Identification of Fast-Acting 2,6-Disithstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized Plasmodium falciparum NODscidIL2R gamma(null) Mouse Model of Malaria

Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual b...

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Published inJournal of medicinal chemistry Vol. 61; no. 9; pp. 4213 - 4227
Main Authors Nchinda, Aloysius T., Le Manach, Claire, Paquet, Tanya, Cabrera, Diego Gonzalez, Wicht, Kathryn J., Brunschwig, Christel, Njoroge, Mathew, Abay, Efrem, Taylor, Dale, Lawrence, Nina, Wittlin, Sergio, Jimenez-Diaz, Maria-Belen, Santos Martinez, Maria, Ferrer, Santiago, Angulo-Barturen, Inigo, Jose Lafuente-Monasterio, Maria, Duffy, James, Burrows, Jeremy, Street, Leslie J., Chibale, Kelly
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 10.05.2018
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
ASSAY
OPTIMIZATION
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Summary:Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00382