ABSTRACT
ortho-Acylation attempt of benzenesulfonamide afforded the corresponding hemiaminal as major product. The in situ reduction of the reaction mixture, reported herein, directly provided 2-hydroxyalkyl benzenesulfonamide, an important pharmacophoric element for designing drug-like scaffolds. Its application is demonstrated through designing a novel series of 1,5-diarylpyrazoles for cyclooxygenase-2 (COX-2) inhibition.
Subject(s)
Aldehydes/chemistry , Alkanes/chemistry , Sulfonamides/chemistry , gamma-Aminobutyric Acid , Carbonic Anhydrase Inhibitors/chemistry , Chemistry, Pharmaceutical , Drug Design , Models, Molecular , Molecular Structure , Oxidation-Reduction , BenzenesulfonamidesABSTRACT
Diverse analogs of 1,5-diarylpyrazoles having 3-hydroxymethyl-4-sulfamoyl (SO2NH2)/methyl sulfonyl (SO2Me)-pheny group at N1 were synthesized and evaluated for their in vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The SAR study mainly involved the variations at positions C-3, C-5 and N1 of the pyrazole ring. Several small hydrophobic groups at/around position-4 of C-5 phenyl, viz. 3,4-dimethylphenyl analog 9, 3-methyl-4-methylsulfanylphenyl analog 14 and 2,3-dihydrobenzo[b]thiophenyl analog 17, exhibited impressive COX-2 inhibitory potency. In general, the sulfonamide analogues with a CHF2 at C-3 were found to be more potent than those having a CF3 group. The three dimensional quantitative structure activity relationship comprising comparative molecular field analysis (3D-QSAR-CoMFA) afforded the models with high predictivity which further validated the acceptance of hydroxymethyl (CH2OH) group in the hydrophilic pocket of the COX-2 enzyme.
Subject(s)
Cyclooxygenase 2/metabolism , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Cyclooxygenase Inhibitors/chemistry , Inhibitory Concentration 50 , Molecular Structure , Pyrazoles/chemical synthesis , Quantitative Structure-Activity Relationship , Structure-Activity RelationshipABSTRACT
Several 2,3-diaryl pyrazines and quinoxalines with 4-sulfamoyl (SO(2)NH(2))/methylsulfonyl (SO(2)Me)-phenyl pharmacophores have been synthesized and evaluated for the cyclooxygenase (COX-1/COX-2) inhibitory activity. Smaller groups such as methoxy, methyl and fluoro when substituted at/around position-4 of the adjacent phenyl ring, have great impact on the selective COX-2 inhibitory activity of the series. Many potential compounds were obtained from a brief structure-activity relationship (SAR) study. Two of these, compounds 11 and 25 exhibited excellent in vivo activity in the established animal model of inflammation. Since compound 25 possessed an amenable sulfonamide group, two of its prodrugs 48 and 49 were also synthesized. Both of them have excellent in vivo potential, and represent a new class of COX-2 inhibitor.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Isoenzymes/antagonists & inhibitors , Pyrazines/chemical synthesis , Quinoxalines/chemical synthesis , Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Cyclooxygenase Inhibitors/therapeutic use , Drug Evaluation, Preclinical/methods , Edema/drug therapy , Edema/enzymology , Isoenzymes/metabolism , Male , Prostaglandin-Endoperoxide Synthases/metabolism , Pyrazines/pharmacology , Pyrazines/therapeutic use , Quinoxalines/pharmacology , Quinoxalines/therapeutic use , Rats , Rats, WistarABSTRACT
Several thiazolidinediones having chroman moieties were synthesized and evaluated for their euglycemic and hypolipidemic activities. Some of the analogues having an aminoalkyl group as a linker between the chroman ring and 4-[5-(2,4-dioxo-1, 3-thiazolidinyl)methyl]phenoxy moiety seem to be better than troglitazone. In vitro transactivation assays of PPARgamma have been carried out with these glitazones to understand their molecular mechanism. For the first time we have found that some of the unsaturated thiazolidinediones are superior to their saturated counterpart in the in vivo assay. A more potent thiazolidinedione analogue than troglitazone is reported. Pharmacokinetic studies have shown that protection of the OH group in the chroman moiety leads to a decrease in metabolism, thereby resulting in a superior pharmacological profile.
Subject(s)
Chromans/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Thiazoles/chemical synthesis , Animals , Blood Glucose/metabolism , Chromans/chemistry , Chromans/pharmacokinetics , Chromans/pharmacology , Female , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Male , Mice , Mice, Inbred C57BL , Rats , Rats, Wistar , Receptors, Cytoplasmic and Nuclear/agonists , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Transcription Factors/agonists , Triglycerides/bloodABSTRACT
Several thiazolidinediones having antioxidant moities in their structural motif have been synthesised and evaluated for their euglycemic and hypolipidemic activities. A few of them have been found to be superior to troglitazone.