2,4-Diaminothienopyrimidines as Orally Active Antimalarial Agents

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• 作者：Diego González Cabrera ; Claire Le Manach ; Frederic Douelle ; Yassir Younis ; Tzu-Shean Feng ; Tanya Paquet ; Aloysius T. Nchinda ; Leslie J. Street ; Dale Taylor ; Carmen de Kock ; Lubbe Wiesner ; Sandra Duffy ; Karen L. White ; K. Mohammed Zabiulla ; Yuvaraj Sambandan ; Sridevi Bashyam ; David Waterson ; Michael J. Witty ; Susan A. Charman ; Vicky M. Avery ; Sergio Wittlin ; Kelly Chibale
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：1014-1022
• 全文大小：494K
• ISSN：1520-4804

文摘

A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure鈥揳ctivity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.