Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

Rozalia A. Dodean, Portland State UniversityFollow
Papireddy Kancharla, Portland State UnivesityFollow
Yuexin Li, Portland State UniversityFollow
Victor Melendez, Walter Reed Army Institute of Research
Lisa Read, Walter Reed Army Institute of ResearchFollow
Charles E. Bane, Walter Reed Army Institute of Research
Brian Vesely, Walter Reed Army Institute of Research
Mara Kreishman-Deitrick, Walter Reed Army Institute of Research
Chad Black, Walter Reed Army Institute of Research
Qigui Li, Walter Reed Army Institute of Research
Richard J. Scott, Walter Reed Army Institute of Research
Raul Olmeda, Walter Reed Army Institute of Research
Thu-Lan Luong, Walter Reed Army Institute of Research
Heather Gaona, Walter Reed Army Institute of Research
Brittney Potter, Walter Reed Army Institute of Research
Jason Sousa, Walter Reed Army Institute of Research
Sean Marcsisin, Walter Reed Army Institute of Research
Diana Caridha, Walter Reed Army Institute of Research
Lisa Xie, Walter Reed Army Institute of Research
Chau Vuong, Walter Reed Army Institute of Research
Qiang Zeng, Walter Reed Army Institute of Research
Jing Zhang, Walter Reed Army Institute of Research
Ping Zhang, Walter Reed Army Institute of Research
Hsiuling Lin, Walter Reed Army Institute of Research
Kirk Butler, Walter Reed Army Institute of Research
Norma Roncal, Walter Reed Army Institute of Research
Lacy Gaynor-Ohnstad, Walter Reed Army Institute of Research
Susan E. Leed, Walter Reed Army Institute of Research
Christina Nolan, Walter Reed Army Institute of Research
Stephanie J. Huezo, Dominican University of California
Stephanie A. Rasmussen, Dominican University of California
Melissa T. Stephens
John C. Tan
Roland A. Cooper, Dominican University of California
Martin J. Smilkstein, Department of Veterans Affairs Medical CenterFollow
Sovitj Pou, Department of Veterans Affairs Medical Center
Rolf W. Winter, Portland State University
Michael K. Riscoe, Portland State UniversityFollow
Jane X. Kelly, Portland State UniversityFollow

Published In

Journal of Medicinal Chemistry

Document Type

Citation

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.

Description

© 2019 American Chemical Society

DOI

10.1021/acs.jmedchem.8b01961

Persistent Identifier

https://archives.pdx.edu/ds/psu/28778

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