Quinolone-3-diarylethers: a new class of antimalarial drug PMID: 23515079

ADC Targets in Oncology

2026-04-10

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

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.

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.