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-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.