The aim of this study was the direct synthesis of new (4,6-dimethyl-pyrimidin-2-yl)thio-N-acetamides derivatives as possible anticonvulsants. The interaction of thiourea with acetylacetone in sodium ethoxide resulted in scaffold of 4,6-dimethyl-2-thiopyrimidine. Thioacetamide derivatives were synthesized by alkylation of 4,6-dimethyl-2-thiopyrimidine with the comparable α-chloroacetamides in DMF environment and К2СО3 presence. The methods of 1H and 13C NMR spectroscopy, LS/MS, elemental analysis established the structure of the synthesized compounds. Molecular docking of the studied compounds into the active sites of GABAA receptor and the GABA aminotransferase enzyme was carried out. The highest affinity was predicted for the compound having 4-bromophenyl substituent: -7.0 (GABAA) and -8.0 kcal/mol (GABAАТ). Nevertheless, all the studied compounds conceded to the reference ligands phenobarbital (-7.6 kcal/mol) and vigabatrin (-9.0 kcal/mol), respectively. The model of pentylenetetrazole-induced seizures in rats has shown that the studied compounds have moderate anticonvulsant activity. 4-bromophenyl acetamide has also shown the most pronounced activity: the substance statistically significantly extended the latency period and reduced the duration of seizures by 3.4 and 2.2 times, respectively, as well as it reduced lethality of the laboratory animals by 80% and by 2.5 times severity of seizures. Correspondence between the docking results and in vivo studies using PTZ-induced seizures, as well as some parameters of structure anticonvulsant activity correlation was determined.
Key words: 2-thiopyrimidine, docking, GABA, anticonvulsant activity.
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