2. Academic Validation
  3. Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

  • J Med Chem. 2019 Apr 11;62(7):3475-3502. doi: 10.1021/acs.jmedchem.8b01961.
Rozalia A Dodean 1 2,  Papireddy Kancharla 1,  Yuexin Li 1 2,  Victor Melendez 3,  Lisa Read 3,  Charles E Bane 3,  Brian Vesely 3,  Mara Kreishman-Deitrick 3,  Chad Black 3,  Qigui Li 3,  Richard J Sciotti 3,  Raul Olmeda 3,  Thu-Lan Luong 3,  Heather Gaona 3,  Brittney Potter 3,  Jason Sousa 3,  Sean Marcsisin 3,  Diana Caridha 3,  Lisa Xie 3,  Chau Vuong 3,  Qiang Zeng 3,  Jing Zhang 3,  Ping Zhang 3,  Hsiuling Lin 3,  Kirk Butler 3,  Norma Roncal 3,  Lacy Gaynor-Ohnstad 3,  Susan E Leed 3,  Christina Nolan 3,  Stephanie J Huezo 4,  Stephanie A Rasmussen 4,  Melissa T Stephens,  John C Tan,  Roland A Cooper 4,  Martin J Smilkstein 2,  Sovitj Pou 2,  Rolf W Winter 1 2,  Michael K Riscoe 1 2,  Jane X Kelly 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry , Portland State University , Portland , Oregon 97201 , United States.
  • 2 Department of Veterans Affairs Medical Center , Portland , Oregon 97239 , United States.
  • 3 Division of Experimental Therapeutics , Walter Reed Army Institute of Research , Silver Spring , Maryland 20910 , United States.
  • 4 Department of Natural Sciences and Mathematics , Dominican University of California , San Rafael , California 94901 , United States.
PMID: 30852885 DOI: 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.

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