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 - http://www.scopus.com/inward/record.url?scp=85196942369&partnerID=8YFLogxK
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 -