Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria

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• 作者：Bryan K. S. Yeung ; Bin Zou ; Matthias Rottmann ; Suresh B. Lakshminarayana ; Shi Hua Ang ; Seh Yong Leong ; Jocelyn Tan ; Josephine Wong ; Sonja Keller-Maerki ; Christoph Fischli ; Anne Goh ; Esther K. Schmitt
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：July 22, 2010
• 年：2010
• 卷：53
• 期：14
• 页码：5155-5164
• 全文大小：966K
• 年卷期：v.53,no.14(July 22, 2010)
• ISSN：1520-4804

文摘

The antiplasmodial activity of a series of spirotetrahydro β-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC₅₀ of 90 nM. Structure−activity relationships for the optimization of 1 to compound 20a (IC₅₀ = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.