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. 2021 Jan 1:209:112871.
doi: 10.1016/j.ejmech.2020.112871. Epub 2020 Oct 5.

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

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

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

William J Robinson et al. Eur J Med Chem. .

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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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Fexinidazole.
Scheme 1
Scheme 1
Reagents and conditions: a) sodium ethoxide, formamidine, reflux b) sodium ethoxide, guanidine hydrochloride, reflux.
Fig. 2
Fig. 2
Crystal structure of compound 13.
Fig. 3
Fig. 3
SAR observations for antitrypanosomal pyrimidines explored.
Fig. 4
Fig. 4
Data generated from the in vitro ADME-Tox assessment of compound 13. The results were reported as percentage inhibition where 0–50% inhibition is indicated as a green tile, 51–70% as amber and 71–100% as a red tile.
Fig. 5
Fig. 5
Docking of compounds 1, 6 and 13 with rhodesain. Red and grey surfaces indicate partially negative and neutral charges, respectively. The protein folds were shown as blue ribbons. Hydrogen bonding amino acid residues were depicted as: Cys25 (red), Trp26 (turquoise), Met68 (yellow), Asp69 (brown), Asp161 (green) and His162 (orange).
Fig. 6
Fig. 6
STD and WaterLOGSY spectra of compound 13 in the presence of rhodesain.
See this image and copyright information in PMC

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