Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized Plasmodium falciparum NODscidIL2Rγ null Mouse Model of Malaria

Aloysius T Nchinda; Claire Le Manach; Tanya Paquet; Diego Gonzàlez Cabrera; Kathryn J Wicht; Christel Brunschwig; Mathew Njoroge; Efrem Abay; Dale Taylor; Nina Lawrence; Sergio Wittlin; María-Belén Jiménez-Díaz; María Santos Martínez; Santiago Ferrer; Iñigo Angulo-Barturen; Maria Jose Lafuente-Monasterio; James Duffy; Jeremy Burrows; Leslie J Street; Kelly Chibale

doi:10.1021/acs.jmedchem.8b00382

Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized Plasmodium falciparum NODscidIL2Rγ ^null Mouse Model of Malaria

J Med Chem. 2018 May 10;61(9):4213-4227. doi: 10.1021/acs.jmedchem.8b00382. Epub 2018 Apr 27.

Authors

Aloysius T Nchinda¹, Claire Le Manach¹, Tanya Paquet¹, Diego Gonzàlez Cabrera¹, Kathryn J Wicht¹, Christel Brunschwig², Mathew Njoroge², Efrem Abay², Dale Taylor², Nina Lawrence², Sergio Wittlin^{3

4}, María-Belén Jiménez-Díaz⁵, María Santos Martínez⁵, Santiago Ferrer⁵, Iñigo Angulo-Barturen⁵, Maria Jose Lafuente-Monasterio⁵, James Duffy⁶, Jeremy Burrows⁶, Leslie J Street¹, Kelly Chibale^{1

7}

Affiliations

¹ Drug Discovery and Development Center (H3D), Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.
² Drug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine , University of Cape Town , Observatory, Cape Town 7925 , South Africa.
³ Swiss Tropical and Public Health Institute , Socinstrasse 57 , 4002 Basel , Switzerland.
⁴ University of Basel , 4003 Basel , Switzerland.
⁵ GlaxoSmithKline, Tres Cantos Medicines Development Campus , Severo Ochoa, 2 , 28760 Tres Cantos, Madrid , Spain.
⁶ Medicines for Malaria Venture, ICC , Route de Pré-Bois 20 , PO Box 1826, 1215 Geneva , Switzerland.
⁷ South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine , University of Cape Town , Rondebosch 7701 , South Africa.

PMID: 29665687
DOI: 10.1021/acs.jmedchem.8b00382

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Drug Discovery*
Drug Stability
ERG1 Potassium Channel / metabolism
Humans
Imidazoles / chemistry*
Imidazoles / metabolism
Imidazoles / pharmacokinetics*
Imidazoles / therapeutic use
Malaria / drug therapy*
Malaria / genetics
Malaria / metabolism
Mice
Plasmodium falciparum / physiology*
Pyridines / chemistry*
Pyridines / metabolism
Pyridines / pharmacokinetics*
Pyridines / therapeutic use
Solubility
Structure-Activity Relationship
Tissue Distribution
Water / chemistry

Substances

ERG1 Potassium Channel
Imidazoles
Pyridines
imidazopyridine
Water