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

• Published in: Journal of medicinal chemistry Vol. 63; no. 11; pp. 6179 - 6202
• Main Authors: Kancharla, Papireddy, Dodean, Rozalia A, Li, Yuexin, Pou, Sovitj, Pybus, Brandon, Melendez, Victor, Read, Lisa, Bane, Charles E, Vesely, Brian, Kreishman-Deitrick, Mara, Black, Chad, Li, Qigui, Sciotti, Richard J, Olmeda, Raul, Luong, Thu-Lan, Gaona, Heather, Potter, Brittney, Sousa, Jason, Marcsisin, Sean, Caridha, Diana, Xie, Lisa, Vuong, Chau, Zeng, Qiang, Zhang, Jing, Zhang, Ping, Lin, Hsiuling, Butler, Kirk, Roncal, Norma, Gaynor-Ohnstad, Lacy, Leed, Susan E, Nolan, Christina, Ceja, Frida G, Rasmussen, Stephanie A, Tumwebaze, Patrick K, Rosenthal, Philip J, Mu, Jianbing, Bayles, Brett R, Cooper, Roland A, Reynolds, Kevin A, Smilkstein, Martin J, Riscoe, Michael K, Kelly, Jane X
• Format: Journal Article
• Language: English
• Published: United States 11-06-2020
• Subjects: Acridones - chemistry; Acridones - pharmacokinetics; Acridones - pharmacology; Acridones - therapeutic use; Administration, Oral; Animals; Antimalarials - chemistry; Antimalarials - pharmacokinetics; Antimalarials - pharmacology; Antimalarials - therapeutic use; Cell Survival - drug effects; Disease Models, Animal; Female; Half-Life; Hep G2 Cells; Humans; Life Cycle Stages - drug effects; Malaria - drug therapy; Malaria - pathology; Male; Mice; Mice, Inbred C57BL; Plasmodium falciparum - drug effects; Plasmodium falciparum - isolation & purification; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00539

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.