Anti-inflammatory effect of 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole derivatives as p38α inhibitors

Abstract

In the present work, the anti-inflammatory effect of 30 compounds containing 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole was investigated. All final target compounds showed significant Inhibitory effect on p38α. P38α is considered one of the key kinases in the inflammatory process due to its regulatory effect on pro-inflammatory mediators. The final target compounds divided into four group based on the type of terminal moiety (amide and sulfonamide) and the linker between pyrimidine ring and terminal moiety (ethyl and propyl). Most compounds with terminal sulfonamide moiety and propyl linker between the sulfonamide and pyrimidine ring were the most potent among all synthesized final target compounds with sub-micromolar IC_50s. Compound 24g (with p-Cl benzene sulfonamide and propyl linker) exhibited the highest activity over P38α with IC₅₀ 0.68 µM. All final target compounds were tested for their ability to inhibit nitric oxide release and prostaglandin E2 production. Compounds having amide terminal moiety with ethyl linker showed higher inhibitory activity for nitric oxide release and compound 21d exhibited the highest activity for nitric oxide release with IC₅₀ 1.21 µM. Compounds with terminal sulfonamide moiety and propyl linker showed the highest activity for inhibiting PGE2 production and compounds 24i and 24g had the lowest IC_50s with value 0.87 and 0.89 µM, respectively. Compounds 21d, 22d and 24g were tested for their ability to inhibit over expression of iNOS, COX1, and COX2. In addition the ability of compounds 21d, 22d and 24g to inhibit inflammatory cytokines were determined. Finally molecular docking of the three compounds were performed on P38α crystal structure to expect their mode of binding.

Keywords: Amide; Antiinflammatory; P38α inhibitors; Sulfonamide, pyrimidinylimidazo[2,1-b]thiazole.