Identification of a Potential Antimalarial Drug Candidate from a Series of 2‑Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle

17 Oct 2016

Claire Le Manach, Aloysius T. Nchinda, Tanya Paquet, Diego Gonzàlez Cabrera, Yassir Younis, Ze Han, Sridevi Bashyam, Mohammed Zabiulla, Dale Taylor, Nina Lawrence, Karen L. White, Susan A. Charman, David Waterson, Michael J. Witty, Sergio Wittlin, Mariëtte E. Botha, Sindisiswe H. Nondaba, Janette Reader, Lyn-Marie Birkholtz, María Belén Jiménez-Díaz, María Santos Martínez, Santiago Ferrer, Iñigo Angulo-Barturen, Stephan Meister, Yevgeniya Antonova-Koch, Elizabeth A. Winzeler, Leslie J. Street, and Kelly Chibale

Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.6b01265


Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rγnull mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.

Read the full article on the Journal of Medicinal Chemistry website.