Identification and development of thiazole leads as COX-2/5-LOX inhibitors through in-vitro and in-vivo biological...

Treatment of inflammation using NSAIDs is coupled with a risk of severe gastric adverse events. Development of dual COX-2/5-LOX inhibitors turns out to be an imperative area devoted to safer NSAIDs. A series of thiourea, thiazole, and thiazolidene derivatives were synthesized by green synthetic approach and COX-1, COX-2 and 5-LOX inhibition screening resulted in the identification of a potent compound 6l with IC₅₀ of 5.55 µM, 0.09 µM, and 0.38 µM respectively. Compound 6l made significant decrease (60.82%) in the carrageenan-induced edema in male Wistar rats. qRT-PCR analysis and determination of PGE₂ and LTB₄ in the rat paw tissues indicated that this thiazole based dual inhibitor significantly reduced the expression of COX-2 and 5-LOX genes besides the marked reduction in both PGE₂ and LTB₄ levels. The gastric safety profiling revealed an enhanced gastrointestinal safety of the compound 6l on histopathological examination. Molecular docking studies at COX-2 and 5-LOX active sites were consistent with biological studies by significant protein-ligand interaction. Besides, results of in-vitro PGE₂ and LTB₄ studies on RAW 264.7 cells as well as antioxidant studies were parallel to the dual inhibitory activity. The present investigations identify a promising lead having anti-inflammatory potential with an improved gastric safety profile.