Benzoxaborole antimalarial agents. Part 4. Discovery of potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles

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

Abstract

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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemistry*
  • Antimalarials / pharmacology*
  • Boron Compounds / chemistry*
  • Boron Compounds / pharmacology*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Cell Survival / drug effects
  • Female
  • Humans
  • Jurkat Cells
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / parasitology
  • Mice
  • Microsomes, Liver / drug effects*
  • Models, Molecular
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Pyrazines / chemistry*
  • Pyrazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Boron Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Pyrazines