Identification of 2,4-Disubstituted Imidazopyridines as Hemozoin Formation Inhibitors with Fast-Killing Kinetics and In Vivo Efficacy in the Plasmodium falciparum NSG Mouse Model

作者：André Horatscheck, Ana Andrijević, Aloysius T. Nchinda, Claire Le Manach, Tanya Paquet, Lutete Peguy Khonde, Jean Dam, Kailash P. Pawar, Dale Taylor, Nina Lawrence, Christel Brunschwig, Liezl Gibhard, Mathew Njoroge, Janette Reader, Mariëtte van der Watt, Kathryn J. Wicht, Ana Carolina C. de Sousa, John Okombo, Keletso Maepa, Timothy J. Egan, Lyn‐Marié Birkholtz, Gregory S. Basarab, Sergio Wittlin, Paul V. Fish, Leslie J. Street, James Duffy, Kelly Chibale · 发表于：Journal of Medicinal Chemistry · 年份：2020 · DOI：10.1021/acs.jmedchem.0c01411 · 被引用次数：18 · 研究领域：Malaria Research and Control、Trypanosoma species research and implications、Mosquito-borne diseases and control

A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite Plasmodium falciparum . Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multidrug-resistant K1 strain, in vitro cytotoxicity, and cardiotoxicity and were addressed through structure–activity and structure–property relationship studies. Pharmacokinetic properties were assessed in mice for compounds showing desirable in vitro activity, a selectivity window over cytotoxicity, and microsomal metabolic stability. Frontrunner compound 37 showed good exposure in mice combined with good in vitro activity against the malaria parasite, which translated into in vivo efficacy in the P. falciparum NOD- scid IL-2Rγ null (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action.