Abstract
Introduction: The use of the pharmacophoric approach is a promising direction for modifying the chemical structure of 2-propylpentanoic (valproic) acid in order to obtain new drugs.
 Materials and methods: In the experiments on mice, acute toxicity, neurotoxicity, antiepileptic activity and analgesic effect of N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide (valprazolamide) were evaluated. LD50 was determined by probit analysis. Neurotoxicity was determined in a rotarod test and a bar test in mice. The effects of valprazolamide on the exploratory behavior of mice in open field test and in a light/dark transition test were evaluated. Its antiepileptic activity was tested in mice against seizures induced by maximal electroshock, pentylenetetrazole(scPTZ); isoniazid, thiosemicarbazide, pilocarpine, and camphor. The analgesic effect was studied in a hot plate test.
 Results and discussion: N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide was obtained by introducing pharmacophores into the structure of 2-propylpentanoic acid: a substituted amide group and an electron-donor domain of 1,3,4-thiadiazole. The LD50 value for intraperitoneal administration of a new 2-propylpentanoic acid: derivative to mice was 924.8 mg/kg, and the TD50 value in the rotarod test and the bar test were 456.7 mg/kg and 546.7 mg/kg, respectively. The suppression of orienting responses in the animals was noted when it was administered in neurotoxic doses. Valprazolamide showed the most antiepileptic activity on models of MES, scPTZ and isoniazid antagonism tests. The ED50 values were 138.4 mg/kg, 74.5 mg/kg, and 126.8 mg/kg, respectively. The therapeutic indices for these models of epilepsy were 6.7; 12.4; 7.3, and protective index – 3.3; 6.1 and 3.6, respectively. In the hot plate test, valprazolamide increased the latency period before a defensive response to a thermal stimulus (ED50 165 mg/kg).
 Conclusion: N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide is a new 1,3,4-thiadiazolylamide derivative of 2-propylpentanoic acid with antiepileptic and analgesic activities, which belongs to the group of low-toxic agents.
Highlights
The use of the pharmacophoric approach is a promising direction for modifying the chemical structure of 2-propylpentanoic acid in order to obtain new drugs
We investigated a new 1,3,4-thiadiazolylamide derivative of 2-propylpentanoic acid with the chemical structure N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide and the laboratory name valprazolamide (VPZ), synthesized at the All-Union Research Center for Safety of Biologically Active Substances (Staraya Kupavna, Moscow region, Russian Federation) by Professor S.Ya
TD50 where: PI – protective index; ED50 is a median therapeutic dose; TD50 is a median toxic dose
Summary
The use of the pharmacophoric approach is a promising direction for modifying the chemical structure of 2-propylpentanoic (valproic) acid in order to obtain new drugs. The prevalence of epilepsy in the Russian Federation is 3.2 per 1000 (Avakyan et al 2017). It is in third place among neurological diseases after strokes and dementia (Gulyaev et al 2011). Along with the development of original molecules, it is promising to modify the chemical structure of the known antiepileptic drugs, including valproic acid (VPA). The antiepileptic effect of VPA is mediated by the inhibition of GABA transaminase and the blockade of voltage-dependent Na+ channels in the brain, which suppresses the over-activation of neuronal cells (Piplani et al 2016; Bertelsen et al 2018). It has been reported that VPA may inhibit histone deacetylase (Heers et al 2018)
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