Synthesis and anticonvulsant activity of 6-methyl-2-thioxo-2, 3-dihydropyrimidin-4(1H)-one acetamides

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(1H)-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 Dimethylformamide (DMF) in the presence of potassium carbonate. The structure of compounds was confirmed by 1H Nuclear magnetic resonance (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 these compound parameters of ED 50 , acute (LD 50 ) and neurotoxicity (TD 50 ), 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.