Abstract

This research aimed at synthesizing new potential anticonvulsants in the series of 2-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio-acetamides. An initial intermediate - 6-methyl-2-thioxo-2,3-dihydro-pyrimidin-4(1Н)-one was obtained by the reaction of thiourea with an acetoacetic ester in the presence of sodium methoxide. The target 2-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl) thioacetamides were synthesized by alkylation of initial 6-methyl-2-thiopyrimidin-4-one with corresponding 2-chloroacetamides in DMF in the presence of potassium carbonate. The structure of compounds was confirmed by 1H NMR-spectroscopy, LCMS and elemental analysis. A screening of anticonvulsant activity of synthesized compounds was carried out using the pentylenetetrazole- and maximal electroshock-induced seizures models. In these studies the highest anticonvulsant activity demonstrated a compound 5.5 2-[(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio]-N-(4-bromophenyl)-acetamide which decreased the lethality, the number and the severity of seizures, and increased their latent period. For this compound parameters of ЕD50, acute (LD50) and neurotoxicity (TD50) as well as therapeutic (TI) and protective (PI) indexes were determined. Logical structure analysis of anticonvulsant activity screening revealed some patterns of “structure-activity” relationship.

Key words: 2-thiopyrimidine; alkylation; acetamides; anticonvulsant activity.