Optimization of Propafenone Analogues as Antimalarial Leads

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• 作者：David J. Lowes ; W. Armand Guiguemde ; Michele C. Connelly ; Fangyi Zhu ; Martina S. Sigal ; Julie A. Clark ; Andrew S. Lemoff ; Joseph L. Derisi ; Emily B. Wilson ; R. Kiplin Guy
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 10, 2011
• 年：2011
• 卷：54
• 期：21
• 页码：7477-7485
• 全文大小：919K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug鈥檚 potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.