DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF ISOXAZOLE-CARBOXAMIDE DERIVATIVES AS COX INHIBITORS

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most utilized line of drugs as a factor for reducing swelling, uncomfortable feel, and fever. They act as competitive inhibitors of the cyclooxygenase enzyme (COX). Here, in this thesis, eight novel pyrazole-carboxamide derivatives were produced, specified, and increased for their selectivity and potency at COX-1 and COX-2 by an in vitro COX inhibition assay kit. MTS assay was used to estimate the cytotoxicity of these compounds against human normal cell lines (Hek293T) and hepatic cell lines (LX-2). All recently synthesized compounds were identified utilizing FTIR, HRMS, 1H-NMR, and 13C-NMR techniques. HRMS results were rational and all derivatives were verified and masses corresponding to the calculated masses. NMR results indicate a successful synthesis and were found to be consistent with the research outputs. Based on the results, it was determined that 3b, with an IC50 value of 0.46±0.25 µM, was the most potent inhibitory agent against COX-1 enzyme. Additionally, it showed a potent COX-2 inhibitory effect with an IC50 value of 3.82 ±1.36 µM. On the other hand, the highest selectivity against COX-2 ratio (1.68) was for compound 3g, with the highest effectiveness against COX-2 also (IC50 = 2.65±1.55 µM) in comparison to ketoprofen selectivity ratio was (0.21) ,and it’s IC50 against COX-2 = 0.164±0.12 µM. The 3d compound demonstrated strong COX-2 selectivity as well. (1.14) with an IC50 of 4.92±2.29 µM. Negligible cytotoxic activities against the utilized normal cell lines while 3a showed cytotoxicity against CaCo2, MCF-7, and HepG2 cancer cell lines. Finally, we recommend doing docking studies of the synthesized compounds for better understanding of the structure-activity relationship and improve COX2 selectivity.