Synthesis, Biological Activity, Molecular Modelling Studies and 3D-QSAR Investigations of N-[2-(aryl/substituted aryl)-4-oxo-1, 3-thiazolidin-3-yl] pyridine-4-carboxamides

In the present research work new 4-thiazolidinones possessing dual cyclooxygenase/lipoxygenase inhibition were synthesized. Sixteen N-[2-(aryl/substitutedaryl)-4-oxo-1,3-thiazolidin-3-yl]pyridine-4-carboxamide derivatives(5a-q) differing by the phenyl group substitution were synthesized by sonication. Compounds N-[2-(4-chlorophenyl)-4-oxo-1, 3thiazolidin-3-yl] pyridine-4-carboxamide (5d) and N-[2-(4-nitrophenyl)-4-oxo-1, 3-thiazolidin-3-yl] pyridine-4-carboxamide (5f) showed promising anti-inflammatory activity investigated by the carrageenan induced edema model in rats. Compound 5f, was the most active in the series with low ulcerogenic index and good safety profile with highest in vitro inhibition of COX-1/COX-2 (89.28; 52.80%, p<0.01) with 27.36% inhibition of 15-LOX. Compounds 5d and 5f, at the dose of 100mg/kg p.o. were also effective in lowering the elevated levels of AST, ALT and ALP in serum and also lowered the elevated levels of MPO in edematous tissue comparable to standard anti-inflammatory drug, Indomethacin. The Autodock investigation of the synthesized compounds within the COX and LOX enzymes predicted fairly good correlation between the anti-inflammatory activities (IC50) and their binding affinities. The 3D-QSAR studies (V-Life Molecular Design Software) of the synthesized 4-thiazolidinones for their anti-inflammatory activity by the developed kNN, PLRS and MLR models suggested that presence of electron withdrawing functional groups like -NO2,-Cl on the phenyl ring were favourable for activity. The results of the present study may help to identify the relative positions and ranges of important electrostatic and steric fields at various positions around the pharmacophore that could be useful in the design of new molecules with improved anti-inflammatory activity.