2. Academic Validation
  3. Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel Plasmodium falciparum Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria

Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel Plasmodium falciparum Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria

  • J Med Chem. 2018 Jul 12;61(13):5692-5703. doi: 10.1021/acs.jmedchem.8b00648.
Nishanth Kandepedu 1,  Diego Gonzàlez Cabrera 1,  Srinivas Eedubilli 1,  Dale Taylor 2,  Christel Brunschwig 2,  Liezl Gibhard 2,  Mathew Njoroge 2,  Nina Lawrence 2,  Tanya Paquet 1,  Charles J Eyermann 1,  Thomas Spangenberg 3,  Gregory S Basarab 1,  Leslie J Street 1,  Kelly Chibale 1 4
Affiliations

Affiliations

  • 1 Drug Discovery and Development Centre (H3D) , University of Cape Town , Rondebosch 7701 , South Africa.
  • 2 Drug Discovery and Development Centre (H3D), DMPK/Pharmacology , University of Cape Town , Observatory 7925 , South Africa.
  • 3 Merck Global Health Institute , Ares Trading S.A. , a subsidiary of Merck KGaA (Darmstadt, Germany), Coinsins 1267 , Switzerland.
  • 4 South African Medical Research Council, Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine , University of Cape Town , Rondebosch 7701 , South Africa.
PMID: 29889526 DOI: 10.1021/acs.jmedchem.8b00648
Abstract

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure-activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite Plasmodium falciparum. In the humanized P. falciparum mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg-1. In vitro mode-of-action studies revealed Plasmodium falciparum phosphatidylinositol-4-kinase as the target.

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