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

作者：Claire Le Manach, Aloysius T. Nchinda, Tanya Paquet, Diego González 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 Botha, Sindisiswe H. Nondaba, Janette Reader, Lyn‐Marié Birkholtz, Marı́a Belén Jiménez-Dı́az, Maria Santos Martínez, Santiago Ferrer, Íñigo Angulo‐Barturen, Stephan Meister, Yevgeniya Antonova‐Koch, Elizabeth A. Winzeler, Leslie J. Street, Kelly Chibale · 发表于：Journal of Medicinal Chemistry · 年份：2016 · DOI：10.1021/acs.jmedchem.6b01265 · 被引用次数：59 · 研究领域：Malaria Research and Control、Phenothiazines and Benzothiazines Synthesis and Activities、Computational Drug Discovery Methods

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-2Rγ null 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.