Promising anticonvulsant N-[(2,4-dichlorophenyl) methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl) acetamide: dose-dependent study and evaluation of anticonvulsant action spectrum in vivo and in silico.

The anticonvulsant spectrum of the original promising anticonvulsant N-[(2,4-dichlorophenyl) methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl) acetamide was studied. The compound had a pronounced anticonvulsant effect, significantly reducing the mortality of mice in models of seizures induced by pentylenetetrazole, picrotoxin, strychnine, and caffeine. In the thiosemicarbazideinduced seizure model, the test compound did not reduce mortality. The obtained results indicated that the mechanism of anticonvulsant action involved GABA-ergic (effective in models of pentylenetetrazole and picrotoxin-induced seizures), glycinergic (efficiency in the strychnine model of paroxysms), and adenosinergic (effectiveness in the model of caffeine induced seizures). Molecular docking of a promising anticonvulsant to anticonvulsant biotargets follow the mechanisms of chemo-induced seizures, namely GABA, glycine, and adenosine receptors type A2A, GABAAT, and BCAT enzymes. The conformity between in vivo and in silico studies results was revealed.

Synthesis, in vivo and in silico anticonvulsant activity studies of new derivatives of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetamide.

In order to expand the arsenal of biologically active substances of anticonvulsive action by the interaction of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetic acid with the corresponding amines in the presence of N,N'-carbonyldiimidazole in the dioxane medium, a systematic series of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-R-acetamides was obtained. A novel approach to synthesis of the key intermediate - 2-(2,4-dioxo-1,4-dihydro-quinazolin-3(2H)-yl)acetic acid was developed. The structure and purity of the resulting substances was confirmed by elemental analysis, 1H NMR, 13C NMR spectroscopy and LC/MS. Based on the results of docking studies using SCIGRESS software, selected compounds with the best affinity for anticonvulsant protein biomes (PDB codes: 4COF, 3F8E and 1 EOU) are promising for experimental studies of anticonvulsant activity. A comparative analysis of the results of molecular docking and in vivo results suggests that there is a positive correlation between scoring protein inhibition and experimental data. Pharmacological studies have revealed the leader compound 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-[(2,4-dichlorophenyl)methyl]acet-amide, which improved all the experimental convulsive syndrome rates in mice without motor coordination impairment and may be recommended for further research. The lowest values of the scoring function of the ligand-peptide interaction are obtained for the synthesized compound and сarbonic anhydrase II (gene name CA2) (PDB code 1 EOU), so its inhibition is proposed by us as the most probable mechanism of the anticonvulsive effect of the leader compound.