Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

Rozalia A. Dodean, Papireddy Kancharla, Yuexin Li, Victor Melendez, Lisa Read, Charles E. Bane, Brian Vesely, Mara Kreishman-Deitrick, Chad Black, Qigui Li, Richard J. Sciotti, Raul Olmeda, Thu Lan Luong, Heather Gaona, Brittney Potter, Jason Sousa, Sean Marcsisin, Diana Caridha, Lisa Xie, Chau VuongQiang Zeng, Jing Zhang, Ping Zhang, Hsiuling Lin, Kirk Butler, Norma Roncal, Lacy Gaynor-Ohnstad, Susan E. Leed, Christina Nolan, Stephanie J. Huezo, Stephanie A. Rasmussen, Melissa T. Stephens, John C. Tan, Roland A. Cooper, Martin J. Smilkstein, Sovitj Pou, Rolf W. Winter, Michael K. Riscoe, Jane X. Kelly

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3475-3502
Number of pages28
JournalJournal of Medicinal Chemistry
Volume62
Issue number7
DOIs
StatePublished - Apr 11 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Dodean, R. A., Kancharla, P., Li, Y., Melendez, V., Read, L., Bane, C. E., Vesely, B., Kreishman-Deitrick, M., Black, C., Li, Q., Sciotti, R. J., Olmeda, R., Luong, T. L., Gaona, H., Potter, B., Sousa, J., Marcsisin, S., Caridha, D., Xie, L., ... 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