2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Plasmodium falciparum Phosphatidylinositol-4-kinase and Hemozoin Formation with In Vivo Efficacy

Godwin Akpeko Dziwornu, Donald Seanego, Stephen Fienberg, Monica Clements, Jasmin Ferreira, Venkata S. Sypu, Sauvik Samanta, Ashlyn D. Bhana, Constance M. Korkor, Larnelle F. Garnie, Nicole Teixeira, Kathryn J. Wicht, Dale Taylor, Ronald Olckers, Mathew Njoroge, Liezl Gibhard, Nicolaas Salomane, Sergio Wittlin, Rohit Mahato, Arnish ChakrabortyNicole Sevilleno, Rachael Coyle, Marcus C. S. Lee, Luiz C. Godoy, Charisse Flerida Pasaje, Jacquin C. Niles, Janette Reader, Mariette van der Watt, Lyn Marié Birkholtz, Judith M. Bolscher, Marloes H.C. de Bruijni, Lauren B. Coulson, Gregory S. Basarab, Sandeep R. Ghorpade (Lead / Corresponding author), Kelly Chibale (Lead / Corresponding author)

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Abstract

Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum (Pf) phosphatidylinositol-4-kinase β (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained Plasmodium PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria.

Original languageEnglish
Pages (from-to)11401-11420
Number of pages20
JournalJournal of Medicinal Chemistry
Volume67
Issue number13
Early online date25 Jun 2024
DOIs
Publication statusPublished - 11 Jul 2024

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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