Syntheses and evaluation of anticonvulsant activity of novel branched alkyl carbamates

Journal of Medicinal Chemistry
Naama HenBoris Yagen

Abstract

A novel class of 19 carbamates was synthesized, and their anticonvulsant activity was comparatively evaluated in the rat maximal electroshock (MES) and subcutaneous metrazol (scMet) seizure tests and pilocarpine-induced status epilepticus (SE) model. In spite of the alkyl-carbamates' close structural features, only compounds 34, 38, and 40 were active at the MES test. The analogues 2-ethyl-3-methyl-butyl-carbamate (34) and 2-ethyl-3-methyl-pentyl-carbamate (38) also exhibited potent activity in the pilocarpine-SE model 30 min postseizure onset. Extending the aliphatic side chains of homologous carbamates from 7 to 8 (34 to 35) and from 8 to 9 carbons in the homologues 38 and 43 decreased the activity in the pilocarpine-SE model from ED(50) = 81 mg/kg (34) to 94 mg/kg (35) and from 96 mg/kg (38) to 114 mg/kg (43), respectively. The most potent carbamate, phenyl-ethyl-carbamate (47) (MES ED(50) = 16 mg/kg) contains an aromatic moiety in its structure. Compounds 34, 38, 40, and 47 offer the optimal efficacy-safety profile and, consequently, are promising candidates for development as new antiepileptics.

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Citations

Feb 26, 2014·European Journal of Medicinal Chemistry·Ivan O EdafioghoSamuel B Kombian
Nov 28, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Cheng-Xi WeiGuo-Hua Gong
Jan 20, 2017·Journal of Enzyme Inhibition and Medicinal Chemistry·Jelena B Popović-DjordjevićTatjana P Stanojković
Jul 27, 2021·Current Research in Toxicology·Dorina V PinkhasovaMaxwell C K Leung

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