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

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journal contribution
posted on 04.11.2020, 14:45 by William J. Robinson, Annie E. Taylor, Solange Lauga-Cami, George Weaver, Randolph R.J. Arroo, Marcel Kaiser, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Kuldip Singh, Tanja Schirmeister, Adolfo Botana, Chatchakorn Eurtivong, Avninder S. Bhambra
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.

History

School

  • Science

Department

  • Chemistry

Published in

European Journal of Medicinal Chemistry

Volume

209

Publisher

Elsevier

Version

VoR (Version of Record)

Rights holder

© Crown Copyright

Publisher statement

This is an Open Access Article. It is published by Elsevier under the Creative Commons Attribution 4.0 International Licence (CC BY 4.0). Full details of this licence are available at: https://creativecommons.org/licenses/by/4.0/

Acceptance date

19/09/2020

Publication date

2020-10-05

Copyright date

2020

ISSN

0223-5234

eISSN

1768-3254

Language

en

Depositor

Dr George Weaver. Deposit date: 3 November 2020

Article number

112871

Licence

Exports