Title

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 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, Dominican University of California
Stephanie A. Rasmussen, Dominican University of California
Melissa T. Stephens, Dominican University of California
John C. Tan, Dominican University of California
Roland A. Cooper, 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 University
Jane X. Kelly, Department of Chemistry , Portland State University

Department

Natural Sciences and Mathematics

Document Type

Article

Source

Journal of Medicinal Chemistry

Publication Date

4-11-2019

ISSN

1520-4804

Volume

62

Issue

7

First Page

3475

Last Page

3502

Digital Object Identifier / DOI

https://doi.org/10.1021/acs.jmedchem.8b01961

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

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