title: Antimicrobial Activity and Mechanism of Action of New N-Heteroaryl-1H-(benz)Imidazoles.
abstract: The antimicrobial activity of sixteen new N-heteroarylated 1H-(benz)imidazoles was evaluated against clinically relevant bacteria (Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa) and fungi (Candida, Aspergillus and dermatophyte) species according to the Clinical and Laboratory Standards Institute guidelines. None of the tested compounds were active against Gram negative bacteria, but only against S. aureus, that was particularly susceptible to N-thianthrenyl- and N-dibenzothienyl imidazole derivatives. Most of the imidazole derivatives showed a broad spectrum of antifungal activity in all tested fungal strains, including fluconazole-resistant species, with a particularly low minimum inhibitory concentration (MIC) for dermatophytes. N-(dibenzofuran-4-yl)-1H-imidazole (1) and N-(dibenzothien-4-yl)-1H-imidazole (3) showed the highest antifungal potential, being most active against C. albicans. Some N-heteroarylated benzimidazoles showed low activity for fungi with the exception of 3-(1H-benzo[d]imidazol-1-yl)quinoline (14) which was selective against dermatophytes (MIC=4-16 µg/mL). The effect of the active compounds in the inhibition of the dimorphic transition, ergosterol biosynthesis and mitochondrial activity was evaluated in Candida albicans. Compounds 1 and 3 showed the capacity to inhibit the germ tube formation in C. albicans, reduced the ergosterol production and impaired the mitochondrial function. Compounds 1 and 3 showed antimicrobial activity and low cytotoxicity, being of interest for further investigation concerning specially the development of new antifungal agents.
authors.affiliation: Faculdade de Farmácia da Universidade do Porto. Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. epinto@ff.up.pt.
authors.forename: Eugénia
authors.initials: E
authors.lastname: Pinto
authors.forename: Helena
authors.initials: H
authors.lastname: Neves
authors.forename: Karnjana
authors.initials: K
authors.lastname: Hrimpeng
authors.forename: Ana-Filipa
authors.initials: AF
authors.lastname: Silva
authors.forename: Agathe
authors.initials: A
authors.lastname: Begouin
authors.forename: Graciliana
authors.initials: G
authors.lastname: Lopes
authors.forename: Maria-João R P
authors.initials: MJ
authors.lastname: Queiroz