Binding Mode and Potency of N-Indolyloxopyridinyl-4-aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51

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• 作者：Debora F. Vieira ; Jun Yong Choi ; Claudia M. Calvet ; Jair Lage Siqueira-Neto ; Jonathan B. Johnston ; Danielle Kellar ; Jiri Gut ; Michael D. Cameron ; James H. McKerrow ; William R. Roush ; Larissa M. Podust
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：10162-10175
• 全文大小：760K
• ISSN：1520-4804

文摘

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鈥揳ctivity 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鈥?.48 脜). The 5-chloro-substituted analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing 鈮?9.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days.