Abstract
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, ED50 of intraperitoneally injected VPZ was 126.8 mg/kg (95% CI: 65.5–245.4). Its therapeutic index was 7.3.
Highlights
Author contribution: Malygin AS — laboratory tests; data analysis; literature analysis; manuscript preparation; Demidova MA — study concept and design; manuscript preparation; Skachilova SYa, Shilova EV— synthesis and analysis of the compound; All authors contributed to the discussion of the study results
Purity of the obtained compound was evaluated by thin-layer (TLC) and high-performance liquid chromatography (HPLC)
Considering that VPZ was the most active in a test with a GABAА-receptor antagonist, we studied the effect of this valproate on the seizures induced by another GABA antagonist isonicotinylhydrazide
Summary
Author contribution: Malygin AS — laboratory tests; data analysis; literature analysis; manuscript preparation; Demidova MA — study concept and design; manuscript preparation; Skachilova SYa, Shilova EV— synthesis and analysis of the compound; All authors contributed to the discussion of the study results. The animals were treated in compliance with the guidelines for laboratory practice in preclinical trials (Order 199n of the Russian Ministry of Healthcare dated April 1, 2016, on the Good laboratory practice). All tests were carried out in accordance with the guidelines for preclinical trials of medicinal drugs and in compliance with the European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes (Directive 2010/63/EU). Противоэпилептическую активность оценивали в тесте антагонизма с изониазидом (250 мг/кг, интраперитонеально) у мышей методом пробит-анализа. В результате исследования был получен N-(5-этил-1,3,4-тиадиазол-2-ил)-2-пропилпентанамид (вальпразоламид). С. Малыгин — экспериментальное исследование, анализ результатов, обзор публикаций по теме статьи, написание текста; М. Все эксперименты осуществляли в соответствии с методическими рекомендациями по проведению доклинических исследований лекарственных средств с соблюдением «Европейской конвенции о защите позвоночных животных, используемых для экспериментов или в иных научных целях» (Directive 2010/63/EU)
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