Optimization of Chloronitrobenzamides (CNBs) as Therapeutic Leads for Human African Trypanosomiasis (HAT)

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• 作者：Jong Yeon Hwang ; David Smithson ; Fangyi Zhu ; Gloria Holbrook ; Michele C. Connelly ; Marcel Kaiser ; Reto Brun ; R. Kiplin Guy
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：2850-2860
• 全文大小：447K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei. Herein we disclose extensive structure鈥揳ctivity relationship and structure鈥損roperty relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC₅₀ = 27 nM for T. b. brucei, 7 nM for T. b. rhodesiense, and 2 nM for T. b. gambiense) with excellent selectivity for parasite cells relative to mammalian cell lines (EC₅₀ > 25 渭M). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t_1/2 > 4 h for human and mouse) to justify pursuing in vivo studies.