Identification of an Orally Efficacious Imidazo[4,5- c ]pyridine-6-Carboxamide Antimalarial with a High Barrier to Resistance

Due to the emergence of resistance to both artemisinin derivatives, and their partner drugs, new antimalarials are urgently needed. Ideally, new orally active antimalarials would not only engage new targets but also demonstrate a high barrier to resistance selection, and the ability to kill both proliferating rings and growth-arrested rings resulting from artemisinin exposure. In this report we disclose a novel antimalarial chemotype, the imidazo[4,5- c ]pyridine-6-carboxamides, and a representative compound 10b that possesses all these qualities. Orally dosed 10b (4 × 60 mg/kg/day or 1 × 160 mg/kg) cures Plasmodium yoelii -infected mice out to 28 days. This compound is unaffected by over 40 distinct target- and efflux-based resistance mutations in the AReBaR resistome screen, suggesting a novel mode of action. Furthermore, at a minimum inoculum of resistance of 10 9 parasites, 10b proved refractory to resistance selection. Lastly, with a 6 h exposure, 250 nM 10b kills both proliferating rings and dihydroartemisinin-induced dormant parasites.