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
  • 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.