American Chemical Society
jm0c00539_si_001.pdf (6.91 MB)

Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials

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journal contribution
posted on 2020-05-26, 14:40 authored by Papireddy Kancharla, Rozalia A. Dodean, Yuexin Li, Sovitj Pou, Brandon Pybus, Victor Melendez, Lisa Read, Charles E. Bane, Brian Vesely, Mara Kreishman-Deitrick, Chad Black, Qigui Li, Richard J. Sciotti, Raul Olmeda, Thu-Lan Luong, Heather Gaona, Brittney Potter, Jason Sousa, Sean Marcsisin, Diana Caridha, Lisa Xie, Chau Vuong, Qiang Zeng, Jing Zhang, Ping Zhang, Hsiuling Lin, Kirk Butler, Norma Roncal, Lacy Gaynor-Ohnstad, Susan E. Leed, Christina Nolan, Frida G. Ceja, Stephanie A. Rasmussen, Patrick K. Tumwebaze, Philip J. Rosenthal, Jianbing Mu, Brett R. Bayles, Roland A. Cooper, Kevin A. Reynolds, Martin J. Smilkstein, Michael K. Riscoe, Jane X. Kelly
The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.