Synthesis of a novel amide derivative of valproic acid and 1,3,4-thiadiazole with antiepileptic activity

Malygin, A.S.; Демидова, М. А.; Skachilova, S. Ya.; Shilova, E. V.

doi:10.24075/brsmu.2020.007

Cited by 4 publications

(1 citation statement)

References 24 publications

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“…It is concluded that the synthesized compound [N-(5-ethyl-1,3,4-thiadiazol-2yl)-2-propyl pentane amide] when injected intraperitoneally was found to be 1.8 times more effective (LD 50 ) than valproic acid, ED 50 was 126.8 mg/kg, and the therapeutic index was found to be 7.3. The synthesized compound was found to be most effective for isoniazid-induced seizures (Malygin et al, 2020).…”

Section: 34-thiadiazole Derivatives As Anti-convulsantmentioning

confidence: 99%

1,3,4-Thiadiazole Scaffold: As Anti-Epileptic Agents

Anthwal

Nain

2022

Front. Chem.

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A wide range of biological activities is exhibited by 1,3,4-thiadiazole moiety such as antidiabetic, anticancer, anti-inflammatory, anticonvulsant, antiviral, antihypertensive, and antimicrobial. To date, drugs such as butazolamide, and acetazolamide. Several modifications have been done in the 1,3,4-thiadiazole moiety which showed good potency as anticonvulsant agents which are highly effective and have less toxicity. After in-depth literature survey in this review, we have compiled various derivatives of 1,3,4-thiadiazole scaffold as anticonvulsant agents.

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Section: 34-thiadiazole Derivatives As Anti-convulsantmentioning

confidence: 99%

1,3,4-Thiadiazole Scaffold: As Anti-Epileptic Agents

Anthwal

Nain

2022

Front. Chem.

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Synthesis of a novel amide derivative of valproic acid and 1,3,4-thiadiazole with antiepileptic activity

Malygin

Демидова

Skachilova³

et al. 2020

BRSMU

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Valproates are commonly used to treat various forms of epilepsy. Problems accompanying their clinical application include drug resistance, adverse effects, acute and chronic toxicity. Safer anticonvulsants with improved efficacy can be obtained through the chemical modification of valproic acid structure. Thiadiazole-linked amide derivatives of valproates hold great promise because 1,3,4-thiadiazole can improve the drug's bioavailability and reduce its toxicity. The aim of this work was to synthesize a novel amide derivative of valproic acid and 1,3,4-thiadiazole exerting antiepileptic activity. The chemical structure of the synthesized valproate was studied by IR, proton NMR and 13С-NMR-spectroscopy, mass spectroscopy and elemental analysis. The purity and individuality of the compound was confirmed by thin-layer and high-performance liquid chromatography. Its antiepileptic activity was assessed in the test with intraperitoneally injected 250 mg/kg isoniazid and subsequent Probit analysis. The synthesized N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propyl pentane amide (valprazolamide) had the following characteristics. ESI + MS: m/z 256.1 [M + H] + ; MRM transitions: m/z 256.1 -m/z 81.0 and m/z 130.1. The valproate exerted antiepileptic activity against isoniazid-induced seizures in mice.In the test with isoniazid, ED 50 of intraperitoneally injected VPZ was 126.8 mg/kg (95% CI: 65.5-245.4). Its therapeutic index was 7.3.

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Design and evaluation of pharmacological properties of a new 1,3,4-thiadiazolylamide derivative of 2-propylpentanoic acid

Malygin¹,

Yasnetsov²

2021

RRP

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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. Graphic abstract N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide (3D) LD50=924.8 mg/kg (mice, intraperitoneally) TD50=456.7 mg/kg (rotarod, mice, intraperitoneally) ED50=138.4 mg/kg (MES, mice, intraperitoneally) ED50=74.5 mg/kg (scPTZ, mice, intraperitoneally)

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Synthesis of a novel amide derivative of valproic acid and 1,3,4-thiadiazole with antiepileptic activity

Cited by 4 publications

References 24 publications

1,3,4-Thiadiazole Scaffold: As Anti-Epileptic Agents

1,3,4-Thiadiazole Scaffold: As Anti-Epileptic Agents

Synthesis of a novel amide derivative of valproic acid and 1,3,4-thiadiazole with antiepileptic activity

Design and evaluation of pharmacological properties of a new 1,3,4-thiadiazolylamide derivative of 2-propylpentanoic acid

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