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.
Highlights
Human African trypanosomiasis (HAT), known as sleeping sickness, is a vector-borne parasitic disease caused by Trypanosoma brucei rhodesiense (T.b.r) and Trypanosoma brucei gambiense (T.b.g), two haemoflagellate subspecies of Trypanosoma brucei [1]
Chalcones were synthesised as previously described by Bhambra et al [13] and subsequently converted to corresponding 4phenyl-6-(pyridin-3-yl)pyrimidines (Scheme 1) as reported by
Our work has described the discovery of novel 4-phenyl-6(pyridine-3-yl)pyrimidines demonstrating promising antitrypanosomal activities in vitro
Summary
Human African trypanosomiasis (HAT), known as sleeping sickness, is a vector-borne parasitic disease caused by Trypanosoma brucei rhodesiense (T.b.r) and Trypanosoma brucei gambiense (T.b.g), two haemoflagellate subspecies of Trypanosoma brucei [1]. Chalcones which contain the a, b-unsaturated carbonyl moiety form the core chemical scaffold for a range of natural products found within fruits, vegetables and other plants This structural motif presents in medications, including sofalcone which is used as a gastric mucosa protective agent [8,9]. Antitrypanosomal activities have been reported for compounds bearing the pyrimidine functional group demonstrating the significance of therapeutic potential [11,12] Within this context, our previous work reported the syntheses of novel antitrypanosomal pyridylchalcones showing sub-micromolar IC50 values against T.b.r [13]. Our previous work reported the syntheses of novel antitrypanosomal pyridylchalcones showing sub-micromolar IC50 values against T.b.r [13] Using this chemical scaffold as a suitable template for modification, we investigated the syntheses and antitrypanosomal activities of substituted 4-phenyl6-(pyridin-3-yl)pyrimidines in a continued interest in antikinetoplastid drug development [14]
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