期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 23, 页码 10162-10175出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm501568b
关键词
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资金
- NIH [AI095437, RR001081]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- FIOCRUZ
- Office of Science, Office of Basic Energy Sciences of the U.S. Department of Energy [DE-AC02-05CH11231]
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 structureactivity 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 angstrom). 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.
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