2. Academic Validation
  3. The discovery of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines

The discovery of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines

  • Eur J Med Chem. 2021 Jan 1:209:112871. doi: 10.1016/j.ejmech.2020.112871.
William J Robinson 1,  Annie E Taylor 1,  Solange Lauga-Cami 1,  George W Weaver 2,  Randolph R J Arroo 3,  Marcel Kaiser 4,  Sheraz Gul 5,  Maria Kuzikov 5,  Bernhard Ellinger 5,  Kuldip Singh 6,  Tanja Schirmeister 7,  Adolfo Botana 8,  Chatchakorn Eurtivong 9,  Avninder S Bhambra 10
Affiliations

Affiliations

  • 1 Leicester School of Allied Health Sciences, De Montfort University, The Gateway, Leicester, LE1 9BH, UK.
  • 2 Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, UK.
  • 3 Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester, LE1 9BH, UK.
  • 4 Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland; University of Basel, Petersplatz 1, 4003, Basel, Switzerland.
  • 5 Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port, Hamburg, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hamburg Site, Hamburg, Germany.
  • 6 Department of Chemistry, University of Leicester, Leicester, LE1 7RH, UK.
  • 7 Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University of Mainz, Staudingerweg 5, D-55128, Mainz, Germany.
  • 8 JEOL UK, JEOL House, Silvert Court, Watchmead, Welwyn Garden City, Herts, AL7 1LT, UK.
  • 9 Program in Chemical Sciences, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok, 10210, Thailand.
  • 10 Leicester School of Allied Health Sciences, De Montfort University, The Gateway, Leicester, LE1 9BH, UK. Electronic address: abhambra@dmu.ac.uk.
PMID: 33070078 DOI: 10.1016/j.ejmech.2020.112871
Abstract

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense which seriously affects human health in Africa. Current therapies present limitations in their application, Parasite resistance, or require further clinical investigation for wider use. Our work herein describes the design and syntheses of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines, with compound 13, the 4-(2-methoxyphenyl)-6-(pyridine-3-yl)pyrimidin-2-amine demonstrating an IC50 value of 0.38 μM and a promising off-target ADME-Tox profile in vitro. In silico molecular target investigations showed rhodesain to be a putative candidate, supported by STD and WaterLOGSY NMR experiments, however, in vitro evaluation of compound 13 against rhodesain exhibited low experimental inhibition. Therefore, our reported library of drug-like pyrimidines present promising scaffolds for further antikinetoplastid drug development for both phenotypic and target-based drug discovery.

Keywords

ADME-Tox; Antitrypanosomal; Docking; Human african trypanosomiasis; Pyrimidines; Rhodesain; Sleeping sickness; Trypanosoma brucei rhodesiense.

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