Antimicrobial Activity and Mechanism of Action of New N-Heteroaryl-1H-(benz)Imidazoles.

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.

Antifungal activity of synthetic di(hetero)arylamines based on the benzo[b]thiophene moiety.

The antifungal activity of several di(hetero)arylamine derivatives of the benzo[b]thiophene system was evaluated against clinically relevant Candida, Aspergillus, and dermatophyte species by a broth macrodilution test based on CLSI (formerly NCCLS) guidelines. The most active compound showed a broad spectrum of activity (against all tested fungal strains, including fluconazole-resistant fungi), with particularly low MICs for dermatophytes. Results from the inhibition of the dimorphic transition in Candida albicans and flow cytometry studies further confirmed their biological activity. With this study it was possible to establish some structure-activity relationships (SARs). The hydroxy groups proved to be essential for the activity in the aryl derivatives. Furthermore, the spectrum of activity in the pyridine derivatives was broadened by the absence of the ester group on position 2 of the benzo[b]thiophene system.

Evaluation of the antioxidant properties of diarylamines in the benzo[b]thiophene series by free radical scavenging activity and reducing power.

The antioxidant properties of substituted diarylamines in the benzo[b]thiophene series were evaluated by their reducing power and free radical scavenging activity. The results were compared with those of standards: acid ascorbic for the first method and BHA and BHT for the second. For both methods it was possible to establish some structure-activity relationships (SARs) based on the position of the arylamination on the benzo[b]thiophene moiety, the presence of different substituents on the phenyl ring (F, 1 or 2 OMe) and on the thiophene ring (H, CO(2)Et, CO(2)H).