertho AL, Miranda AL, Barreiro EJ, Fraga CA.
Abstract : We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity.
|
Antihyperalgesic effect against formalin-induced pain in mouse at 100 umol/kg, po assessed as licking activity in inflammatory phase
|
Mus musculus
|
70.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives: Discovery of LASSBio-881, a new ligand of cannabinoid receptors.
Year : 2007
Volume : 15
Issue : 6
First Page : 2421
Last Page : 2433
Authors : Duarte CD, Tributino JL, Lacerda DI, Martins MV, Alexandre-Moreira MS, Dutra F, Bechara EJ, De-Paula FS, Goulart MO, Ferreira J, Calixto JB, Nunes MP, Bertho AL, Miranda AL, Barreiro EJ, Fraga CA.
Abstract : We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity.
|
Inhibition of sheep COX2 at 50 uM
|
Ovis aries
|
50.0
%
|
|
Journal : J. Nat. Prod.
Title : Chamazulene carboxylic acid and matricin: a natural profen and its natural prodrug, identified through similarity to synthetic drug substances.
Year : 2006
Volume : 69
Issue : 7
First Page : 1041
Last Page : 1045
Authors : Ramadan M, Goeters S, Watzer B, Krause E, Lohmann K, Bauer R, Hempel B, Imming P.
Abstract : Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
|
Inhibition of COX2 at 0.1 mM
|
None
|
7.0
%
|
|
Journal : J. Nat. Prod.
Title : Expanding the ChemGPS chemical space with natural products.
Year : 2005
Volume : 68
Issue : 7
First Page : 985
Last Page : 991
Authors : Larsson J, Gottfries J, Bohlin L, Backlund A.
Abstract : Recently various attempts have been made to increase the efficacy and precision of chemical libraries used in high-throughput screening (HTS) drug discovery approaches. One such approach is ChemGPS, which provides a defined chemical space for prescreening evaluation of chemical compound properties or virtual dereplication. In the present study, ChemGPS has been applied to a set of natural products shown to exhibit cyclooxygenase-1 and/or -2 (COX-1/2) inhibition. With the purpose of defining chemical properties and linking these to the observed mode of enzyme inhibition, this resulted in two lines of reasoning. On one hand several specific features of these compounds have been identified and discussed. Overall COX inhibition was frequently correlated with the presence of at least one ring in the structure, fragments exhibiting structural rigidity, and a relatively large molecular size. The concept "size" includes several parameters, e.g., molecular volume, weight, and number of bonds. On the other hand, and possibly even more important, was the unexpected finding that the natural products studied to a large extent fell outside the defined ChemGPS chemical space. Therefore, we also propose an expanded space for natural products: ChemGPS-NP.
|
Inhibition of COX1 at 0.01 mM
|
None
|
76.0
%
|
|
Journal : J. Nat. Prod.
Title : Expanding the ChemGPS chemical space with natural products.
Year : 2005
Volume : 68
Issue : 7
First Page : 985
Last Page : 991
Authors : Larsson J, Gottfries J, Bohlin L, Backlund A.
Abstract : Recently various attempts have been made to increase the efficacy and precision of chemical libraries used in high-throughput screening (HTS) drug discovery approaches. One such approach is ChemGPS, which provides a defined chemical space for prescreening evaluation of chemical compound properties or virtual dereplication. In the present study, ChemGPS has been applied to a set of natural products shown to exhibit cyclooxygenase-1 and/or -2 (COX-1/2) inhibition. With the purpose of defining chemical properties and linking these to the observed mode of enzyme inhibition, this resulted in two lines of reasoning. On one hand several specific features of these compounds have been identified and discussed. Overall COX inhibition was frequently correlated with the presence of at least one ring in the structure, fragments exhibiting structural rigidity, and a relatively large molecular size. The concept "size" includes several parameters, e.g., molecular volume, weight, and number of bonds. On the other hand, and possibly even more important, was the unexpected finding that the natural products studied to a large extent fell outside the defined ChemGPS chemical space. Therefore, we also propose an expanded space for natural products: ChemGPS-NP.
|
Inhibition of COX2 in LPS-stimulated human whole blood assessed as PGE2 production by enzyme immunoassay
|
Homo sapiens
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyridine analogues of nimesulide: design, synthesis, and in vitro and in vivo pharmacological evaluation as promising cyclooxygenase 1 and 2 inhibitors.
Year : 2009
Volume : 52
Issue : 19
First Page : 5864
Last Page : 5871
Authors : Renard JF, Arslan D, Garbacki N, Pirotte B, de Leval X.
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most prescribed medications, although the chronic use of such pharmacological agents is commonly associated with numerous side effects. The demonstration that the use of COX-2 selective or preferential inhibitors is associated with a better tolerability opened new horizons in the search of safer drugs for the management of inflammation. In the present study, we report the synthesis and the pharmacological evaluation of pyridine analogues of nimesulide, a COX-2 preferential inhibitor. The cyclooxygenases (COXs) inhibitory activities were evaluated in vitro using a human whole blood model. According to the in vitro results, a selection of compounds exhibiting moderate to high COX-2/COX-1 selectivity ratio (from weak COX-2 preferential inhibitors to compounds displaying a celecoxib-like selectivity profile) were further evaluated in vivo in a model of lambda carrageenan-induced pleurisy in rats. Some of the selected compounds displayed similar or improved anti-inflammatory properties when compared to nimesulide and celecoxib.
|
Antiinflammatory activity against gamma carrageenan-induced pleurisy in Wistar rat assessed as inhibition of exudate production in pleural cavity at 5 mg/kg, ip administered 30 mins before gamma carrageenan challenge measured after 4 hrs
|
Rattus norvegicus
|
31.05
%
|
|
Journal : J. Med. Chem.
Title : Pyridine analogues of nimesulide: design, synthesis, and in vitro and in vivo pharmacological evaluation as promising cyclooxygenase 1 and 2 inhibitors.
Year : 2009
Volume : 52
Issue : 19
First Page : 5864
Last Page : 5871
Authors : Renard JF, Arslan D, Garbacki N, Pirotte B, de Leval X.
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most prescribed medications, although the chronic use of such pharmacological agents is commonly associated with numerous side effects. The demonstration that the use of COX-2 selective or preferential inhibitors is associated with a better tolerability opened new horizons in the search of safer drugs for the management of inflammation. In the present study, we report the synthesis and the pharmacological evaluation of pyridine analogues of nimesulide, a COX-2 preferential inhibitor. The cyclooxygenases (COXs) inhibitory activities were evaluated in vitro using a human whole blood model. According to the in vitro results, a selection of compounds exhibiting moderate to high COX-2/COX-1 selectivity ratio (from weak COX-2 preferential inhibitors to compounds displaying a celecoxib-like selectivity profile) were further evaluated in vivo in a model of lambda carrageenan-induced pleurisy in rats. Some of the selected compounds displayed similar or improved anti-inflammatory properties when compared to nimesulide and celecoxib.
|
Antiinflammatory activity against gamma carrageenan-induced pleurisy in Wistar rat assessed as inhibition of exudate production in pleural cavity at 10 mg/kg, ip administered 30 mins before gamma carrageenan challenge measured after 4 hrs
|
Rattus norvegicus
|
48.44
%
|
|
Journal : J. Med. Chem.
Title : Pyridine analogues of nimesulide: design, synthesis, and in vitro and in vivo pharmacological evaluation as promising cyclooxygenase 1 and 2 inhibitors.
Year : 2009
Volume : 52
Issue : 19
First Page : 5864
Last Page : 5871
Authors : Renard JF, Arslan D, Garbacki N, Pirotte B, de Leval X.
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most prescribed medications, although the chronic use of such pharmacological agents is commonly associated with numerous side effects. The demonstration that the use of COX-2 selective or preferential inhibitors is associated with a better tolerability opened new horizons in the search of safer drugs for the management of inflammation. In the present study, we report the synthesis and the pharmacological evaluation of pyridine analogues of nimesulide, a COX-2 preferential inhibitor. The cyclooxygenases (COXs) inhibitory activities were evaluated in vitro using a human whole blood model. According to the in vitro results, a selection of compounds exhibiting moderate to high COX-2/COX-1 selectivity ratio (from weak COX-2 preferential inhibitors to compounds displaying a celecoxib-like selectivity profile) were further evaluated in vivo in a model of lambda carrageenan-induced pleurisy in rats. Some of the selected compounds displayed similar or improved anti-inflammatory properties when compared to nimesulide and celecoxib.
|
Antiinflammatory activity against gamma carrageenan-induced pleurisy in Wistar rat assessed as inhibition of exudate production in pleural cavity at 20 mg/kg, ip administered 30 mins before gamma carrageenan challenge measured after 4 hrs
|
Rattus norvegicus
|
61.53
%
|
|
Journal : J. Med. Chem.
Title : Pyridine analogues of nimesulide: design, synthesis, and in vitro and in vivo pharmacological evaluation as promising cyclooxygenase 1 and 2 inhibitors.
Year : 2009
Volume : 52
Issue : 19
First Page : 5864
Last Page : 5871
Authors : Renard JF, Arslan D, Garbacki N, Pirotte B, de Leval X.
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most prescribed medications, although the chronic use of such pharmacological agents is commonly associated with numerous side effects. The demonstration that the use of COX-2 selective or preferential inhibitors is associated with a better tolerability opened new horizons in the search of safer drugs for the management of inflammation. In the present study, we report the synthesis and the pharmacological evaluation of pyridine analogues of nimesulide, a COX-2 preferential inhibitor. The cyclooxygenases (COXs) inhibitory activities were evaluated in vitro using a human whole blood model. According to the in vitro results, a selection of compounds exhibiting moderate to high COX-2/COX-1 selectivity ratio (from weak COX-2 preferential inhibitors to compounds displaying a celecoxib-like selectivity profile) were further evaluated in vivo in a model of lambda carrageenan-induced pleurisy in rats. Some of the selected compounds displayed similar or improved anti-inflammatory properties when compared to nimesulide and celecoxib.
|
Antiinflammatory activity in albino rat assessed as inhibition of carrageenan-induced paw oedema at 50 mg/kg, po measured after 30 mins of carrageenan challenge relative to control
|
Rattus norvegicus
|
15.3
%
|
|
Journal : Eur. J. Med. Chem.
Title : In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives.
Year : 2010
Volume : 45
Issue : 5
First Page : 2048
Last Page : 2054
Authors : Achar KC, Hosamani KM, Seetharamareddy HR.
Abstract : A series of 2-methylaminobenzimidazole derivatives (1-11) were synthesized by the reaction of 2-(chloromethyl)-1H-benzimidazole derivatives with primary aromatic amines. All these compounds were characterized by IR, 1H NMR, 13C NMR, GC-MS and elemental analysis. The newly synthesized compounds were screened for analgesic and anti-inflammatory activities on acetic acid induced writhing in mice and carrageenan induced paw oedema in rats. Compounds (7) and (2) showed a potent analgesic (89% at 100 mg/kg b.w) and anti-inflammatory (100% at 100 mg/kg b.w) activities compared with standard drug Nimesulide (100% at 50 mg/kg b.w) respectively. The other compounds showed good analgesic and anti-inflammatory activities.
|
Antiinflammatory activity in albino rat assessed as inhibition of carrageenan-induced paw oedema at 50 mg/kg, po measured after 60 mins of carrageenan challenge relative to control
|
Rattus norvegicus
|
26.6
%
|
|
Journal : Eur. J. Med. Chem.
Title : In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives.
Year : 2010
Volume : 45
Issue : 5
First Page : 2048
Last Page : 2054
Authors : Achar KC, Hosamani KM, Seetharamareddy HR.
Abstract : A series of 2-methylaminobenzimidazole derivatives (1-11) were synthesized by the reaction of 2-(chloromethyl)-1H-benzimidazole derivatives with primary aromatic amines. All these compounds were characterized by IR, 1H NMR, 13C NMR, GC-MS and elemental analysis. The newly synthesized compounds were screened for analgesic and anti-inflammatory activities on acetic acid induced writhing in mice and carrageenan induced paw oedema in rats. Compounds (7) and (2) showed a potent analgesic (89% at 100 mg/kg b.w) and anti-inflammatory (100% at 100 mg/kg b.w) activities compared with standard drug Nimesulide (100% at 50 mg/kg b.w) respectively. The other compounds showed good analgesic and anti-inflammatory activities.
|
Antiinflammatory activity in albino rat assessed as inhibition of carrageenan-induced paw oedema at 50 mg/kg, po measured after 120 mins of carrageenan challenge relative to control
|
Rattus norvegicus
|
41.1
%
|
|
Journal : Eur. J. Med. Chem.
Title : In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives.
Year : 2010
Volume : 45
Issue : 5
First Page : 2048
Last Page : 2054
Authors : Achar KC, Hosamani KM, Seetharamareddy HR.
Abstract : A series of 2-methylaminobenzimidazole derivatives (1-11) were synthesized by the reaction of 2-(chloromethyl)-1H-benzimidazole derivatives with primary aromatic amines. All these compounds were characterized by IR, 1H NMR, 13C NMR, GC-MS and elemental analysis. The newly synthesized compounds were screened for analgesic and anti-inflammatory activities on acetic acid induced writhing in mice and carrageenan induced paw oedema in rats. Compounds (7) and (2) showed a potent analgesic (89% at 100 mg/kg b.w) and anti-inflammatory (100% at 100 mg/kg b.w) activities compared with standard drug Nimesulide (100% at 50 mg/kg b.w) respectively. The other compounds showed good analgesic and anti-inflammatory activities.
|
Antiinflammatory activity in albino rat assessed as inhibition of carrageenan-induced paw oedema at 50 mg/kg, po measured after 180 mins of carrageenan challenge relative to control
|
Rattus norvegicus
|
44.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives.
Year : 2010
Volume : 45
Issue : 5
First Page : 2048
Last Page : 2054
Authors : Achar KC, Hosamani KM, Seetharamareddy HR.
Abstract : A series of 2-methylaminobenzimidazole derivatives (1-11) were synthesized by the reaction of 2-(chloromethyl)-1H-benzimidazole derivatives with primary aromatic amines. All these compounds were characterized by IR, 1H NMR, 13C NMR, GC-MS and elemental analysis. The newly synthesized compounds were screened for analgesic and anti-inflammatory activities on acetic acid induced writhing in mice and carrageenan induced paw oedema in rats. Compounds (7) and (2) showed a potent analgesic (89% at 100 mg/kg b.w) and anti-inflammatory (100% at 100 mg/kg b.w) activities compared with standard drug Nimesulide (100% at 50 mg/kg b.w) respectively. The other compounds showed good analgesic and anti-inflammatory activities.
|
Antiinflammatory activity in Wistar albino rat assessed as inhibition of carrageenan-induced paw edema at 4 mg/kg, po administered 30 mins before carrageenan challenge measured after 30 mins relative to control
|
Rattus norvegicus
|
37.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of some pyrazolylpyrazolines as anti-inflammatory-antimicrobial agents.
Year : 2010
Volume : 45
Issue : 6
First Page : 2650
Last Page : 2655
Authors : Sharma PK, Kumar S, Kumar P, Kaushik P, Kaushik D, Dhingra Y, Aneja KR.
Abstract : A new series of pyrazolylpyrazolines (5a-k) was synthesized by the reaction of appropriate chalcones (3a-k) with 4-hydrazinobenzenesulfonamide hydrochloride (4) in ethanol. All the newly synthesized target compounds (5a-k) were screened for their anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compounds 5g and 5j showed pronounced anti-inflammatory activity comparable to the reference standard nimesulide, whereas, compounds 5b, 5d and 5h displayed good anti-inflammatory activity. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity against two Gram-positive bacteria and two Gram-negative bacteria. Four compounds 5c, 5h-5j showed good broad spectrum activity against all the tested Gram-positive and Gram-negative bacterial strains. Compound 5j could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory and antibacterial profile.
|
Antiinflammatory activity in Wistar albino rat assessed as inhibition of carrageenan-induced paw edema at 4 mg/kg, po administered 30 mins before carrageenan challenge measured after 60 mins relative to control
|
Rattus norvegicus
|
43.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of some pyrazolylpyrazolines as anti-inflammatory-antimicrobial agents.
Year : 2010
Volume : 45
Issue : 6
First Page : 2650
Last Page : 2655
Authors : Sharma PK, Kumar S, Kumar P, Kaushik P, Kaushik D, Dhingra Y, Aneja KR.
Abstract : A new series of pyrazolylpyrazolines (5a-k) was synthesized by the reaction of appropriate chalcones (3a-k) with 4-hydrazinobenzenesulfonamide hydrochloride (4) in ethanol. All the newly synthesized target compounds (5a-k) were screened for their anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compounds 5g and 5j showed pronounced anti-inflammatory activity comparable to the reference standard nimesulide, whereas, compounds 5b, 5d and 5h displayed good anti-inflammatory activity. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity against two Gram-positive bacteria and two Gram-negative bacteria. Four compounds 5c, 5h-5j showed good broad spectrum activity against all the tested Gram-positive and Gram-negative bacterial strains. Compound 5j could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory and antibacterial profile.
|
Antiinflammatory activity in Wistar albino rat assessed as inhibition of carrageenan-induced paw edema at 4 mg/kg, po administered 30 mins before carrageenan challenge measured after 90 mins relative to control
|
Rattus norvegicus
|
45.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of some pyrazolylpyrazolines as anti-inflammatory-antimicrobial agents.
Year : 2010
Volume : 45
Issue : 6
First Page : 2650
Last Page : 2655
Authors : Sharma PK, Kumar S, Kumar P, Kaushik P, Kaushik D, Dhingra Y, Aneja KR.
Abstract : A new series of pyrazolylpyrazolines (5a-k) was synthesized by the reaction of appropriate chalcones (3a-k) with 4-hydrazinobenzenesulfonamide hydrochloride (4) in ethanol. All the newly synthesized target compounds (5a-k) were screened for their anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compounds 5g and 5j showed pronounced anti-inflammatory activity comparable to the reference standard nimesulide, whereas, compounds 5b, 5d and 5h displayed good anti-inflammatory activity. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity against two Gram-positive bacteria and two Gram-negative bacteria. Four compounds 5c, 5h-5j showed good broad spectrum activity against all the tested Gram-positive and Gram-negative bacterial strains. Compound 5j could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory and antibacterial profile.
|
Antiinflammatory activity in Wistar albino rat assessed as inhibition of carrageenan-induced paw edema at 4 mg/kg, po administered 30 mins before carrageenan challenge measured after 120 mins relative to control
|
Rattus norvegicus
|
36.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of some pyrazolylpyrazolines as anti-inflammatory-antimicrobial agents.
Year : 2010
Volume : 45
Issue : 6
First Page : 2650
Last Page : 2655
Authors : Sharma PK, Kumar S, Kumar P, Kaushik P, Kaushik D, Dhingra Y, Aneja KR.
Abstract : A new series of pyrazolylpyrazolines (5a-k) was synthesized by the reaction of appropriate chalcones (3a-k) with 4-hydrazinobenzenesulfonamide hydrochloride (4) in ethanol. All the newly synthesized target compounds (5a-k) were screened for their anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compounds 5g and 5j showed pronounced anti-inflammatory activity comparable to the reference standard nimesulide, whereas, compounds 5b, 5d and 5h displayed good anti-inflammatory activity. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity against two Gram-positive bacteria and two Gram-negative bacteria. Four compounds 5c, 5h-5j showed good broad spectrum activity against all the tested Gram-positive and Gram-negative bacterial strains. Compound 5j could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory and antibacterial profile.
|
Inhibition of ovine COX2 assessed as PGF2alpha level by EIA
|
Ovis aries
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Syntheses and characterization of nimesulide derivatives for dual enzyme inhibitors of both cyclooxygenase-1/2 and 5-lipoxygenase.
Year : 2011
Volume : 19
Issue : 6
First Page : 2074
Last Page : 2083
Authors : Li Y, Chen SH, Ou TM, Tan JH, Li D, Gu LQ, Huang ZS.
Abstract : Cyclooxygenase-1/2 (COX-1/2) and 5-lipoxygenase (5-LOX) are enzymes in two different pathways in the inflammatory process. In the present study, a variety of new nimesulide derivatives were synthesized through incorporation of a 5-LOX pharmacophore into nimesulide followed with some structural modifications, which were then characterized for dual enzyme inhibitors for these two types of enzymes. Their structure-activity relationships (SARs) were studied, and compound 20f was found to be an excellent dual enzyme inhibitor. Its binding conformation and interaction mode were studied with molecular docking experiments. Compound 20f could become a lead compound for further development for potential anti-inflammatory drugs.
|
Inhibition of purified COX2 assessed as formation of oxidized TMPD during reduction og PGG2 to PGH2 preincubated for 15 mins by chromogenic assay
|
None
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of dual target inhibitors against cyclooxygenases and leukotriene A4 hydrolyase.
Year : 2011
Volume : 54
Issue : 10
First Page : 3650
Last Page : 3660
Authors : Chen Z, Wu Y, Liu Y, Yang S, Chen Y, Lai L.
Abstract : Dual target inhibitors against COX-2 and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activities using enzyme assays and human whole blood assay. Introduction of small electron withdrawing groups like NO(2) and CF(3) in the ortho-position of the terminal phenyl ring was found to change the original single target LTA(4)H inhibitor to dual target LTA(4)H and COX-2 inhibitors. Compound 5a and 5m showed dual LTA(4)H and COX-2 inhibition activities in the enzyme assays and the HWB assay with IC(50) values in the micromolar to submicromolar range. As their activities in HWB assay were comparable to the two starting single target inhibitors, the two compounds are promising for further studies. The strategy used in the current study may be generally applicable to other dual target drug designs.
|
Antiinflammatory activity in rat assessed as inhibition of paw edema at 10 mg/kg
|
Rattus norvegicus
|
58.0
%
|
|
Journal : J. Med. Chem.
Title : Synopsis of some recent tactical application of bioisosteres in drug design.
Year : 2011
Volume : 54
Issue : 8
First Page : 2529
Last Page : 2591
Authors : Meanwell NA.
|
Inhibition of COX2
|
None
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Synopsis of some recent tactical application of bioisosteres in drug design.
Year : 2011
Volume : 54
Issue : 8
First Page : 2529
Last Page : 2591
Authors : Meanwell NA.
|
Anti-inflammatory activity in Rattus norvegicus Wistar albino (rat) assessed as inhibition of carrageenan-induced paw edema after 180 min (Rvb = 22.3%)
|
Rattus norvegicus
|
2.54
%
|
|
Journal : Med Chem Res
Title : Synthesis of pyrazole-based 1,5-diaryl compounds as potent anti-inflammatory agents
Year : 2012
Volume : 21
Issue : 9
First Page : 2465
Last Page : 2475
Authors : Shrivastava P, Singh P, Tewari AK
|
Anti-inflammatory activity in Rattus norvegicus Wistar albino (rat) assessed as inhibition of carrageenan-induced paw edema after 60 min (Rvb = 38.7%)
|
Rattus norvegicus
|
7.9
%
|
|
Journal : Med Chem Res
Title : Synthesis of pyrazole-based 1,5-diaryl compounds as potent anti-inflammatory agents
Year : 2012
Volume : 21
Issue : 9
First Page : 2465
Last Page : 2475
Authors : Shrivastava P, Singh P, Tewari AK
|
Anti-inflammatory activity in Rattus norvegicus Wistar albino (rat) assessed as inhibition of carrageenan-induced paw edema after 30 min (Rvb = 30.1%)
|
Rattus norvegicus
|
10.8
%
|
|
Journal : Med Chem Res
Title : Synthesis of pyrazole-based 1,5-diaryl compounds as potent anti-inflammatory agents
Year : 2012
Volume : 21
Issue : 9
First Page : 2465
Last Page : 2475
Authors : Shrivastava P, Singh P, Tewari AK
|
Inhibition of COX-2 (unknown origin)-mediated TMPD oxidation using PGG2 as substrate at 100 uM incubated 15 mins prior to substrate addition measured after 36 secs by spectrophotometric analysis
|
Homo sapiens
|
89.8
%
|
|
Journal : J. Med. Chem.
Title : Discovery of highly potent microsomal prostaglandin e2 synthase 1 inhibitors using the active conformation structural model and virtual screen.
Year : 2013
Volume : 56
Issue : 8
First Page : 3296
Last Page : 3309
Authors : He S, Li C, Liu Y, Lai L.
Abstract : Microsomal prostaglandin E2 synthase 1 (mPGES-1) has been identified as a promising drug target due to its key role in prostaglandin biosynthesis. However, the lack of a well-characterized structure constitutes a great challenge for the development of inhibitors. Recently, we have built a model for the active conformation of mPGES-1. In the present study, the model was used for structure-based virtual screen of novel mPGES-1 inhibitors. Of the 142 compounds tested in the cell-free assay, 10 molecules are highly potent with IC50 values of single digit nanomolar and the strongest inhibition of 1.1 nM. Moreover, nine compounds showed strong activity in the human whole blood (HWB) assay with IC50 values of less than 10 μM. The lead compounds 1 and 2 showed HWB IC50 values of 0.3 and 0.7 μM which are among the most potent mPGES-1 inhibitors reported. These compounds represent new scaffolds for future development of drugs against mPGES-1.
|
Inhibition of COX-1 (unknown origin)-mediated TMPD oxidation using PGG2 as substrate at 100 uM incubated 15 mins prior to substrate addition measured after 36 secs by spectrophotometric analysis
|
Homo sapiens
|
60.2
%
|
|
Journal : J. Med. Chem.
Title : Discovery of highly potent microsomal prostaglandin e2 synthase 1 inhibitors using the active conformation structural model and virtual screen.
Year : 2013
Volume : 56
Issue : 8
First Page : 3296
Last Page : 3309
Authors : He S, Li C, Liu Y, Lai L.
Abstract : Microsomal prostaglandin E2 synthase 1 (mPGES-1) has been identified as a promising drug target due to its key role in prostaglandin biosynthesis. However, the lack of a well-characterized structure constitutes a great challenge for the development of inhibitors. Recently, we have built a model for the active conformation of mPGES-1. In the present study, the model was used for structure-based virtual screen of novel mPGES-1 inhibitors. Of the 142 compounds tested in the cell-free assay, 10 molecules are highly potent with IC50 values of single digit nanomolar and the strongest inhibition of 1.1 nM. Moreover, nine compounds showed strong activity in the human whole blood (HWB) assay with IC50 values of less than 10 μM. The lead compounds 1 and 2 showed HWB IC50 values of 0.3 and 0.7 μM which are among the most potent mPGES-1 inhibitors reported. These compounds represent new scaffolds for future development of drugs against mPGES-1.
|
Inhibition of bovine brain tubulin polymerization at 100 uM after 20 mins by spectrophotometric analysis relative to control in presence of GTP
|
Bos taurus
|
14.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and anticancer mechanism investigation of dual Hsp27 and tubulin inhibitors.
Year : 2013
Volume : 56
Issue : 13
First Page : 5306
Last Page : 5320
Authors : Zhong B, Chennamaneni S, Lama R, Yi X, Geldenhuys WJ, Pink JJ, Dowlati A, Xu Y, Zhou A, Su B.
Abstract : Heat shock protein 27 (Hsp27) is a chaperone protein, and its expression is increased in response to various stress stimuli including anticancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anticancer drug development.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
82.48
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
58.26
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Antiinflammatory activity in Wistar rat lambda carrageenan-induced pleurisy model assessed as decrease in exudate volume at 20 mg/kg, ip pretreated for 30 mins followed by lambda carrageenan-challenge measured after 4 hrs relative to control
|
Rattus norvegicus
|
61.53
%
|
|
Journal : Eur. J. Med. Chem.
Title : N-(3-Arylaminopyridin-4-yl)alkanesulfonamides as pyridine analogs of nimesulide: cyclooxygenases inhibition, anti-inflammatory studies and insight on metabolism.
Year : 2014
Volume : 74
First Page : 12
Last Page : 22
Authors : Renard JF, Lecomte F, Hubert P, de Leval X, Pirotte B.
Abstract : Nimesulide, a COX-2 preferential inhibitor with a favorable gastric and cardiovascular safety profile, was responsible for some cases of acute liver failure attributed to the nitrobenzene ring. A series of analogs of nimesulide resulting from isosteric replacement of the nitrobenzene ring by the pyridine nucleus, was synthesized and their ability to inhibit both cyclooxygenases (COXs) isoforms was evaluated in vitro using a human whole blood model. Compounds 19c, 23b and 23c displayed an important inhibitory activity associated to a COX-2/COX-1 selectivity ratio similar to or higher than that of celecoxib. The anti-inflammatory activity and the ability of several compounds to decrease leukocyte infiltration were further evaluated in vivo in a model of a λ carrageenan-induced pleurisy. Plasma assays were performed on blood samples collected from rats and allowed us to identify the 4-position of the phenyl ring as a major metabolism site explaining the occasionally observed lack of correlation between in vitro and in vivo results.
|
Antiinflammatory activity in Wistar rat lambda carrageenan-induced pleurisy model assessed as decrease in exudate volume at 10 mg/kg, ip pretreated for 30 mins followed by lambda carrageenan-challenge measured after 4 hrs relative to control
|
Rattus norvegicus
|
48.44
%
|
|
Journal : Eur. J. Med. Chem.
Title : N-(3-Arylaminopyridin-4-yl)alkanesulfonamides as pyridine analogs of nimesulide: cyclooxygenases inhibition, anti-inflammatory studies and insight on metabolism.
Year : 2014
Volume : 74
First Page : 12
Last Page : 22
Authors : Renard JF, Lecomte F, Hubert P, de Leval X, Pirotte B.
Abstract : Nimesulide, a COX-2 preferential inhibitor with a favorable gastric and cardiovascular safety profile, was responsible for some cases of acute liver failure attributed to the nitrobenzene ring. A series of analogs of nimesulide resulting from isosteric replacement of the nitrobenzene ring by the pyridine nucleus, was synthesized and their ability to inhibit both cyclooxygenases (COXs) isoforms was evaluated in vitro using a human whole blood model. Compounds 19c, 23b and 23c displayed an important inhibitory activity associated to a COX-2/COX-1 selectivity ratio similar to or higher than that of celecoxib. The anti-inflammatory activity and the ability of several compounds to decrease leukocyte infiltration were further evaluated in vivo in a model of a λ carrageenan-induced pleurisy. Plasma assays were performed on blood samples collected from rats and allowed us to identify the 4-position of the phenyl ring as a major metabolism site explaining the occasionally observed lack of correlation between in vitro and in vivo results.
|
Antiinflammatory activity in Wistar rat lambda carrageenan-induced pleurisy model assessed as decrease in exudate volume at 5 mg/kg, ip pretreated for 30 mins followed by lambda carrageenan-challenge measured after 4 hrs relative to control
|
Rattus norvegicus
|
31.05
%
|
|
Journal : Eur. J. Med. Chem.
Title : N-(3-Arylaminopyridin-4-yl)alkanesulfonamides as pyridine analogs of nimesulide: cyclooxygenases inhibition, anti-inflammatory studies and insight on metabolism.
Year : 2014
Volume : 74
First Page : 12
Last Page : 22
Authors : Renard JF, Lecomte F, Hubert P, de Leval X, Pirotte B.
Abstract : Nimesulide, a COX-2 preferential inhibitor with a favorable gastric and cardiovascular safety profile, was responsible for some cases of acute liver failure attributed to the nitrobenzene ring. A series of analogs of nimesulide resulting from isosteric replacement of the nitrobenzene ring by the pyridine nucleus, was synthesized and their ability to inhibit both cyclooxygenases (COXs) isoforms was evaluated in vitro using a human whole blood model. Compounds 19c, 23b and 23c displayed an important inhibitory activity associated to a COX-2/COX-1 selectivity ratio similar to or higher than that of celecoxib. The anti-inflammatory activity and the ability of several compounds to decrease leukocyte infiltration were further evaluated in vivo in a model of a λ carrageenan-induced pleurisy. Plasma assays were performed on blood samples collected from rats and allowed us to identify the 4-position of the phenyl ring as a major metabolism site explaining the occasionally observed lack of correlation between in vitro and in vivo results.
|
Inhibition of COX-2 in human whole blood assessed as PGE2 level in plasma after 5 mins by enzyme immunoassay
|
Homo sapiens
|
700.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : N-(3-Arylaminopyridin-4-yl)alkanesulfonamides as pyridine analogs of nimesulide: cyclooxygenases inhibition, anti-inflammatory studies and insight on metabolism.
Year : 2014
Volume : 74
First Page : 12
Last Page : 22
Authors : Renard JF, Lecomte F, Hubert P, de Leval X, Pirotte B.
Abstract : Nimesulide, a COX-2 preferential inhibitor with a favorable gastric and cardiovascular safety profile, was responsible for some cases of acute liver failure attributed to the nitrobenzene ring. A series of analogs of nimesulide resulting from isosteric replacement of the nitrobenzene ring by the pyridine nucleus, was synthesized and their ability to inhibit both cyclooxygenases (COXs) isoforms was evaluated in vitro using a human whole blood model. Compounds 19c, 23b and 23c displayed an important inhibitory activity associated to a COX-2/COX-1 selectivity ratio similar to or higher than that of celecoxib. The anti-inflammatory activity and the ability of several compounds to decrease leukocyte infiltration were further evaluated in vivo in a model of a λ carrageenan-induced pleurisy. Plasma assays were performed on blood samples collected from rats and allowed us to identify the 4-position of the phenyl ring as a major metabolism site explaining the occasionally observed lack of correlation between in vitro and in vivo results.
|
Inhibition of human recombinant COX-2 assessed as PGF2-alpha formation using arachidonic acid as substrate at 20 uM by enzyme immunoassay
|
Homo sapiens
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Design of novel potent antihyperlipidemic agents with antioxidant/anti-inflammatory properties: exploiting phenothiazine's strong antioxidant activity.
Year : 2014
Volume : 57
Issue : 6
First Page : 2568
Last Page : 2581
Authors : Matralis AN, Kourounakis AP.
Abstract : Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis.
|
Inhibition of LPS/IFN-gamma-induced PGE2 production in mouse RAW264.7 cells after 17 to 20 hrs by enzyme immunoassay
|
Mus musculus
|
78.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines.
Year : 2016
Volume : 26
Issue : 10
First Page : 2531
Last Page : 2538
Authors : Mohd Aluwi MF, Rullah K, Yamin BM, Leong SW, Abdul Bahari MN, Lim SJ, Mohd Faudzi SM, Jalil J, Abas F, Mohd Fauzi N, Ismail NH, Jantan I, Lam KW.
Abstract : The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50=12.01μM and 8c, IC50=4.86μM) and U937 (8b, IC50=3.44μM and 8c, IC50=1.65μM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50=0.78μM and 15b, IC50=1.9μM while U937: 15a, IC50=0.95μM and 15b, IC50=0.92μM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-β, ERK, JNK2, p38α and p38β were performed using the conformation of 15a determined by single-crystal XRD.
|
Inhibition of LPS/IFN-gamma-induced PGE2 production in PMA-treated human U937 cells after 17 to 20 hrs by enzyme immunoassay
|
Homo sapiens
|
78.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines.
Year : 2016
Volume : 26
Issue : 10
First Page : 2531
Last Page : 2538
Authors : Mohd Aluwi MF, Rullah K, Yamin BM, Leong SW, Abdul Bahari MN, Lim SJ, Mohd Faudzi SM, Jalil J, Abas F, Mohd Fauzi N, Ismail NH, Jantan I, Lam KW.
Abstract : The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50=12.01μM and 8c, IC50=4.86μM) and U937 (8b, IC50=3.44μM and 8c, IC50=1.65μM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50=0.78μM and 15b, IC50=1.9μM while U937: 15a, IC50=0.95μM and 15b, IC50=0.92μM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-β, ERK, JNK2, p38α and p38β were performed using the conformation of 15a determined by single-crystal XRD.
|
Inhibition of LPS/IFN-gamma-induced PGE2 production in mouse RAW264.7 cells at 5 uM after 17 to 20 hrs by enzyme immunoassay relative to control
|
Mus musculus
|
66.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines.
Year : 2016
Volume : 26
Issue : 10
First Page : 2531
Last Page : 2538
Authors : Mohd Aluwi MF, Rullah K, Yamin BM, Leong SW, Abdul Bahari MN, Lim SJ, Mohd Faudzi SM, Jalil J, Abas F, Mohd Fauzi N, Ismail NH, Jantan I, Lam KW.
Abstract : The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50=12.01μM and 8c, IC50=4.86μM) and U937 (8b, IC50=3.44μM and 8c, IC50=1.65μM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50=0.78μM and 15b, IC50=1.9μM while U937: 15a, IC50=0.95μM and 15b, IC50=0.92μM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-β, ERK, JNK2, p38α and p38β were performed using the conformation of 15a determined by single-crystal XRD.
|
Inhibition of LPS/IFN-gamma-induced PGE2 production in PMA-treated human U937 cells at 5 uM after 17 to 20 hrs by enzyme immunoassay relative to control
|
Homo sapiens
|
89.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines.
Year : 2016
Volume : 26
Issue : 10
First Page : 2531
Last Page : 2538
Authors : Mohd Aluwi MF, Rullah K, Yamin BM, Leong SW, Abdul Bahari MN, Lim SJ, Mohd Faudzi SM, Jalil J, Abas F, Mohd Fauzi N, Ismail NH, Jantan I, Lam KW.
Abstract : The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50=12.01μM and 8c, IC50=4.86μM) and U937 (8b, IC50=3.44μM and 8c, IC50=1.65μM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50=0.78μM and 15b, IC50=1.9μM while U937: 15a, IC50=0.95μM and 15b, IC50=0.92μM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-β, ERK, JNK2, p38α and p38β were performed using the conformation of 15a determined by single-crystal XRD.
|
Inhibition of recombinant His-tagged PDE4B1 (unknown origin) expressed in baculovirus infected sf9 cells at 10 uM using cAMP as substrate preincubated for 15 mins followed by cAMP addition measured after 1 hr by PDE light HTS assay relative to control
|
Homo sapiens
|
52.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : 1,2,3-Triazole-nimesulide hybrid: Their design, synthesis and evaluation as potential anticancer agents.
Year : 2017
Volume : 27
Issue : 3
First Page : 518
Last Page : 523
Authors : Mareddy J, Suresh N, Kumar CG, Kapavarapu R, Jayasree A, Pal S.
Abstract : A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC50 ∼6-10μM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60-70% at 10μM) that was supported by the docking studies (PLP score 87-94) in silico.
|
Inhibition of human COX2 expressed in baculovirus infected sf9 microsomes at 10 uM using arachidonic acid as substrate preincubated for 15 mins followed by substrate addition by TMPD oxidation based assay relative to control
|
Homo sapiens
|
90.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : 1,2,3-Triazole-nimesulide hybrid: Their design, synthesis and evaluation as potential anticancer agents.
Year : 2017
Volume : 27
Issue : 3
First Page : 518
Last Page : 523
Authors : Mareddy J, Suresh N, Kumar CG, Kapavarapu R, Jayasree A, Pal S.
Abstract : A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC50 ∼6-10μM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60-70% at 10μM) that was supported by the docking studies (PLP score 87-94) in silico.
|
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
|
2.52
%
|
|
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.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-0.4225
%
|
|
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
|
-0.13
%
|
|
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
|
-0.13
%
|
|
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 COX-2 (unknown origin) using arachidonic acid as substrate at 1000 uM measured after 10 mins by fluorometric based multimode microplate reader relative to control
|
Homo sapiens
|
97.82
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological assessment of new selective COX-2 inhibitors including methyl sulfonyl moiety.
Year : 2021
Volume : 209
First Page : 112918
Last Page : 112918
Authors : Sağlık BN,Osmaniye D,Levent S,Çevik UA,Çavuşoğlu BK,Özkay Y,Kaplancıklı ZA
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as H NMR, C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a, 3e, 3f, 3g, 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies.
|
Inhibition of COX-2 (unknown origin) using arachidonic acid as substrate at 100 uM measured after 10 mins by fluorometric based multimode microplate reader relative to control
|
Homo sapiens
|
89.58
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological assessment of new selective COX-2 inhibitors including methyl sulfonyl moiety.
Year : 2021
Volume : 209
First Page : 112918
Last Page : 112918
Authors : Sağlık BN,Osmaniye D,Levent S,Çevik UA,Çavuşoğlu BK,Özkay Y,Kaplancıklı ZA
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as H NMR, C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a, 3e, 3f, 3g, 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies.
|
Inhibition of COX-2 (unknown origin) using arachidonic acid as substrate at 10 uM measured after 10 mins by fluorometric based multimode microplate reader relative to control
|
Homo sapiens
|
78.69
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological assessment of new selective COX-2 inhibitors including methyl sulfonyl moiety.
Year : 2021
Volume : 209
First Page : 112918
Last Page : 112918
Authors : Sağlık BN,Osmaniye D,Levent S,Çevik UA,Çavuşoğlu BK,Özkay Y,Kaplancıklı ZA
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as H NMR, C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a, 3e, 3f, 3g, 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies.
|
Inhibition of COX-2 (unknown origin) using arachidonic acid as substrate at 1 uM measured after 10 mins by fluorometric based multimode microplate reader relative to control
|
Homo sapiens
|
48.28
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological assessment of new selective COX-2 inhibitors including methyl sulfonyl moiety.
Year : 2021
Volume : 209
First Page : 112918
Last Page : 112918
Authors : Sağlık BN,Osmaniye D,Levent S,Çevik UA,Çavuşoğlu BK,Özkay Y,Kaplancıklı ZA
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as H NMR, C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a, 3e, 3f, 3g, 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies.
|
Inhibition of COX-2 (unknown origin) using arachidonic acid as substrate at 0.1 uM measured after 10 mins by fluorometric based multimode microplate reader relative to control
|
Homo sapiens
|
32.98
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological assessment of new selective COX-2 inhibitors including methyl sulfonyl moiety.
Year : 2021
Volume : 209
First Page : 112918
Last Page : 112918
Authors : Sağlık BN,Osmaniye D,Levent S,Çevik UA,Çavuşoğlu BK,Özkay Y,Kaplancıklı ZA
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as H NMR, C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a, 3e, 3f, 3g, 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies.
|
Inhibition of COX-2 (unknown origin) using arachidonic acid as substrate at 0.01 uM measured after 10 mins by fluorometric based multimode microplate reader relative to control
|
Homo sapiens
|
21.3
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological assessment of new selective COX-2 inhibitors including methyl sulfonyl moiety.
Year : 2021
Volume : 209
First Page : 112918
Last Page : 112918
Authors : Sağlık BN,Osmaniye D,Levent S,Çevik UA,Çavuşoğlu BK,Özkay Y,Kaplancıklı ZA
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as H NMR, C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a, 3e, 3f, 3g, 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies.
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Inhibition of COX-2 (unknown origin) using arachidonic acid as substrate at 0.001 uM measured after 10 mins by fluorometric based multimode microplate reader relative to control
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Homo sapiens
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14.12
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Journal : Eur J Med Chem
Title : Design, synthesis and biological assessment of new selective COX-2 inhibitors including methyl sulfonyl moiety.
Year : 2021
Volume : 209
First Page : 112918
Last Page : 112918
Authors : Sağlık BN,Osmaniye D,Levent S,Çevik UA,Çavuşoğlu BK,Özkay Y,Kaplancıklı ZA
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as H NMR, C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a, 3e, 3f, 3g, 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies.
