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.
Journal article

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.

  • Le Manach C Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
  • Nchinda AT Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
  • Paquet T Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
  • Gonzàlez Cabrera D Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
  • Younis Y Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
  • Han Z Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
  • Bashyam S Syngene International Ltd. , Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Zabiulla M Syngene International Ltd. , Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Taylor D Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town, 7925, South Africa.
  • Lawrence N Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town, 7925, South Africa.
  • White KL Centre for Drug Candidate Optimisation, Monash University , 381 Royal Parade, Parkville, Victoria 3052 Australia.
  • Charman SA Centre for Drug Candidate Optimisation, Monash University , 381 Royal Parade, Parkville, Victoria 3052 Australia.
  • Waterson D Medicines for Malaria Venture , ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
  • Witty MJ Medicines for Malaria Venture , ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
  • Wittlin S Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.
  • Botha ME Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
  • Nondaba SH Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
  • Reader J Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
  • Birkholtz LM Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
  • Jiménez-Díaz MB GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
  • Martínez MS GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
  • Ferrer S GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
  • Angulo-Barturen I GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
  • Meister S 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.
  • Antonova-Koch Y 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.
  • Winzeler EA 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.
  • Street LJ Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
  • Chibale K Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
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  • 2016-10-18
Published in:
  • Journal of medicinal chemistry. - 2016
English 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-2Rγnull 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.
Language
  • English
Open access status
closed
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Persistent URL
https://sonar.ch/global/documents/231930
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