Abstract
Introduction: The search for new anticonvulsants for epilepsy treatment with higher efficacy and better tolerability remains important. The aim of the present research was an in silico and in vivo pharmacological study of N-(3,4-dimethoxyphenyl)-2-((2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)thio)acetamide (Epirimil) as a promising anticonvulsant.
 Materials and methods: A 1H and 13C NMR spectroscopy, LS/MS, and an elemental analysis were used to determine Epirimil structure. An ADMET analysis, as well as a docking study using anticonvulsant biotargets, e.g.: GABAAR, GABAAT, CA II, NMDAR, and AMPAR, was carried out. Anticonvulsant activity was proved, using PTZ- and MES-induced seizures in rats and mice, and neurotoxicity was determined using a rotarod test. Influence of Epirimil on the psycho-emotional state of the laboratory animals was determined by an open field test.
 Results and discussion: A synthesis method of a promising anticonvulsant Epirimil was modified. The calculated ADMET parameters and a molecular docking into the active sites of anticonvulsant biotargets allowed evaluating the research prospects and predicting possible mechanisms for implementing anticonvulsant activity. A prominent anticonvulsant activity of Epirimil was established using in vivo studies on the model of PTZ-induced seizures in rats and MES-induced seizures in mice. In terms of toxicity, Epirimil belongs to class IV – low toxic substances. The open field test showed that Epirimil had almost no effect on the animals’ behavioral responses: it neither changed their psycho-emotional activity, nor increased their anxiety level. ED50, TD50 and protective index of Epirimil according to its anticonvulsant activity were calculated.
 Conclusion: The obtained experimental results substantiate the prospects of N-(3,4-Dimethoxyphenyl)-2-((2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)thio)acetamide as a promising active pharmaceutical ingredient having a multifactor mechanism of anticonvulsant activity.
 Graphical abstract:
Highlights
The search for new anticonvulsants for epilepsy treatment with higher efficacy and better tolerability remains important
The obtained experimental results substantiate the prospects of N-(3,4-Dimethoxyphenyl)-2-((2-methyl6-(pyridin-2-yl)pyrimidin-4-yl)thio)acetamide as a promising active pharmaceutical ingredient having a multifactor mechanism of anticonvulsant activity
Scientific achievements of the last decades concerning determination of anticonvulsant activity mechanisms, the crystal structure of target proteins, and an amino acid composition of active receptor sites, as well as a range of in silico methods developed to analyze and evaluate the ligand affinity to the receptor and ADMET parameters, make it possible to rationalize the search for new anti-epileptic drugs (AEDs) (Danielson et al 2017)
Summary
The search for new anticonvulsants for epilepsy treatment with higher efficacy and better tolerability remains important. Despite the successful development of various new anti-epileptic drugs (AEDs) over the recent decades (Vossler et al 2018), all of them are characterized by a wide range of side effects, most of which are CNS disorders, i.e. depression, anxiety states, and cognitive disorders (Piedad et al 2012; Perucca 2014). The search for new innovative drugs with better efficacy and tolerability remains an important goal for scientists. Finding and developing a new AED depend to a great extent on the rational, reasonable and comprehensive preclinical use of screening animal models in combination with in silico methods (Löscher 2017)
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