Novel Mefenamic Acid Analogs Featuring 4-Thiazolidinone Moiety: Design, Synthesis, In Silico Modeling and Biological Evaluation

In this work, a novel series of mefenamic acid analogs were developed and synthesized with the goal of developing a lead chemical that has anti-inflammatory efficacy and avoids the adverse effects of NSAIDs. Molecular docking analysis was performed by recruiting the ligands, COX-1 and COX-2 to identify the best-fitted molecule using AutoDock software. Afterwards, the compounds were synthesized and analyzed. To assess the drug's efficacy, the compounds were subjected to in vivo analgesic and anti-inflammatory experiments. Most of synthesized ligands have greater binding free energy than mefenamic acid on COX-1. When compared to the positive control, the compounds 2-(2,3-dimethylphenylamino)-N-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxothiazolidin-3-yl) benzamide, 2-(2,3-dimethylphenylamino)-N-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)benzamide, 2-(2, 3-dimethylphenylamino)-N-(4-oxo-2-p-tolylthiazolidin-3-yl) benzamide and 2-(2,3-dimethylphenylamino)-N-(2-(4-chlorophenyl)-4-oxothiazolidin-3-yl) benzamide, 2-(2,3-dimethylphenylamino)-N-(2-(4-nitrophenyl)-4-oxothiazolidin-3-yl)benzamide demonstrated a larger or comparable proportion of analgesic and anti-inflammatory action respectively. Furthermore, the selected compounds “2-(2,3-dimethylphenylamino)-N-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxothiazolidin-3-yl) benzamide”, and “2-(2,3-dimethylphenylamino)-N-(4-oxo-2-p-tolylthiazolidin-3-yl) benzamide” seemed to have the least ulcerogenic activity. These findings show that some of the newly created mefenamic acid analogs may be selected as lead compounds due to their significant biological properties without ulcerogenic activity.