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

## TL;DR

Researchers discovered a new class of malaria-fighting compounds with promising activity and a potentially new mechanism of action.

## Contribution

A novel class of phenylglycine–benzoxaborole conjugates with antimalarial activity and high selectivity was developed.

## Key findings

- Compounds showed potent in vitro activity against both drug-sensitive and drug-resistant malaria strains.
- Selected compounds demonstrated high solubility and metabolic stability in human and animal liver microsomes.
- Oral dosing of two compounds in a mouse malaria model showed encouraging in vivo efficacy.

## Abstract

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.