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 mu M), IVc (IC50=2.4 +/- 1.3 mu M), IVd (IC50=5.0 +/- 0.6 mu M), and IVg (IC50=10.4 +/- 4.6 mu M) have shown potent anti-inflammatory activity, several fold more active than the standard drug, ibuprofen (IC50=11.2 +/- 1.9 mu M). Whereas, compounds IVa (IC50=18.0 +/- 1.1 mu M), and IVh (IC50=26.0 +/- 3.4 mu M) 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 mu M) 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.