Development of Next-Generation Antimalarial Acridones with Radical Cure Potential
Rozalia A. Dodean, Yuexin Li, Xiaowei Zhang, Diana Caridha, Michael S. Madejczyk, Xiannu Jin, William E. Dennis, Ravi Chetree, Karl Kudyba, Sharon McEnearney, Patricia Lee, Cameron Blount, Jesse DeLuca, Chau Vuong, Kristina Pannone, Hieu Dinh, Kennedy Mdaki, Susan E. Leed, Monica L. Martin, Brandon Pybus, Sovitj Pou, Rolf W. Winter, Katherine M. Liebman, Rachel Williams, Amrendra Kumar, Anongruk Chim-Ong, Liwang Cui, Stephen Orena, Jackson Assimwe, Innocent Tibagambirwa, Oswald Byaruhanga, Patrick Angutoko, Jennifer Legac, Oriana Kreutzfeld, Philip J. Rosenthal, Roland A. Cooper, Aaron Nilsen, Michael K. Riscoe, Alison Roth, Papireddy Kancharla, Jane X. Kelly
Abstract
Building from our previous lead compound T111 ( 1 ) possessing activity against both Plasmodium falciparum asexual blood-stage (ABS) and Plasmodium berghei liver-stage (LS) parasites, next-generation antimalarial acridones were systematically designed and synthesized. A large number of newly generated acridones displayed excellent antimalarial activities against both ABS and LS parasites, with feasible safety and metabolic profiles. In a high-throughput hypnozoitocidal assay using Plasmodium cynomolgi, a number of these acridones significantly inhibited schizont and hypnozoite formation in both prophylactic and radical cure-dosing modes. Notably, newer generation acridones substantially mitigated cross-resistance with atovaquone. Representative compound 28 (T229) provided full LS protection and a sustained blood-stage cure for murine P. berghei infection dosed at both 10 and 40 mg/kg/day orally. Furthermore, compound 28 demonstrated a low risk of both genotoxicity and cardiotoxicity and was highly effective against ART-resistant parasites. This study demonstrated the first and robust antirelapse LS activity from a novel acridone family.