苯并硼唑抗疟药。第4部分。强效6-(2-(烷氧羰基)吡嗪基-5-氧基)-1,3-二氢-1-羟基-2,1-苯并硼唑的发现。

Zhang Yong-Kang, Plattner Jacob J, Easom Eric E, Jacobs Robert T, Guo Denghui, Sanders Virginia, Freund Yvonne R, Campo Brice, Rosenthal Philip J, Bu Wei, Gamo Francisco-Javier, Sanz Laura M, Ge Min, Li Liang, Ding Jie, Yang Yin

†Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.

§Department of Medicine, University of California, San Francisco, Box 0811, San Francisco, California 94143, United States.

J Med Chem. 2015 Jul 9;58(13):5344-54. doi: 10.1021/acs.jmedchem.5b00678. Epub 2015 Jun 23.

A series of 6-hetaryloxy benzoxaborole compounds was designed and synthesized for a structure-activity 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, 27-34) with IC50s = 0.2-22 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).

设计并合成了一系列6-杂芳氧基苯并硼氧杂环戊烷化合物，用于结构-活性关系（SAR）研究，以评估6-芳氧基结构变化、吡嗪环上取代基修饰以及侧链酯基优化对抗疟活性的影响。该SAR研究发现了高效的6-(2-(烷氧羰基)吡嗪基-5-氧基)-1,3-二氢-1-羟基-2,1-苯并硼氧杂环戊烷（9, 27 - 34），对培养的恶性疟原虫W2和3D7菌株的IC50值为0.2 - 22 nM。化合物9在感染伯氏疟原虫的小鼠体内也表现出优异的疗效（ED90 = 7.0 mg/kg）。