Design, Synthesis, Molecular docking, and biological evaluation of novel 2,3-diaryl-1,3-thiazolidine-4-one derivatives as potential anti-inflammatory and cytotoxic agents

A new series of 2,3-diaryl-1,3thiazolidin-4-one derivatives was designed, synthesized, and evaluated for their cytotoxicity and COXs inhibitory activities. Among these derivatives, compounds 4 k and 4j exhibited the highest inhibitory activities against COX-2 at IC50 values of 0.05 and 0.06 mu M, respectively. Compounds 4a, 4b, 4e, 4 g, 4j, 4 k, 5b, and 6b, which exhibited the highest inhibition% against COX-2, were evaluated for their anti-inflammatory activity in rats. Results showed 41.08-82.00 % inhibition of paw edema thickness by the test compounds compared to celecoxib (inhibition% = 89.51 %). In addition, compounds 4b, 4j, 4 k, and 6b exhibited better GIT safety profiles compared to celecoxib and indomethacin. The four compounds were also evaluated for their antioxidant activity. The results revealed the highest antioxidant activity for 4j (IC50 = 45.27 mu M) comparable to torolox (IC50 = 62.03 mu M). The antiproliferative activity of the new compounds was eval-uated against HePG-2, HCT-116, MCF-7, and PC-3 cancer cell lines. The results showed the highest cytotoxicity for compounds 4b, 4j, 4 k, and 6b (IC50 = 2.31-27.19 mu M), with 4j being the most potent. Mechanistic studies revealed the ability of 4j and 4 k by inducing marked apoptosis and cell cycle arrest at the G1 phase in HePG-2 cancer cells. These biological results may also suggest a role for COX-2 inhibition in the antiproliferative activity of these compounds. The results of the molecular docking study for 4 k and 4j into the active site of COX-2 revealed good fitting and correlation with the results of the in vitro COX-2 inhibition assay.

Automated summary

A series of 2,3-diaryl-1,3thiazolidin-4-one derivatives were synthesized and evaluated for their cytotoxicity and COXs inhibitory activities. Compounds 4k and 4j exhibited the highest inhibitory activities against COX-2, while compounds 4b, 4j, 4k, and 6b showed promising anti-proliferative activity against cancer cells. These compounds also demonstrated good antioxidant activity. The molecular docking study confirmed the binding affinity of compounds 4k and 4j to the active site of COX-2.