Endoperoxide Carbonyl Falcipain 2/3 Inhibitor Hybrids: Toward Combination Chemotherapy of Malaria through a Single Chemical Entity

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• 作者：Peter Gibbons ; Edite Verissimo ; Nuna C. Araujo ; Victoria Barton ; Gemma L. Nixon ; Richard K. Amewu ; James Chadwick ; Paul A. Stocks ; Giancarlo A. Biagini ; Abhishek Srivastava ; Philip J. Rosenthal ; Jiri
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：November 25, 2010
• 年：2010
• 卷：53
• 期：22
• 页码：8202-8206
• 全文大小：865K
• 年卷期：v.53,no.22(November 25, 2010)
• ISSN：1520-4804

文摘

We extend our approach of combination chemotherapy through a single prodrug entity (O’Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target “heme”, we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.