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

23 Jun 2015

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, and Yin Yang

Journal of Medicinal Chemistry
DOI: 10.1021/acs.jmedchem.5b00678



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).

View the full article on the Journal of Medicinal Chemistry website.