Publication: 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
Horatscheck, A. ; Andrijevic, A. ; Nchinda, A.T. ; Manach, C.L. ; Paquet, T. ; Khonde, L.P. ; Dam, J. ; Pawar, K. ; Taylor, D. ; Lawrence, N. ... show 10 more
Horatscheck, A.
Andrijevic, A.
Nchinda, A.T.
Manach, C.L.
Paquet, T.
Khonde, L.P.
Dam, J.
Pawar, K.
Taylor, D.
Lawrence, N.
Citations
Altmetric:
Abstract
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-2RĪ³null (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action.
Description
Date
2020-11-12
Journal Title
Journal ISSN
Volume Title
Publisher
ACS
Collections
Research Projects
Organizational Units
Journal Issue
Keywords
Plasmodium falciparum,Kinetics,NSG mouse model,Pharmacokinetic properties
Citation
Horatscheck A, Andrijevic A, Nchinda AT, Le Manach C, Paquet T, Khonde LP, Dam J, Pawar K, Taylor D, Lawrence N, Brunschwig C, Gibhard L, Njoroge M, Reader J, van der Watt M, Wicht K, de Sousa ACC, Okombo J, Maepa K, Egan TJ, Birkholtz LM, Basarab GS, Wittlin S, Fish PV, Street LJ, Duffy J, Chibale K. 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. J Med Chem. 2020 Nov 12;63(21):13013-13030. doi: 10.1021/acs.jmedchem.0c01411. Epub 2020 Oct 25.