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 Articles uri icon

authors

  • LE MANACH, CLAIRE
  • NCHINDA, ALOYSIUS T.
  • PAQUET, TANYA
  • CABRERA, DIEGO GONZALEZ
  • 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, MARIETTE E.
  • NONDABA, SINDISISWE H.
  • READER, JANETTE
  • BIRKHOLTZ, LYN-MARIE
  • JIMÉNEZ DÍAZ, MARÍA BELÉN
  • SANTOS MARTINEZ, MARIA
  • FERRER BAZAGA, SANTIAGO
  • ANGULO BARTUREN, ÍÑIGO
  • MEISTER, STEPHAN
  • ANTONOVA-KOCH, YEVGENIYA
  • WINZELER, ELIZABETH A.
  • STREET, LESLIE J.
  • CHIBALE, KELLY

publication date

  • November 2016

start page

  • 9890

end page

  • 9905

issue

  • 21

volume

  • 59

International Standard Serial Number (ISSN)

  • 0022-2623

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

abstract

  • 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.

subjects

  • Biology and Biomedicine
  • Medicine

keywords

  • amides; anatomy; parasites; rodent models; solubility