2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase and Hemozoin Formation with <i>In Vivo</i> 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 Chakraborty, Nicole Sevilleno, Rachael Coyle, Lee M, Luiz C. Godoy, Charisse Flerida A. Pasaje, Jacquin C. Niles, Janette Reader, Mariëtte van der Watt, Lyn‐Marié Birkholtz, Judith M. Bolscher, Marloes H.C. de Bruijni, Lauren B. Coulson, Gregory S. Basarab, Sandeep R. Ghorpade, Kelly Chibale
Abstract
High Resolution Image Download MS PowerPoint Slide 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 Pf PI4K 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.