title: Anti-enterovirus activity and structure-activity relationship of a series of 2,6-dihalophenyl-substituted 1H,3H-thiazolo[3,4-a]benzimidazoles.
abstract: 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 11 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 (EC50) of 0.41 microg/ml without any detectable cytotoxicity at the highest concentration (100 microg/ml) tested.
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Armando M
authors.initials: AM
authors.lastname: De Palma
authors.forename: Ward
authors.initials: W
authors.lastname: Heggermont
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Gerhard
authors.initials: G
authors.lastname: Pürstinger
authors.forename: Eva
authors.initials: E
authors.lastname: Wimmer
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Angela
authors.initials: A
authors.lastname: Rao
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Monforte
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004769:Enterovirus Infections / Q000188:drug therapy*; D006367:HeLa Cells; D006801:Humans; D010849:Picornaviridae / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D013844:Thiazoles