ABSTRACT
The aim of this study is the direct synthesis of new (4,6-dimethylpyrimidin-2-yl)thio-N-acetamides derivatives aspossible anticonvulsants. The interaction of thiourea with acetylacetone in sodium ethoxide resulted in the scaffoldof 4,6-dimethyl-2-thiopyrimidine. Thioacetamide derivatives were synthesized by alkylation of 4,6-dimethyl-2-thiopyrimidine with comparable α-chloroacetamides in the Dimethylformamide (DMF) environment and in the presenceof К2СО3. The methods of 1H and 13C Nuclear magnetic resonance (NMR) spectroscopy, Liquid chromatography–mass spectrometry (LS/MS), and elemental analysis established the structure of the synthesized compounds. Theaffinity of the studied compounds with anticonvulsant biotargets— Type-A γ-aminobutyric acid receptor (GABAAR)and the gamma-aminobutyric acid-aminotransferase enzyme—was carried out using the molecular-docking method.The highest affinity was predicted for the compound having 4-bromophenyl substituent: −7.0 (GABAA) and −8.0(GABAАТ) kcal/mol. Nevertheless, all the studied compounds conceded to the reference ligands—phenobarbital(−7.6 kcal/mol) and vigabatrin (−9.0 kcal/mol). The model of pentylenetetrazole-induced seizures in rats has shownthat the studied compounds have moderate anticonvulsant activity. 4-Bromophenyl acetamide has also shown the mostpronounced activity: the substance statistically significantly extended the latency period and reduced the duration ofseizures by 3.4 and 2.2 times, respectively; moreover, it reduced lethality of the laboratory animals by 80% and by2.5 times severity of seizures. Correspondence between the docking results and in vivo studies, using PTZ-inducedseizures, as well as some parameters of “structure-anticonvulsant activity” correlation, was determined.
ABSTRACT
This research aimed at synthesizing new potential anticonvulsants in the series of 2-(4-methyl-6-oxo-1,6-dihydropyrimidin2-yl)thio-acetamides. An initial intermediate 6-methyl-2-thioxo-2,3-dihydro-pyrimidin-4(1Н)-one was obtained by thereaction 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 withcorresponding 2-chloroacetamides in Dimethylformamide (DMF) in the presence of potassium carbonate. The structureof 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- andmaximal electroshock-induced seizures models. In these studies, the highest anticonvulsant activity demonstrated acompound 5.5 2-[(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio]-N-(4-bromophenyl)-acetamide, which decreased thelethality, the number and the severity of seizures, and increased their latent period. For these compound parameters ofЕD50, 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.