Anti-enterovirus activity and structure-activity relationship of a series of 2,6-dihalophenyl-substituted 1H,3H-thiazolo[3,4-a]benzimidazoles

作者:De Palma Armando M; Heggermont Ward; Leyssen Pieter; Puerstinger Gerhard; Wimmer Eva; De Clercq Erik; Rao Angela; Monforte Anna Maria; Chimirri Alba; Neyts Johan*
来源:Biochemical and Biophysical Research Communications, 2007, 353(3): 628-632.
DOI:10.1016/j.bbrc.2006.12.063

摘要

Despite the fact that enteroviruses are implicated in a variety of human diseases, there is no approved therapy for the treatment of enteroviral infections. Here, a series of 2,6-dihalophenyl-substituted 1H,3H-thiazolo[3,4-a]benzimidazoles with anti-enterovirus activity is reported. The compounds elicit potent activity against coxsackievirus A9, echovirus 9 and I I and all six strains of coxsackievirus B. A structure-activity relationship analysis revealed that the presence of substituents at position 6 of the tricyclic system positively influences the antiviral activity, whereas substitutions at position 7 are less favorable. In particular a 6-trifluoromethyl substitution leads to a substantial improvement of the antiviral activity as compared to the unsubstituted structure. Furthermore, an additional introduction of a 2-Cl, 6-F substitution on the phenyl at C-1 results in a further increase of the antiviral activity. Hence, 1-(2-chloro-6-fluorophenyl)-6-trifluoromethyl-1H,3H-thiazolo[3,4-a]benzimidazole results in a dose-dependent inhibition of viral replication with a 50% effective concentration (EC(50)) of 0.41 mu g/ml without any detectable cytotoxicity at the highest concentration (100 mu g/ml) tested.