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Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized Plasmodium falciparum NODscidIL2Rγ null Mouse Model of Malaria.

Aloysius T NchindaClaire Le ManachTanya PaquetDiego Gonzàlez CabreraKathryn J WichtChristel BrunschwigMathew NjorogeEfrem AbayDale TaylorNina LawrenceSergio WittlinMaría-Belén Jiménez-DíazMaría Santos MartínezSantiago FerrerIñigo Angulo-BarturenMaria Jose Lafuente-MonasterioJames DuffyJeremy BurrowsLeslie J StreetKelly Chibale
Published in: Journal of medicinal chemistry (2018)
Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.
Keyphrases
  • bone marrow
  • plasmodium falciparum
  • mouse model
  • endothelial cells
  • single cell
  • molecular docking
  • combination therapy
  • monoclonal antibody
  • pluripotent stem cells
  • replacement therapy