Selective cyclooxygenase inhibition and ulcerogenic liability of some newly prepared anti-inflammatory agents having thiazolo[4,5-d]pyrimidine scaffold

Article abstract of DOI:10.1016/j.bioorg.2019.102964

Novel candidates of thiazolo[4,5-d]pyrimidines (9a-l)were synthesized and their structures were elucidated by spectral and elemental analyses. All the novel derivatives were screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity, especially 1-(4-[7-(4-nitrophenyl)-5-thioxo-5,6-dihydro-3H-thiazolo[4,5-d]pyrimidin-2-ylideneamino]phenyl)ethanone (9g)was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively. Furthermore, this derivative 9g recorded higher anti-inflammatory activity than celecoxib which showed 43%, 43% and 54% inhibition after 1, 3 and 5h, sequentially. Moreover, the target derivatives 9a-l demonstrated moderate to high potent inhibitory action towards COX-2 (IC₅₀ = 0.87–3.78 μM), in particular, the derivatives 9e (IC₅₀ = 0.92 μM), 9g (IC₅₀ = 0.87 μM)and 9k (IC₅₀ = 1.02 μM)recorded higher COX-2 inhibitory effect than the selective COX-2 inhibitor drug celecoxib (IC₅₀ = 1.11 μM). The in vivo potent compounds (9e, 9g and 9k)caused variable ulceration effect (ulcer index = 5–12.25)in comparison to that of celecoxib (ulcer index = 3). Molecular docking was performed to the most potent COX-2 inhibitors (9e, 9g and 9k)to explore the binding mode of these derivatives with Cyclooxygenase-2 enzyme.