2. Academic Validation
  3. Optimization of 2,8-Diaryl-1,5-naphthyridines as Plasmodium falciparum Phosphatidylinositol 4-Kinase Inhibitors with Improved ADME Profiles and In Vivo Efficacy

Optimization of 2,8-Diaryl-1,5-naphthyridines as Plasmodium falciparum Phosphatidylinositol 4-Kinase Inhibitors with Improved ADME Profiles and In Vivo Efficacy

  • J Med Chem. 2025 Oct 23;68(20):21878-21891. doi: 10.1021/acs.jmedchem.5c02248.
Godwin A Dziwornu 1,  Donald Seanego 1,  Stephen Fienberg 1,  Venkata S Sypu 1,  Nicolaas Salomane 2,  Liezl Krugmann 2,  Dale Taylor 2,  Keabetswe Masike 2,  Mathew Njoroge 2,  Nonlawat Boonyalai 3,  Marcus C S Lee 3,  Luiz C Godoy 4,  Charisse Flerida Pasaje 4,  Jacquin C Niles 4,  Gregory S Basarab 1,  Lauren B Coulson 2,  Sandeep R Ghorpade 1,  Kelly Chibale 1 5
Affiliations

Affiliations

  • 1 Holistic Drug Discovery and Development (H3D) Centre, Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • 2 Holistic Drug Discovery and Development (H3D) Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town 7925, South Africa.
  • 3 Biological Chemistry and Drug Discovery, Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee DD1 5EH, U.K.
  • 4 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
  • 5 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: 41056343 DOI: 10.1021/acs.jmedchem.5c02248
Abstract

Previously reported antimalarial Plasmodium phosphatidylinositol 4-kinase IIIβ 2,8-diaryl-1,5-naphthyridine inhibitors have shown suboptimal physicochemical and pharmacokinetic properties. A focused target-based structure-activity relationship and structure-property optimization studies identified several compounds with good target and whole-cell activities and improved physicochemical properties. A new frontrunner compound 27 showed an improved pharmacokinetic profile and reduced parasitaemia (91% at 4 × 50 mg/kg QD doses) in the humanized NOD-scid IL-2Rγnull mouse model of Plasmodium falciparum malaria. Compound 27 poses no hERG channel inhibition at high concentrations or mammalian cytotoxicity but shows low selectivity against related human lipid kinases (PI3Kα and PI4Kβ); however, significantly higher selectivity margins were observed against the human MINK1 and MAP4K4 kinases.

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