A Novel Class of Orally Bioavailable Phenylglycine-Benzoxaborole Conjugates with Antimalarial Activity and Potentially Novel Mechanism of Action.

A new class of benzoxaboroles with a phenylglycine appendage was found to display in vitro blood stage activity against the human malaria parasite Plasmodium falciparum (Pf). Structure-activity relationship studies of the starting hit compound 3 resulted in compounds active against PfNF54 drug-sensitive and PfK1 drug-resistant strains with an in vitro antiplasmodium IC50 < 0.4 μM, selectivity over mammalian cell-lines (selectivity index > 47) and high aqueous solubility (160 to >200 μM). Selected compounds showed good in vitro metabolic stability when incubated with human, rat, and mouse liver microsomes and showed no cross-resistance against barcoded mutant lines. Two frontrunner compounds, 6 and 7, were dosed orally at 50 mg·kg-1 using a standard quadrupole dosing regimen in a P. berghei mouse infection model and showed encouraging in vivo efficacy. This work identifies a promising new class of phenylglycine-based benzoxaboroles, which warrants further medicinal chemistry optimization.