| Literature DB >> 30852885 |
Rozalia A Dodean1,2, Papireddy Kancharla1, Yuexin Li1,2, Victor Melendez3, Lisa Read3, Charles E Bane3, Brian Vesely3, Mara Kreishman-Deitrick3, Chad Black3, Qigui Li3, Richard J Sciotti3, Raul Olmeda3, Thu-Lan Luong3, Heather Gaona3, Brittney Potter3, Jason Sousa3, Sean Marcsisin3, Diana Caridha3, Lisa Xie3, Chau Vuong3, Qiang Zeng3, Jing Zhang3, Ping Zhang3, Hsiuling Lin3, Kirk Butler3, Norma Roncal3, Lacy Gaynor-Ohnstad3, Susan E Leed3, Christina Nolan3, Stephanie J Huezo4, Stephanie A Rasmussen4, Melissa T Stephens, John C Tan, Roland A Cooper4, Martin J Smilkstein2, Sovitj Pou2, Rolf W Winter1,2, Michael K Riscoe1,2, Jane X Kelly1,2.
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 falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-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.Entities:
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Year: 2019 PMID： 30852885 PMCID： PMC6822569 DOI： 10.1021/acs.jmedchem.8b01961
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446