Skip to main content
profile image
Selected Works of Roland A. Cooper
Article
Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.
Natural Sciences and Mathematics | Faculty Scholarship
  • 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 Research
  • 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 Research
  • 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 California
  • 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 California
  • 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 University
  • Jane X. Kelly, Department of Chemistry , Portland State University
Link Find in your library
Department
Natural Sciences and Mathematics
Document Type
Article
Source
Journal of Medicinal Chemistry
Publication Date
4-11-2019
Disciplines
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.

PubMed ID
30852885
Rights
Copyright © 2019 American Chemical Society
Citation Information
Rozalia A. Dodean, Papireddy Kancharla, Yuexin Li, Victor Melendez, et al.. "Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials." Vol. 62 Iss. 7 (2019) p. 3475 - 3502 ISSN: 1520-4804
Available at: http://works.bepress.com/roland_cooper/45/