Benzoxaborole AntimalarialAgents. Part 4. Discoveryof Potent 6-(2-(Alkoxycarbonyl)pyrazinyl-5-oxy)-13-dihydro-1-hydroxy-21-benzoxaboroles

摘要

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).