Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

Authors

• 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

Sponsor

This project was supported by NIH/NIAID (award 1R01AI093784) and DOD/PRMRP (award PR160693/W81XWH-17-2-0041).

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

Locate the Document

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

DOI

10.1021/acs.jmedchem.8b01961

Persistent Identifier

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

Citation Details

Dodean, R. A., Kancharla, P., Li, Y., Melendez, V., Read, L., Bane, C. E., … Kelly, J. X. (2019). Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials. Journal Of Medicinal Chemistry, 62(7), 3475–3502. https://doi.org/10.1021/acs.jmedchem.8b01961