2. Academic Validation
  3. Quinolone-3-diarylethers: a new class of antimalarial drug

Quinolone-3-diarylethers: a new class of antimalarial drug

  • Sci Transl Med. 2013 Mar 20;5(177):177ra37. doi: 10.1126/scitranslmed.3005029.
Aaron Nilsen  # 1,  Alexis N LaCrue  # 2,  Karen L White 3,  Isaac P Forquer 1,  Richard M Cross 4,  Jutta Marfurt 5,  Michael W Mather 6,  Michael J Delves 7,  David M Shackleford 3,  Fabian E Saenz 2,  Joanne M Morrisey 6,  Jessica Steuten 3,  Tina Mutka 2,  Yuexin Li 1,  Grennady Wirjanata 5,  Eileen Ryan 3,  Sandra Duffy 8,  Jane Xu Kelly 1,  Boni F Sebayang 9,  Anne-Marie Zeeman 10,  Rintis Noviyanti 9,  Robert E Sinden 7,  Clemens H M Kocken 10,  Ric N Price 5 11,  Vicky M Avery 8,  Iñigo Angulo-Barturen 12,  María Belén Jiménez-Díaz 12,  Santiago Ferrer 12,  Esperanza Herreros 12,  Laura M Sanz 12,  Francisco-Javier Gamo 12,  Ian Bathurst 13,  Jeremy N Burrows 13,  Peter Siegl 14,  R Kiplin Guy 15,  Rolf W Winter 1,  Akhil B Vaidya 6,  Susan A Charman 3,  Dennis E Kyle 2,  Roman Manetsch 4,  Michael K Riscoe 1 16
Affiliations

Affiliations

  • 1 VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, USA.
  • 2 Department of Global Health, College of Public Health, 3720 Spectrum Blvd. (Ste 304), Tampa, FL 33612, USA.
  • 3 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 4 Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL 33620-5250, USA.
  • 5 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
  • 6 Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
  • 7 Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
  • 8 Eskitis Institute for Cell & Molecular Therapies, Brisbane Innovation Park, Nathan campus, Griffith University, QLD 4111, Australia.
  • 9 Eijkman Institute for Molecular Biology, Jl. Diponegoro 69, Jakarta 10430, Indonesia.
  • 10 Department of Parasitology, Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands.
  • 11 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7LJ, UK.
  • 12 GlaxoSmithKline, Medicines Development Campus, Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
  • 13 Medicines for Malaria Venture, 20, route de Pré-Bois, PO Box 1826, 1215 Geneva 15, Switzerland.
  • 14 Siegl Pharma Consulting LLC, Blue Bell, PA, USA.
  • 15 Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678 USA.
  • 16 Department of Molecular Microbiology and Immunology, 3181 Sam Jackson Blvd., Portland, Oregon 97239, USA.
  • # Contributed equally.
PMID: 23515079 DOI: 10.1126/scitranslmed.3005029
Abstract

The goal for developing new antimalarial drugs is to find a molecule that can target multiple stages of the parasite's life cycle, thus impacting prevention, treatment, and transmission of the disease. The 4(1H)-quinolone-3-diarylethers are selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. These compounds are highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax. They target both the liver and blood stages of the Parasite as well as the forms that are crucial for disease transmission, that is, the gametocytes, the zygote, the ookinete, and the oocyst. Selected as a preclinical candidate, ELQ-300 has good oral bioavailability at efficacious doses in mice, is metabolically stable, and is highly active in blocking transmission in rodent models of malaria. Given its predicted low dose in patients and its predicted long half-life, ELQ-300 has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria.

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