Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials

  • J Med Chem. 2020 Jun 11;63(11):6179-6202. doi: 10.1021/acs.jmedchem.0c00539.
Papireddy Kancharla  1 ,  Rozalia A Dodean  2 ,  Yuexin Li  2 ,  Sovitj Pou  2 ,  Brandon Pybus  3 ,  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 ,  Frida G Ceja  4 ,  Stephanie A Rasmussen  4 ,  Patrick K Tumwebaze  5 ,  Philip J Rosenthal  6 ,  Jianbing Mu  7 ,  Brett R Bayles  4  8 ,  Roland A Cooper  4 ,  Kevin A Reynolds  1 ,  Martin J Smilkstein  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.
  • 5. Infectious Diseases Research Collaboration, Kampala, Uganda.
  • 6. Department of Medicine, University of California, San Francisco, San Francisco, California 94143, United States.
  • 7. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, United States.
  • 8. Global Public Health Program, Dominican University of California, San Rafael, California 94901, United States.
PMID: 32390431 DOI: 10.1021/acs.jmedchem.0c00539
Abstract

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.