Identification of an orally-efficacious imidazo[4,5-c]pyridine-6-carboxamide antimalarial with a high barrier to resistance

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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 that result 2 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 x 60 mg/kg/day or 1 x 160 mg/kg) cures P. yoeliiinfected 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.

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