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

TY - JOUR

T1 - 2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Plasmodium falciparum Phosphatidylinositol-4-kinase and Hemozoin Formation with In Vivo Efficacy

AU - Dziwornu, Godwin Akpeko

AU - Seanego, Donald

AU - Fienberg, Stephen

AU - Clements, Monica

AU - Ferreira, Jasmin

AU - Sypu, Venkata S.

AU - Samanta, Sauvik

AU - Bhana, Ashlyn D.

AU - Korkor, Constance M.

AU - Garnie, Larnelle F.

AU - Teixeira, Nicole

AU - Wicht, Kathryn J.

AU - Taylor, Dale

AU - Olckers, Ronald

AU - Njoroge, Mathew

AU - Gibhard, Liezl

AU - Salomane, Nicolaas

AU - Wittlin, Sergio

AU - Mahato, Rohit

AU - Chakraborty, Arnish

AU - Sevilleno, Nicole

AU - Coyle, Rachael

AU - Lee, Marcus C. S.

AU - Godoy, Luiz C.

AU - Pasaje, Charisse Flerida

AU - Niles, Jacquin C.

AU - Reader, Janette

AU - van der Watt, Mariette

AU - Birkholtz, Lyn Marié

AU - Bolscher, Judith M.

AU - de Bruijni, Marloes H.C.

AU - Coulson, Lauren B.

AU - Basarab, Gregory S.

AU - Ghorpade, Sandeep R.

AU - Chibale, Kelly

N1 - Publisher Copyright: © 2024 The Authors. Published by American Chemical Society.

PY - 2024/7/11

Y1 - 2024/7/11

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85196942369

U2 - 10.1021/acs.jmedchem.4c01154

DO - 10.1021/acs.jmedchem.4c01154

M3 - Article

C2 - 38918002

AN - SCOPUS:85196942369

SN - 0022-2623

VL - 67

SP - 11401

EP - 11420

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 13

ER -