Design, Synthesis and Pharmacological Screening of Heterocyclic Molecules as Selective COZ-2 Inhibitors

Abstract

Drug induced gastrointestinal ulceration, renal; Hepatotoxicity and cardiovascular stroke are the leading causes due to which many NSAIDs have been withdrawn from the market. Also it has been associated with erectile dysfunction and defects in ovulatory action. COX-2 inhibitors developed to reduce the gastrointestinal issues but other cardiovascular problems occured in this advent. Thus many new methods and strategies were developed wherein structural modifications of the existing drugs were done. Main change was done in the free carboxylic group of the NSAIDs which was modified into various acid derivatives. All these changes were done so that the efficacy of the drugs improves, selectivity increases and toxicity decreases. In this study according molecular docking studies of designed compounds were done using PDB ID- 4PH9 for Mefenamic acid and 3NT1 for Indomethacin. Molecules showed high scores and maximum interaction. Synthesis using DCC/DMAP coupling was done. In-vivo screening of compounds with high GOLD score such as JS-AMA, JS-OCA, JS-AP, JS- PAN, JS-PTOL showed maximum inhibition. Comparing the results of docking and In- vivo screening it was found that amide derivatives of parent NSAIDs are more selective, potent and shows less side-effect.