Synthesis and Evaluation of Bioactivity of 6-[(2-Pyridinyloxy)](Benzo)Imidazo[2,1-b][1,3]Thiazine Derivatives

Abstract

A series of new 6-[(pyridine-2-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b]thiazines 4a-l and their benzoannelated derivatives 4m-r was synthesized by the reaction between 3-hydroxy(benzo)imidazo[2,1-b][1,3]thiazines and substituted 2-chloropyridines under the mild conditions with the yield 53-74 %. The structure of the target compound was proven by the results of 1H NMR, 13C NMR spectrometry, and LC-MS. In silico evaluation of these drug-like compounds proved that many of them comply with the Lipinski ‘rule of five’ and the Veber rule. Antibacterial, antifungal, and anti-inflammatory activity of all synthesized compounds were investigated in the in vitro and in vivo experiments. According to the bio screening results, the compounds 6-[(5-сhloropyridin-2-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 4a, 6-[(3,5-dichloropyridin-2-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 4e and 6-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}-2,3-diphenyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 4l proved antifungal activity against Candida albicans. On the other hand, 3-[(3,5-dichloropyridin-2-yl)oxy]-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine 4q proved the best antifungal activity against Aspergillus niger K 9 (MIC=15.62 µg/ml) and comparatively high antiedema activity against the carrageenan-induced edema of the hind paws of albino rats (the inflammation suppression index was 39.1 %).