Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle

Claire Le Manach; Aloysius T Nchinda; Tanya Paquet; Diego Gonzàlez Cabrera; Yassir Younis; Ze Han; Sridevi Bashyam; Mohammed Zabiulla; Dale Taylor; Nina Lawrence; Karen L White; Susan A Charman; David Waterson; Michael J Witty; Sergio Wittlin; Mariëtte E Botha; Sindisiswe H Nondaba; Janette Reader; Lyn-Marie Birkholtz; María Belén Jiménez-Díaz; María Santos Martínez; Santiago Ferrer; Iñigo Angulo-Barturen; Stephan Meister; Yevgeniya Antonova-Koch; Elizabeth A Winzeler; Leslie J Street; Kelly Chibale

doi:10.1021/acs.jmedchem.6b01265

Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle

J Med Chem. 2016 Nov 10;59(21):9890-9905. doi: 10.1021/acs.jmedchem.6b01265. Epub 2016 Oct 26.

Authors

Claire Le Manach¹, Aloysius T Nchinda¹, Tanya Paquet¹, Diego Gonzàlez Cabrera¹, Yassir Younis¹, Ze Han¹, Sridevi Bashyam², Mohammed Zabiulla², Dale Taylor³, Nina Lawrence³, Karen L White⁴, Susan A Charman⁴, David Waterson⁵, Michael J Witty⁵, Sergio Wittlin^{6

7}, Mariëtte E Botha⁸, Sindisiswe H Nondaba⁸, Janette Reader⁸, Lyn-Marie Birkholtz⁸, María Belén Jiménez-Díaz⁹, María Santos Martínez⁹, Santiago Ferrer⁹, Iñigo Angulo-Barturen⁹, Stephan Meister¹⁰, Yevgeniya Antonova-Koch¹⁰, Elizabeth A Winzeler¹⁰, Leslie J Street¹, Kelly Chibale^{1

11}

Affiliations

¹ Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
² Syngene International Ltd. , Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
³ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town, 7925, South Africa.
⁴ Centre for Drug Candidate Optimisation, Monash University , 381 Royal Parade, Parkville, Victoria 3052 Australia.
⁵ Medicines for Malaria Venture , ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
⁶ Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.
⁷ University of Basel , 4003 Basel, Switzerland.
⁸ Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
⁹ GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
¹⁰ Department of Pediatrics, Pharmacology and Drug Discovery, School of Medicine, University of California, San Diego (UCSD) , 9500 Gilman Drive, La Jolla, California 92093, United States.
¹¹ 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: 27748596
DOI: 10.1021/acs.jmedchem.6b01265

Abstract

Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rγ^null mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.

Publication types

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

MeSH terms

Animals
Antimalarials / chemistry
Antimalarials / metabolism
Antimalarials / pharmacology*
Disease Models, Animal
Dose-Response Relationship, Drug
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Ether-A-Go-Go Potassium Channels / metabolism
Hep G2 Cells
Humans
Life Cycle Stages / drug effects*
Malaria / drug therapy*
Mice
Mice, SCID
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Parasitic Diseases, Animal / drug therapy*
Parasitic Diseases, Animal / parasitology
Parasitic Sensitivity Tests
Plasmodium berghei / drug effects*
Plasmodium berghei / growth & development
Plasmodium falciparum / drug effects*
Plasmodium falciparum / growth & development
Pyrazines / chemistry
Pyrazines / metabolism
Pyrazines / pharmacology*
Solubility
Structure-Activity Relationship
Water / chemistry

Substances

Antimalarials
Ether-A-Go-Go Potassium Channels
Pyrazines
Water
2-aminopyrazine