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

TY - JOUR

T1 - Identification of an Orally Efficacious Imidazo[4,5-c]pyridine-6-Carboxamide Antimalarial with a High Barrier to Resistance

AU - Zhou, Bo

AU - Do Amaral, Leticia S.

AU - Bremers, Emily K.

AU - Haney, Reagan S.

AU - Wardlaw, Lyric A.

AU - Merino, Emilio F.

AU - Li, Yuexin

AU - Buchanan, Mairi

AU - Baud, Delphine

AU - Brand, Stephen

AU - Lee, Marcus C.S.

AU - Kelly, Jane X.

AU - Totrov, Maxim

AU - Cassera, Maria B.

AU - Carlier, Paul R.

N1 - Publisher Copyright: © 2026 The Authors. Published by American Chemical Society

PY - 2026/5/14

Y1 - 2026/5/14

N2 - 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 109 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.

AB - 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 109 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.

UR - https://www.scopus.com/pages/publications/105038691116

U2 - 10.1021/acs.jmedchem.6c00461

DO - 10.1021/acs.jmedchem.6c00461

M3 - Article

C2 - 42045167

AN - SCOPUS:105038691116

SN - 0022-2623

VL - 69

SP - 11292

EP - 11311

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 9

ER -