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

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.