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

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DOI:

https://doi.org/10.3897/rrpharmacology.7.70179

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.

Keywords:

acute toxicity, analgesic effect, anticonvulsant activity, neurotoxicity, 2-propylpentanoic acid, pharmacophore, thiadiazole

Author Contribution

Alexandr S. Malygin, Tver State Medical University

Full-time postgraduate student, Tver State Medical University, Tver, Russian Federation, e-mail: dr.a.s.m@yandex.ru, ORCID ID https://orcid.org/0000-0003-1955-5105. The author developed the design of the study, conducted the experiments, conducted a statistical analysis, conducted a literature analysis and wrote the initial draft.

Victor V. Yasnetsov, Institute of Biomedical Problems of the Russian Academy of Sciences

Doctor Habil. of Medical Sciences, Lead Researcher, Laboratory of Experimental and Clinical Pharmacology, State Scientific Center of Russian Federation – Institute of Biomedical Problems of the Russian Academy of Sciences, e-mail: vicyas@yandex.ru, ORCID ID https://orcid.org/0000-0002-6399-3703. The author defined the idea of research, analyzed the experimental material, results and conclusions and prepared the final version of the article.

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Published

20-12-2021

How to Cite

Malygin AS, Yasnetsov VV (2021) Design and evaluation of pharmacological properties of a new 1,3,4-thiadiazolylamide derivative of 2-propylpentanoic acid. Research Results in Pharmacology 7(4): 89–98. https://doi.org/10.3897/rrpharmacology.7.70179

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Review article

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