Design, Synthesis & Biological Evaluation of Novel Spiro-isoxazolin Derivatives as Selective COX-2 Inhibitors and their QSAR studies

Abstract

Selective COX-2 inhibitors are used as analgesic, anti-pyretic and anti-inflammatory agents. Moreover, COX-2 inhibitors have emerged in recent years as candidates for drugs due to their anti-cancer activity. Nowadays Cancer is one of the leading causes of death worldwide, so design and synthesis of compounds with dual cytotoxic mechanism (anti-tubulin and COX-2 inhibitory effects) is very valuable. In this study based on the structure-activity relationship of selective COX-2 inhibitors, new Isoxazoline and spiroisoxazoline derivatives were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors by Cayman kit and some new spiroisoxazoline derivatives were designed and synthesized based on the structure-activity relationship of antitubulins, for evaluation as cytotoxic agents by MTT assay. New spiroisoxazoline hybrid structures encompassing pharmacophores of antitubulins and COX-2 inhibitors were designed and synthesized. These derivatives were synthesized using different reactions and docking studies were performed using GOLD software and finally molecular structures of the synthesized compounds have been confirmed by IR, 1HNMR, 13CNMR, Mass spectroscopy and X-ray Crystallography. Cytotoxic effects of some synthesized compounds were evaluated on MCF7, T47D, HT29 and HFF cell lines. Also QSAR studies of selective COX-2 inhibitors were done by 21 compounds. Based on the results of biological evaluations, most of the synthesized compounds as selective COX-2 inhibitors inhibited COX-2 selectively and some of them showed strong antiproliferative activities at submicromolar concentrations on MCF7 and T47D cancer cells. QSAR studies provide prediction of selective COX-2 inhibitor activity for diaryl Isoxazoline and spiroisoxazoline derivatives. The results of this study propose that Isoxazoline and spiroisoxazoline derivatives are suitable scaffolds for designing new anti-cancer agents with antiproliferative and anti-COX-2 activities.