2. Academic Validation
  3. 2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Plasmodium falciparum Phosphatidylinositol-4-kinase and Hemozoin Formation with In Vivo Efficacy

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

  • J Med Chem. 2024 Jun 25. doi: 10.1021/acs.jmedchem.4c01154.
Godwin Akpeko Dziwornu 1,  Donald Seanego 1,  Stephen Fienberg 1,  Monica Clements 1,  Jasmin Ferreira 1,  Venkata S Sypu 1,  Sauvik Samanta 1,  Ashlyn D Bhana 1,  Constance M Korkor 2,  Larnelle F Garnie 2,  Nicole Teixeira 2,  Kathryn J Wicht 3,  Dale Taylor 4,  Ronald Olckers 4,  Mathew Njoroge 4,  Liezl Gibhard 4,  Nicolaas Salomane 5,  Sergio Wittlin 6 7,  Rohit Mahato 8,  Arnish Chakraborty 8,  Nicole Sevilleno 9,  Rachael Coyle 9,  Marcus C S Lee 9,  Luiz C Godoy 10,  Charisse Flerida Pasaje 10,  Jacquin C Niles 10,  Janette Reader 11,  Mariette van der Watt 12,  Lyn-Marié Birkholtz 11,  Judith M Bolscher 13,  Marloes H C de Bruijni 13,  Lauren B Coulson 5,  Gregory S Basarab 1 4,  Sandeep R Ghorpade 1,  Kelly Chibale 1 14
Affiliations

Affiliations

  • 1 Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • 2 Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • 3 Drug Discovery and Development Centre (H3D), Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
  • 4 Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
  • 5 Drug Discovery and Development Centre (H3D), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town 7925, South Africa.
  • 6 Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland.
  • 7 University of Basel, 4001 Basel, Switzerland.
  • 8 TCG Lifesciences, Kolkata, 700091, India.
  • 9 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, U.K.
  • 10 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
  • 11 Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria 0028, South Africa.
  • 12 Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria 0028, South Africa.
  • 13 TropIQ Health Sciences, Transistorweg 5, 6534 AT Nijmegen, The Netherlands.
  • 14 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: 38918002 DOI: 10.1021/acs.jmedchem.4c01154
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.

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