Identification, characterization, and optimization of 2,8-disubstituted-1,5-naphthyridines as novel plasmodium falciparum phosphatidylinositol-4-kinase inhibitors with in vivo efficacy in a humanized mouse Model of malaria

Kandepedu, N; Gonzàlez Cabrera, D; Eedubilli, S; Taylor, D; Brunschwig, C; Gibhard, L; Njoroge, M; Lawrence, N; Paquet, T; Eyermann, C.J; Spangenberg, T; Basarab, G.S; Street, L.J; Chibale, K

Identification, characterization, and optimization of 2,8-disubstituted-1,5-naphthyridines as novel plasmodium falciparum phosphatidylinositol-4-kinase inhibitors with in vivo efficacy in a humanized mouse Model of malaria

Date

2018-07-12

Authors

Kandepedu, N

Gonzàlez Cabrera, D

Eedubilli, S

Taylor, D

Brunschwig, C

Gibhard, L

Njoroge, M

Lawrence, N

Paquet, T

Eyermann, C.J

Publisher

ACS Publications

Abstract

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure-activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite Plasmodium falciparum. In the humanized P. falciparum mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg. In vitro mode-of-action studies revealed Plasmodium falciparum phosphatidylinositol-4-kinase as the target.

Citation

Kandepedu N, Gonzàlez Cabrera D, Eedubilli S, Taylor D, Brunschwig C, Gibhard L, Njoroge M, Lawrence N, Paquet T, Eyermann CJ, Spangenberg T, Basarab GS, Street LJ, Chibale K. Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel Plasmodium falciparum Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria. J Med Chem. 2018 Jul 12;61(13):5692-5703. doi: 10.1021/acs.jmedchem.8b00648.