2. Academic Validation
  3. Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials

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

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.

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