Discovery and Optimization of a Novel Carboxamide Scaffold with Selective Antimalarial Activity

Artemisinin combination therapies (ACTs) are critical components of malaria control worldwide. Alarmingly, ACTs have begun to fail, owing to the rise in artemisinin resistance. Thus, there is an urgent need for an expanded set of novel antimalarials to generate new combination therapies. Herein, through a virtual high-throughput screen (vHTS), cheminformatics-driven down-selection, and structure-activity relationship (SAR) studies, we have identified a 1,2,4-triazole-containing carboxamide scaffold; while the most promising triazole displayed 519 nM potency against the asexual blood stages of the parasite, this activity was unable to be surpassed. Scaffold hopping efforts then revealed three alternative cores with up to a 2.5-fold increase in potency from the aforementioned front-runner triazole. The lead compound of this class, a deuterated picolinamide, displays moderate aqueous solubility (13.4 µM) and metabolic stability (CLintapp HLM 17.3 µL/min/mg) in vitro, as well as moderate oral bioavailability (% F 16.2) in in vivo pharmacokinetic studies. Front-runners representing three cores were confirmed potent against a panel of three clinical isolates harboring different resistance profiles, suggesting a novel mechanism of action, and the lead compound displayed a slow-to-moderate rate of killing (average PRR 2.4) in a parasite reduction ratio assay, making the series appealing for further development.