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Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51.
Vieira, Debora F; Choi, Jun Yong; Calvet, Claudia M; Siqueira-Neto, Jair Lage; Johnston, Jonathan B; Kellar, Danielle; Gut, Jiri; Cameron, Michael D; McKerrow, James H; Roush, William R; Podust, Larissa M.
Afiliação
  • Vieira DF; Center for Discovery and Innovation in Parasitic Diseases, ‡Department of Pathology, and §Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
J Med Chem ; 57(23): 10162-75, 2014 Dec 11.
Article em En | MEDLINE | ID: mdl-25393646
Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in T. cruzi. We report the structure-activity relationships (SAR) of an N-arylpiperazine series of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal N-phenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95-2.48 Å). The 5-chloro-substituted analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing ≥ 99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperazinas / Piridinas / Tripanossomicidas / Inibidores de 14-alfa Desmetilase Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperazinas / Piridinas / Tripanossomicidas / Inibidores de 14-alfa Desmetilase Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos