Benzoxaborole Antimalarial Agents. Part 5. Lead Optimization of Novel Amide Pyrazinyloxy Benzoxaboroles and Identification of a Preclinical Candidate

J Med Chem. 2017 Jul 13;60(13):5889-5908. doi: 10.1021/acs.jmedchem.7b00621. Epub 2017 Jun 29.

Abstract

Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amides / chemistry
  • Amides / pharmacokinetics
  • Amides / pharmacology
  • Amides / therapeutic use
  • Animals
  • Antimalarials / chemistry*
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology*
  • Antimalarials / therapeutic use
  • Boron Compounds / chemistry*
  • Boron Compounds / pharmacokinetics
  • Boron Compounds / pharmacology*
  • Boron Compounds / therapeutic use
  • Dogs
  • Female
  • Humans
  • Malaria / drug therapy*
  • Malaria, Falciparum / drug therapy
  • Male
  • Mice
  • Plasmodium berghei / drug effects*
  • Plasmodium falciparum / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Amides
  • Antimalarials
  • Boron Compounds