Title

Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.

Authors

Papireddy Kancharla, Department of Chemistry, Portland State University
Rozalia A. Dodean, Department of Veterans Affairs Medical Center
Yuexin Li, Department of Veterans Affairs Medical Center
Sovitj Pou, Department of Veterans Affairs Medical Center
Brandon Pybus, Division of Experimental Therapeutics, Walter Reed Army Institute of Research
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
Frida G. Ceja, Dominican University of California
Stephanie A. Rasmussen, Dominican University of California
Patrick K. Tumwebaze, Infectious Diseases Research Collaboration
Philip J. Rosenthal, Department of Medicine, University of California, San Francisco
Jianbing Mu, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Brett R. Bayles, Dominican University of CaliforniaFollow
Roland A. Cooper, Dominican University of CaliforniaFollow
Kevin A. Reynolds, Department of Chemistry, Portland State University
Martin J. Smilkstein, Department of Veterans Affairs Medical Center
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

6-11-2020

ISSN

1520-4804

Volume

63

Issue

11

First Page

6179

Last Page

6202

Digital Object Identifier / DOI

https://doi.org/10.1021/acs.jmedchem.0c00539

Abstract

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

PubMed ID

32390431

Rights

Copyright © 2020 American Chemical Society

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