title: Identification of Phenoxyalkylbenzimidazoles with Antitubercular Activity.
abstract: 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.
authors: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
authors: N Susantha
authors: NS
authors: Chandrasekera
authors: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
authors: Torey
authors: T
authors: Alling
authors: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
authors: Mai A
authors: MA
authors: Bailey
authors: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
authors: Megan
authors: M
authors: Files
authors: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
authors: Julie V
authors: JV
authors: Early
authors: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
authors: Juliane
authors: J
authors: Ollinger
authors: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
authors: Yulia
authors: Y
authors: Ovechkina
authors: Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
authors: Thierry
authors: T
authors: Masquelin
authors: Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
authors: Prashant V
authors: PV
authors: Desai
authors: Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
authors: Jeffrey W
authors: JW
authors: Cramer
authors: Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
authors: Philip A
authors: PA
authors: Hipskind
authors: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
authors: Joshua O
authors: JO
authors: Odingo
authors: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
authors: Tanya
authors: T
authors: Parish
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D004285:Dogs; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010539:Permeability; D051381:Rats; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D001562:Benzimidazoles