LAUSR

A new series of pyrimidine-5-carbonitrile derivatives 8a-p carrying the 1,3-thiazole moiety has been designed and synthesized as novel anti-inflammatory EGFR inhibitors with cardiac and gastric safety profiles. 8a-p have been assessed for their inhibitory activity against COX-1/COX-2 activity. Compounds 8h, 8n, and 8p were found to be potent and selective COX-2 inhibitors (IC50 = 1.03-1.71 μM) relative to celecoxib (IC50 = 0.88 μM). The most potent COX-2 inhibitors have been further investigated for their in-vivo anti-inflammatory effect. Compounds 8h, 8n, and 8p showed anti-inflammatory activity up to 90%, 94% and 86% of meloxicam after 4 h interval. 8h, 8n, and 8p showed higher gastric safety profiles than meloxicam. A substantial reduction in serum concentrations of PGE2, TNF-α, IL-6, iNO and MDA and a significant induction of TAC was also observed. In vivo experiments on heart rate and blood pressure established the cardiovascular safety profile of 8h, 8n, and 8p. Anti-proliferative and wild-type EGFR inhibitory assays displayed similar results to selective COX-2 inhibition where compounds 8h, 8n, and 8p had a superior inhibition than other tested ones. Molecular docking study demonstrated that these compounds revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to enter the side pocket selectively. Also, they interacted with EGFR tyrosine kinase main amino acids similar to erlotinib with a strong binding energy score.