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RESEARCH PRODUCT
The discovery of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines
Tanja SchirmeisterBernhard EllingerSolange Lauga-camiChatchakorn EurtivongAvninder S. BhambraAnnie E. TaylorWilliam J. RobinsonMarcel KaiserMaria KuzikovSheraz GulAdolfo BotanaGeorge W. WeaverKuldip SinghRandolph R.j. Arroosubject
Models MolecularTrypanosoma brucei rhodesiensepyrimidinessleeping sicknessIn silicoHuman african trypanosomiasis01 natural sciencesDockingCell Line03 medical and health sciencesantitrypanosomalDrug DiscoverymedicineAnimalsHumansAfrican trypanosomiasisIC50030304 developmental biologyrhodesainPharmacology0303 health sciences010405 organic chemistryChemistryDrug discoveryOrganic ChemistryAntitrypanosomalSleeping sicknessTrypanosoma brucei rhodesienseGeneral MedicineHuman African Trypanosomiasismedicine.diseaseTrypanocidal AgentsIn vitroRats0104 chemical sciencesPyrimidinesRhodesainTrypanosomiasis AfricanBiochemistryDrug developmentDocking (molecular)dockingADME-ToxResearch Paperdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-01-01 |