Design, synthesis, molecular docking and anticonvulsant evaluation of 6-methyl-2-arylaminopyrimidin-4(3h)-one

Abstract

The aim. Synthesis of 2-aminoaryl derivatives of 6-methyl-pyrimidin-4(3H)-one, target-based virtual screening followed by the study of anticonvulsant activity and the establishment of structure-activity patterns.

Materials and methods. The standard methods of organic synthesis were used, synthesized compounds structure was proved with elemental analysis, 1H NMR spectroscopy, chromatography-mass spectrometry. Molecular docking was performed using AutoDockTools-1.5.6 and AutoDock Vina. Anticonvulsant activity was studied in а model of pentylenetetrazole seizures in rats.

Results. Methylation of 6-methyl-2-thiopyrimidin-4 (3H)-one with dimethyl sulfate or methyl iodide gave a 2-thiomethyl derivative. By heating the latter with aromatic amines at 140 ºC, the target 2-aminoaryl derivatives of 6-methyl-pyrimidin-4 (3H)-one were obtained. The prospect of screening the synthesized compounds on the pentylenetetrazole model by seizure and the selection of the objects was performed by the results of binding energy and conformation evaluation at the active sites of GABA receptor and GABA-AT. The test substances did not show anticonvulsant activity: only 2 compounds tended to exhibit activity according to the criterion of integral protective index - a decrease in mortality compared to control, preventing mortality in 100 and 80 % of animals, respectively. Comparison with previous activity results of 2-thioacetanilide derivatives allowed to prove the positive role of thioacetamide and phenyl fragments, as well as 4-Br, 4-MeO radicals in the manifestation of anticonvulsant activity and increase of lethality in the presence of Cl atoms.

Conclusions. The synthesis was performed and construction of the 2-aminoaryl derivatives of 6-methyl-pyrimidin-4(3H)-one was proved. PTZ seizures model in rats did not show anticonvulsant activity. However, the obtained results allowed us to identify a number of structural fragments that influence anticonvulsant activity. A positive correlation between in vivo studies on PTZ seizures model and docking results in active sites of GABAA and GABAAT enzyme was determined