Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.
Authors
Rozalia A. Dodean, Department of Chemistry , Portland State University
Papireddy Kancharla, Department of Chemistry , Portland State University
Yuexin Li, Department of Chemistry , Portland State University
Victor Melendez, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Lisa Read, Division of Experimental Therapeutics , Walter Reed Army Institute of ResearchFollow
Charles E. Bane, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Brian Vesely, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Mara Kreishman-Deitrick, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Chad Black, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Qigui Li, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Richard J. Sciotti, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Raul Olmeda, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Thu-Lan Luong, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Heather Gaona, Division of Experimental Therapeutics, Walter Reed Army Institute of Research
Brittney Potter, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Jason Sousa, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Sean Marcsisin, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Diana Caridha, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Lisa Xie, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Chau Vuong, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Qiang Zeng, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Jing Zhang, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Ping Zhang, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Hsiuling Lin, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Kirk Butler, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Norma Roncal, Division of Experimental Therapeutics , Walter Reed Army Institute of ResearchFollow
Lacy Gaynor-Ohnstad, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Susan E. Leed, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Christina Nolan, Division of Experimental Therapeutics , Walter Reed Army Institute of Research
Stephanie J. Huezo, Department of Natural Sciences and Mathematics, Dominican University of California
Stephanie A. Rasmussen, Dominican University of CaliforniaFollow
Melissa T. Stephens, Department of Natural Sciences and Mathematics, Dominican University of California
John C. Tan, Department of Natural Sciences and Mathematics, Dominican University of California
Roland A. Cooper, Department of Natural Sciences and Mathematics, Dominican University of CaliforniaFollow
Martin J. Smilkstein, Department of Veterans Affairs Medical Center
Sovitj Pou, Department of Veterans Affairs Medical Center
Rolf W. Winter, Department of Chemistry , Portland State University
Michael K. Riscoe, Department of Chemistry , Portland State UniversityFollow
Jane X. Kelly, Department of Chemistry , Portland State University
Department
Natural Sciences and Mathematics
Source
Journal of Medicinal Chemistry
Publication Date
4-11-2019
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.
Rights
Copyright © 2019 American Chemical Society
