Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model

Kawaljit Singh; John Okombo; Christel Brunschwig; Ferdinand Ndubi; Linley Barnard; Chad Wilkinson; Peter M Njogu; Mathew Njoroge; Lizahn Laing; Marta Machado; Miguel Prudêncio; Janette Reader; Mariette Botha; Sindisiwe Nondaba; Lyn-Marie Birkholtz; Sonja Lauterbach; Alisje Churchyard; Theresa L Coetzer; Jeremy N Burrows; Clive Yeates; Paolo Denti; Lubbe Wiesner; Timothy J Egan; Sergio Wittlin; Kelly Chibale

doi:10.1021/acs.jmedchem.6b01641

Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model

J Med Chem. 2017 Feb 23;60(4):1432-1448. doi: 10.1021/acs.jmedchem.6b01641. Epub 2017 Feb 7.

Authors

Kawaljit Singh^{1

2}, John Okombo¹, Christel Brunschwig³, Ferdinand Ndubi¹, Linley Barnard¹, Chad Wilkinson¹, Peter M Njogu⁴, Mathew Njoroge³, Lizahn Laing³, Marta Machado⁵, Miguel Prudêncio⁵, Janette Reader⁶, Mariette Botha⁶, Sindisiwe Nondaba⁶, Lyn-Marie Birkholtz⁶, Sonja Lauterbach⁷, Alisje Churchyard⁷, Theresa L Coetzer⁷, Jeremy N Burrows⁸, Clive Yeates⁹, Paolo Denti³, Lubbe Wiesner³, Timothy J Egan¹, Sergio Wittlin^{10

11}, Kelly Chibale^{1

2}

Affiliations

¹ Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
² 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.
³ Department of Medicine, Division of Clinical Pharmacology, University of Cape Town , Observatory, 7925, South Africa.
⁴ Department of Pharmaceutical Chemistry, University of Nairobi , P.O. Box 19676, Nairobi, 00202, Kenya.
⁵ Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
⁶ Department of Biochemistry, Institute for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
⁷ Wits Research Institute for Malaria, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service , Johannesburg 2193, South Africa.
⁸ Medicines for Malaria Venture , ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
⁹ Inpharma Consultancy , 6 Dudley Hill Close, Welwyn, Hertfordshire AL60QQ, U.K.
¹⁰ Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.
¹¹ University of Basel , 4003 Basel, Switzerland.

PMID: 28094524
DOI: 10.1021/acs.jmedchem.6b01641

Abstract

Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.

Publication types

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

MeSH terms

Animals
Antimalarials / chemistry*
Antimalarials / pharmacokinetics
Antimalarials / pharmacology
Antimalarials / therapeutic use*
Benzimidazoles / chemistry*
Benzimidazoles / pharmacokinetics
Benzimidazoles / pharmacology
Benzimidazoles / therapeutic use*
Life Cycle Stages / drug effects
Malaria / drug therapy*
Malaria / parasitology*
Male
Mice
Plasmodium berghei / drug effects*
Plasmodium berghei / growth & development
Structure-Activity Relationship

Substances

Antimalarials
Benzimidazoles