Synthesis of Oxindole Analogues, Biological Activity, and In Silico Studies

Highly divergent complexity molecules, having spirooxindole core structure, possess excellent bioactivities. The 1,3‐dipolar cycloaddition reaction is one of the most efficient approach for the rapid synthesis of spirooxindole analogues. Herein, we report the synthesis of a series of spirooxindolone analogues via multicomponent reaction of chalcone, based on cyclohexanone, substituted isatin (isatin, 5‐Cl‐isatin, and 5‐Br‐isatin), and secondary amine of the amino acids (L‐Proline and Thioproline). The included activities of the resulting spirooxazolines, including anti‐inflammatory, anti‐leishmanial, and cytotoxic activity against 3T3 and HeLa cell lines. Among series of nine diphenyl substituted derivatives of spiro fused benzylidine thioazol indolines (IVa–IVi), compounds IVb (IC50=5.8±0.9 μM), IVc (IC50=2.4±1.3 μM), IVd (IC50=5.0±0.6 μM), and IVg (IC50=10.4±4.6 μM) have shown potent anti‐inflammatory activity, several fold more active than the standard drug, ibuprofen (IC50=11.2±1.9 μM). Whereas, compounds IVa (IC50=18.0±1.1 μM), and IVh (IC50=26.0±3.4 μM) exhibited a significant anti‐inflammatory potential. All other compounds (IVe and IVf) were found to be inactive. Two meta flouro substituted phenyl rings containing compound IVc (IC50=2.4±1.3 μM) was the most potent member of the series. In order to rationalize the observed biological activities of the spirooxindole‐pyrrolothiazole derivatives, in silico studies were also performed. The results of present study identify a new series of potent anti‐inflammatory agents, deserve to be further investigated as leads. Small library encompasses spirooxindole derivatives were reported. The anti‐inflammatory, anti‐leishmanial and anti‐proliferative activities for the synthesized compounds were tested. Compounds IVc (IC50=2.4±1.3 μM), and IVc (IC50=2.4±1.3 μM) shown potent anti‐inflammatory activity and appeared several fold more active than the tested standard ibuprofen (IC50=11.2±1.9 μM). These results, may deserve further consideration for development new derivatives as potent anti‐inflammatory agents.