Discovery of a Pyrazine-2-Carboxamide Derivative as a Potent Plasmodium falciparum Inhibitor with Potential for Single-Dose Cure

Malaria remains a major cause of morbidity and mortality, particularly among young children, in endemic regions such as sub-Saharan Africa and Southeast Asia. Moreover, the emerging resistance of Plasmodium parasites to front-line therapeutics underscores the need for new blood-stage antimalarial drugs. Utilizing a Plasmodium falciparum (Pf) growth inhibition assay, we identified a novel pyrazine-2-carboxamide series. Lead optimization improved anti-plasmodial potency, metabolic stability, and reduced CYP2D6 inhibition risk, leading to the selection of IWY357 (1). A single dose of 100 mg per kg (mpk) is fully curative in a Pf-humanized severe combined immunodeficient mouse model (TADhuMouse®-Pfalc), and IWY357 (1) also exhibits a high barrier to resistance in drug selection studies. Given the significant potential to provide a curative therapy for uncomplicated malaria with short dosing regimens, either alone or in combination, IWY357 (1) was progressed through GLP toxicology studies into phase 1 clinical trials.