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

• Published in: Bioorganic chemistry Vol. 88; pp. 102964 - 102972
• Main Authors: Bakr, Rania B., Ghoneim, Amira A., Azouz, Amany A.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.07.2019; Elsevier
• Subjects: Anti-inflammatory; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Cox-2 inhibitors; Life Sciences & Biomedicine; Physical Sciences; Science & Technology; Thiazolidine; Thiazolo[4,5-d]pyrimidine; Cox-2 inhibitors; Thiazolo[4,5-d]pyrimidine; Anti-inflammatory; Thiazolidine; PYRIMIDINE-DERIVATIVES; Thiazolo[4,5-d] pyrimidine; MOIETIES; DISCOVERY; HYBRID
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.102964

New thiazolo[4,5-d]pyrimidines (9a-l) were prepared and screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity; especially 9g was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively. [Display omitted] •Novel candidates of thiazolo[4,5-d]pyrimidines (9a-l) were synthesized.•The target compound 9g was the most active derivative.•The target derivatives 9a-l demonstrated moderate to high potent inhibitory action towards COX-2.•The target compound (9e) recorded the lowest ulcerogenic effect (Ulcer index = 5). 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.