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

European journal of medicinal chemistry 2021 Jan 01

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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. Crown Copyright © 2020. Published by Elsevier Masson SAS. All rights reserved.

Citation

William J Robinson, Annie E Taylor, Solange Lauga-Cami, George W Weaver, Randolph R J Arroo, Marcel Kaiser, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Kuldip Singh, Tanja Schirmeister, Adolfo Botana, Chatchakorn Eurtivong, Avninder S Bhambra. The discovery of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines. European journal of medicinal chemistry. 2021 Jan 01;209:112871