Benzoxaborole Antimalarial Agents. Part 4. Discovery of Potent 6-(2-(Alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles

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• 作者：Yong-Kang Zhang ; Jacob J. Plattner ; Eric E. Easom ; Robert T. Jacobs ; Denghui Guo ; Virginia Sanders ; Yvonne R. Freund ; Brice Campo ; Philip J. Rosenthal ; Wei Bu ; Francisco-Javier Gamo ; Laura M. Sanz ; Min Ge ; Liang Li ; Jie Ding ; Yin Yang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 9, 2015
• 年：2015
• 卷：58
• 期：13
• 页码：5344-5354
• 全文大小：435K
• ISSN：1520-4804

文摘

A series of 6-hetaryloxy benzoxaborole compounds was designed and synthesized for a structure鈥揳ctivity relationship (SAR) investigation to assess the changes in antimalarial activity which result from 6-aryloxy structural variation, substituent modification on the pyrazine ring, and optimization of the side chain ester group. This SAR study discovered highly potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 27鈥?b>34) with IC₅₀s = 0.2鈥?2 nM against cultured Plasmodium falciparum W2 and 3D7 strains. Compound 9 also demonstrated excellent in vivo efficacy against P. berghei in infected mice (ED₉₀ = 7.0 mg/kg).