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Identification of Phenoxyalkylbenzimidazoles with Antitubercular Activity.
Chandrasekera, N Susantha; Alling, Torey; Bailey, Mai A; Files, Megan; Early, Julie V; Ollinger, Juliane; Ovechkina, Yulia; Masquelin, Thierry; Desai, Prashant V; Cramer, Jeffrey W; Hipskind, Philip A; Odingo, Joshua O; Parish, Tanya.
Afiliación
  • Chandrasekera NS; Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
  • Alling T; Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
  • Bailey MA; Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
  • Files M; Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
  • Early JV; Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
  • Ollinger J; Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
  • Ovechkina Y; Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
  • Masquelin T; Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
  • Desai PV; Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
  • Cramer JW; Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
  • Hipskind PA; Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
  • Odingo JO; Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
  • Parish T; Infectious Disease Research Institute, 1616 Eastlake Avenue East, Seattle, Washington 98102, United States.
J Med Chem ; 58(18): 7273-85, 2015 Sep 24.
Article en En | MEDLINE | ID: mdl-26295286
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 3_ND Problema de salud: 3_neglected_diseases / 3_tuberculosis Asunto principal: Bencimidazoles / Antituberculosos Tipo de estudio: Diagnostic_studies Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 3_ND Problema de salud: 3_neglected_diseases / 3_tuberculosis Asunto principal: Bencimidazoles / Antituberculosos Tipo de estudio: Diagnostic_studies Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos
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