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Anticonvulsant activity, crystal structures, and preliminary safety evaluation of N-trans-cinnamoyl derivatives of selected (un)modified aminoalkanols.

Abstract：

:Adequate control of seizures remains an unmet need in epilepsy. In order to identify new anticonvulsant agents, a series of N-trans-cinnamoyl derivatives of selected aminoalkanols was synthetized. The compounds were obtained in the reaction of N-acylation carried out in a two-phase system. The substances were tested in animal models of seizures induced either electrically (maximal electroshock--MES; 6-Hz test) or chemically, by subcutaneous injection of pentetrazol (scPTZ). Neurotoxicity was determined by the rotarod test. Lipophilicity of the active compounds, expressed as RM0, was determined by reversed-phase thin layer chromatography and it ranged from 1.390 to 2.219. From among the tested series of compounds, R,S-(E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide (1) and R,S-(E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide (3) exhibited the best anticonvulsant activity. Compound 1, when administered to mice by intraperitoneal (i.p.) injection, showed the ED50 values of 86.6, 60.9, and 109.6 mg/kg in the MES, 6-Hz, and scPTZ tests, respectively. For compound 3, the ED50 values were found to be 47.1 mg/kg in MES and 77.1 mg/kg in scPTZ (mice, i.p.). The distances measured in crystals of compound 1 were: 7.99 Å--from the phenyl ring to the hydroxyl group in the amide moiety, 5.729 Å--from the phenyl ring to the amide group, and 3.112 Å--from the amide group to the hydroxyl group in the amide moiety. The reported compounds did not exhibit mutagenic potential when assayed in the Ames test. Compounds 1 and 3 did not affect viability and morphology of human hepatocellular carcinoma cells (HepG2).

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Gunia-Krzyżak A,Żesławska E,Słoczyńska K,Koczurkiewicz P,Nitek W,Żelaszczyk D,Szkaradek N,Waszkielewicz AM,Pękala E,Marona H

doi

10.1016/j.ejmech.2015.10.051

subject

Has Abstract

pub_date

2016-01-01 00:00:00

pages

26-37

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(15)30333-0

journal_volume

107

pub_type

杂志文章

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Anticonvulsant activity, crystal structures, and preliminary safety evaluation of N-trans-cinnamoyl derivatives of selected (un)modified aminoalkanols.