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 R M0 , 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 ED 50 values of 86.6, 60.9, and 109.6 mg/kg in the MES, 6-Hz, and scPTZ tests, respectively. For compound 3 , the ED 50 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 A – from the phenyl ring to the hydroxyl group in the amide moiety, 5.729 A – from the phenyl ring to the amide group, and 3.112 A – 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).