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
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-2Rnull 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.
Le Manach, Claire,Nchinda, Aloysius T.,Paquet, Tanya,Gonzàlez Cabrera, Diego,Younis, Yassir,Han, Ze,Bashyam, Sridevi,Zabiulla, Mohammed,Taylor, Dale,Lawrence, Nina,White, Karen L.,Charman, Susan A.,Waterson, David,Witty, Michael J.,Wittlin, Sergio,Botha, Mari?tte E.,Nondaba, Sindisiswe H.,Reader, Janette,Birkholtz, Lyn-Marie,Jiménez-Díaz, María Belén,Martínez, María Santos,Ferrer, Santiago,Angulo-Barturen, Inìigo,Meister, Stephan,Antonova-Koch, Yevgeniya,Winzeler, Elizabeth A.,Street, Leslie J.,Chibale, Kelly
p. 9890 - 9905
(2016/11/19)
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