Design and synthesis of thiazolidin-4-one–ketoprofen hybrids as potential COX-2 inhibitors with anti-inflammatory activity

Several ketoprofen thiazolidin-4-one hybrids were designed and evaluated to determine whether they could be used as anti-inflammatory drugs. The synthesis involved converting ketoprofen into the methyl ester and hydrazide. Then, the hydrazide was reacted with different benzaldehydes to produce hydrazones, and finally, cyclization with thioglycolic acid produced the thiazolidin-4-one derivatives. FT-IR, 1 H NMR, and 13 C NMR spectroscopy were used to determine the structures. In silico ADME predictions showed that the compounds had generally acceptable drug-like properties. All derivatives had a molecular weight below 500 Da, and the predicted values for human oral absorption ranged from 87.473% to 100%. Solubility, however, was identified as a possible problem for several analogues. Molecular docking against COX-2 (PDB ID: 5KIR) showed good binding across the series. AR1 had the best GOLD PLP fitness score (81.10), AR5 had the best Glide XP score (–13.685), AR3 had the best IFD score (–2435.132), and AR7 had the best MM-GBSA binding energy (Δ G bind = –73.136). The molecular dynamics simulation of the AR1–COX-2 complex spanning 100.102 ns supported a stable protein–ligand association during the simulated timescale, with ongoing interactions involving Tyr385, Tyr355, Arg120, and Glu524. The anti-inflammatory effects were evaluated in vivo using the egg-white-induced paw edema model in mice. The longitudinal mixed-effects analysis indicated significant influences of treatment, duration, and the interaction between treatment and time. AR3 showed the most consistent late-phase anti-edema activity, including greater efficacy than ketoprofen at the 240 min time point, whereas AR1 remained notable mainly because of its strong computational profile and late-phase activity vs. vehicle control. These results collectively suggest that ketoprofen-derived thiazolidin-4-one hybrids, particularly AR3 and AR1, merit further investigation as potential anti-inflammatory agents, with AR3 prioritized mainly by in vivo activity and AR1 supported by computational evidence.