Design, synthesis, in vivo and in silico anticonvulsant activity studies of derivatives of 6-amino-4-hydroxy-2-thio-pyrimidine

Abstract

The aim of the given research was the targeted synthesis of anticonvulsants - (4-amino-6-hydroxy-pyrimidin-2-yl)thio-N-acetamides derivatives. Perspective of the search of anticonvulsants was evaluated by the ADMET method and docking study. The starting 6-amino-2-thiopyrimidine was obtained in result of reaction between thiourea and ethyl cyanoacetate in sodium ethoxide environment. The targeted thioacetamide derivatives were synthesized by alkylation of 6-amino-2-thiopyrimidine with the corresponding 2-chloroacetamides in DMFA environment in potassium carbonate presence. The structure of the synthesized compounds was determined using 1 H and 13C NMR spectroscopy, LS/MS, and elemental analysis. A screening study of anticonvulsant activity on the model of pentylenetetrazole-induced seizures in rats was carried out. A lead compound – 2-((4-amino-6-hydroxypyrimidin-2-yl)thio)- N-(3-methylphenyl)acetamide – was found. The mentioned compound has shown its ability to prevented lethality, reduce the number and severity of seizures, as well as to increase latency period. Some correlation features between structure and anticonvulsant activity were determined. The obtained results of molecular docking study have shown the affinity of the lead compound to GABAA, GABAAT, Carbonic Anhydrase II, and NMDA receptors, and a possible mechanism for anticonvulsant action.