Quinolone-3-Diarylethers: A New Class of Antimalarial Drug

20 Mar 2013

Aaron Nilsen, Alexis N. LaCrue, Karen L. White, Isaac P. Forquer, R. Matthew Cross, Jutta Marfurt, Michael W. Mather, Michael J. Delves, David M. Shackleford, Fabian E. Saenz, Joanne M. Morrisey, Jessica Steuten, Tina Mutka, Yuexin Li, Grennady Wirjanata, Eileen Ryan, Sandra Duffy, Jane Xu Kelly, Boni F. Sebayang, Anne-Marie Zeeman, Rintis Noviyanti, Robert E. Sinden, Clemens H. M. Kocken, Ric N. Price, Vicky M. Avery, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Santiago Ferrer, Esperanza Herreros, Laura M. Sanz, Francisco-Javier Gamo, Ian Bathurst, Jeremy N. Burrows, Peter Sieg, R. Kiplin Guy, Rolf W. Winter, Akhil B. Vaidya, Susan A. Charman, Dennis E. Kyle, Roman Manetsch and Michael K. Riscoe

Science Translational Medicine

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.

Read the full article on the Science Translational Medicine website.