Identification of Phenoxyalkylbenzimidazoles with Antitubercular Activity

We
conducted an evaluation of the phenoxyalkylbenzimidazole series
based on the exemplar 2-ethyl-1-(3-phenoxypropyl)-1H-benzo­[d]­imidazole for its antitubercular activity.
Four segments of the molecule were examined systematically to define
a structure–activity relationship with respect to biological
activity. Compounds had submicromolar activity against Mycobacterium tuberculosis; the most potent compound
had a minimum inhibitory concentration (MIC) of 52 nM and was not
cytotoxic against eukaryotic cells (selectivity index = 523). Compounds
were selective for M. tuberculosis over other bacterial
species, including the closely related Mycobacterium
smegmatis. Compounds had a bacteriostatic effect against
aerobically grown, replicating M. tuberculosis, but
were bactericidal against nonreplicating bacteria. Representative
compounds had moderate to high permeability in MDCK cells, but were
rapidly metabolized in rodents and human liver microsomes, suggesting
the possibility of rapid in vivo hepatic clearance mediated by oxidative
metabolism. These results indicate that the readily synthesized phenoxyalkylbenzimidazoles
are a promising class of potent and selective antitubercular agents,
if the metabolic liability can be solved.