Lead Optimization of 3-Carboxyl-4(1H)-Quinolones to Deliver Orally Bioavailable Antimalarials

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• 作者：Yiqun Zhang ; Julie A. Clark ; Michele C. Connelly ; Fangyi Zhu ; Jaeki Min ; W. Armand Guiguemde ; Anupam Pradhan ; Lalitha Iyer ; Anna Furimsky ; Jason Gow ; Toufan Parman ; Farah El Mazouni ; Margaret A. Phillips ; Dennis E. Kyle ; Jon Mirsalis ; R. Kiplin Guy
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4205-4219
• 全文大小：642K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.