Synthesis, evaluation and docking studies of some 4-thiazolone derivatives as effective lipoxygenase inhibitors
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Some promising 4-thiazolone derivatives as lipoxygenase inhibitors were designed, synthesized, characterized and evaluated for anti-inflammatory activity and respective ulcerogenic liabilities. Compounds (1b, 1e, 3b, and 3e) exhibited considerable in vivo anti-inflammatory activity (57.61, 79.35, 75.00, and 79.35%) against carrageenan-induced rat paw edema model, whereas compounds (1e, 3b, and 3e) were found active against the arachidonic acid-induced paw edema model (55.38, 55.38, and 58.46%). The most potent compound (3e) exhibited lesser ulcerogenic liability compared to the standard diclofenac and zileuton. Further, the promising compounds (1e and 3e) were evaluated for in vitro lipoxygenase (LOX; IC50 = 12.98 µM and IC50 = 12.67 µM) and cyclooxygenase (COX) inhibition assay (COX-1; IC50 > 50 µM and, COX-2; IC50 > 50 µM). The enzyme kinetics of compound 3e was evaluated against LOX enzyme and supported by in silico molecular docking and molecular dynamics simulations studies. Overall, the results substantiated that 5-benzylidene-2-phenyl-4-thiazolones are promising pharmacophore for anti-inflammatory activity.
Keywords4-Thiazolone One-pot multicomponent reaction Anti-inflammatory Lipoxygenase
The authors gratefully acknowledge Indian Institute of Technology (BHU) for providing financial assistance through Institute Research Project (IRP) scheme and Design Innovation Center (DIC) scheme. Grant No. IIT (BHU)/R&D/IRP/2015-16/3471/L and Grant No. DIC-IIT(BHU)/L-11, respectively. The authors are also thankful to Department of Health Research, Ministry of Health and Family Welfare for providing the Young Scientist Project in newer areas of Drugs Chemistry (DHR/HRD/YS-15-2015-16).
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