Morake, MokhitliTaylor, DaleCoertzen, DinaNjoroge, MathewKrugmann, LiezlLeshabane, Meta KgaogeloDa Rocha, ShanteQahash, TarrickGirling, GarethCoyle, RachaelLee, Marcus C.S.Wittlin, SergioLlinas, ManuelBirkholtz, Lyn-MarieBasarab, Gregory S.Chibale, Kelly2026-02-132026-02-132026-01-08Morake, M., Taylor, D., Coertzen, D. et al. 2026, 'A novel class of orally bioavailable phenylglycine–benzoxaborole conjugates with antimalarial activity and potentially novel mechanism of action', ACS Medicinal Chemistry Letters, vol. 17, no. 1, pp. 22-31, doi : 10.1021/acsmedchemlett.5c00549.10.1021/acsmedchemlett.5c005491948-5875 (online)http://hdl.handle.net/2263/108231SUPPLEMENTARY MATERIAL : All intermediates and target compounds were characterized using NMR, and purity was determined using LC-MS; experimental procedures, characterization of key intermediates as well as final compounds, description of biochemical, solubility, and metabolic stability assays are provided. In vitro gametocytocidal activity of selected compounds is included.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.en© 2025 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0.BenzoxaborolesMicrosomal stabilityStructure−activity relationshipCPSF3Plasmodium falciparumMalariaArticle