Discovery and Structure鈥揂ctivity Relationships of Pyrrolone Antimalarials

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• 作者：Dinakaran Murugesan ; Alka Mital ; Marcel Kaiser ; David M. Shackleford ; Julia Morizzi ; Kasiram Katneni ; Michael Campbell ; Alan Hudson ; Susan A. Charman ; Clive Yeates ; Ian H. Gilbert
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：2975-2990
• 全文大小：632K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC₅₀ 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure鈥揳ctivity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.