Design and synthesis of benzo[d]imidazo-6,7-dihydrobenzo[d] imidazo[2,1-b]thiazol-8(5H)-ones as potent anti-infective agents

Abstract

In this study, we present a series of 2-(5-chlorothiophen-2-yl)-1H-benzo-[d]-imidazol-2-yl)-6,7-dihydrobenzo-[d]-imidazo[2,1-b]thiazol-8(5H)-ones (7a–q) through a short, four-step process using readily available starting materials. The synthesis included crucial transformations such as the condensation of 1,3-cyclohexanediones with thiourea, cyclization with acetophenones, and the Vilsmeier-Haack-Arnold reaction. All the compounds were fully characterized and systematically screened for antibacterial, antifungal and antiviral activity. Among all, the compounds 7b (CC50: >1000 µM, IC50 = 4.8 µM, SI = > 63) and 7h (CC50: >1000 µM, IC50 = 5.6 µM, SI = > 54) with 3-methyl and 3-trifluoromethyl groups showed significant virus inhibitory activity against the pandemic influenza virus A/Puerto Rico/8/34 (H1N1) with high selectivity index values and favorable toxicity profiles. The compounds were also evaluated for antibacterial and antifungal activity, exhibited only moderate inhibition. Molecular docking studies have elucidated strong binding interactions with the viral target, the RNA polymerase PB1-PB2 subunits of influenza A virus. ADMET profiles highlighted encouraging drug-like properties and positioned 2-(5-chlorothiophen-2-yl)-1H-benzo-[d]-imidazol-2-yl)-6,7-dihydrobenzo-[d]-imidazo [2,1-b]thiazol-8(5H)-one as a promising candidate for further development as antiviral therapeutics.

A collection of 17 compounds comprising benzimidazole with a dihydroimidazobenzothiazole scaffolds were synthesized and evaluated against the pandemic influenza virus A/Puerto Rico/8/34 (H1N1); resulted two compounds with high selectivity index and favourable toxicity profile.