title: 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).
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland. Electronic address: agnieszka.gunia@uj.edu.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Gunia-Krzyżak
authors.affiliation: Departament of Chemistry, Institute of Biology, Pedagogical University, Podchorążych 2, 30-084 Kraków, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Żesławska
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Słoczyńska
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Koczurkiewicz
authors.affiliation: Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Kraków, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Nitek
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Żelaszczyk
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Szkaradek
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Waszkielewicz
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Henryk
authors.initials: H
authors.lastname: Marona
mesh_terms: D000605:Amino Alcohols / Q000737:chemistry; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004597:Electroshock / Q000009:adverse effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D009152:Mutagenicity Tests; D010433:Pentylenetetrazole / Q000009:adverse effects; D051381:Rats; D045442:Rotarod Performance Test; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D013329:Structure-Activity Relationship
chemical_list: D000605:Amino Alcohols; D000927:Anticonvulsants; D010433:Pentylenetetrazole
keywords: Anticonvulsant activity; Cinnamamide; Crystal structure; Hepatotoxicity; Mutagenicity