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, we have identified a 1,2,4-triazole-containing carboxamide scaffold that, through scaffold hopping efforts, resulted in a nanomolar potent deuterated picolinamide (110). The lead compound of this class (110) 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 invivo pharmacokinetic studies. Compound 110 also displayed activity against various P. falciparum isolates with different genetic backgrounds and a slow-to-moderate rate of killing (average parasite reduction ratio 2.4), making the series appealing for further development.
Alicia Wagner, Roger Trombley, Maris Podgurski, Anthony A Ruberto, Meng Cui, Caitlin A Cooper, William E Long, Gia-Bao Nguyen, Adriana A Marin, Sarah Lee Mai, Franco Lombardo, Steven P Maher, Dennis E Kyle, Roman Manetsch.Eur J Med Chem. 2025 Mar 28:291:117572. doi: 10.1016/j.ejmech.2025.117572.