posted on 2020-05-26, 14:40authored byPapireddy 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.