학술논문
Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials
Document Type
Article
Author
Dodean, Rozalia A.; Kancharla, Papireddy; Li, Yuexin; 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; Huezo, Stephanie J.; Rasmussen, Stephanie A.; Stephens, Melissa T.; Tan, John C.; Cooper, Roland A.; Smilkstein, Martin J.; Pou, Sovitj; Winter, Rolf W.; Riscoe, Michael K.; Kelly, Jane X.
Source
Journal of Medicinal Chemistry; April 2019, Vol. 62 Issue: 7 p3475-3502, 28p
Subject
Language
ISSN
00222623; 15204804
Abstract
Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparumblood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoeliimurine malaria model; (3) prevention of in vitro Plasmodium bergheisporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. bergheisporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure–activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.