Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3. Issue 2 (15th January 2017)

• Record Type: Journal Article
• Authors: Gunia-Krzyżak, Agnieszka; Żelaszczyk, Dorota; Rapacz, Anna; Żesławska, Ewa; Waszkielewicz, Anna M.; Pańczyk, Katarzyna; Słoczyńska, Karolina; Pękala, Elżbieta; Nitek, Wojciech; Filipek, Barbara; Marona, Henryk
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 2(2017)
• Page Start: 471
• Page End: 482
• Publication Date: 2017-01-15
• Subjects: Anticonvulsant -- Cinnamamide -- Crystal structure -- MES -- Pharmacophore -- scPTZ -- 6-Hz; LHOCIRAREVNAKF-AEZGRPFRSA-N -- PRRQIMZFWXXIRY-VMPITWQZSA-N -- SVLVGTSFQFZIBO-QPJJXVBHSA-N; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.11.014
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: ( E )- N- cinnamoyl derivatives of aminoalkanols were tested in rodents. Maximal electroshock, subcutaneous pentylenetetrazole and 6-Hz tests were performed. Anticonvulsant activity was enhanced by p -Cl and o -CH3 substitution in phenyl ring. Benzodiazepine receptors and serotonergic receptors were possible molecular targets. Tested compounds were stable in rat liver microsomes model of biotransformation. Abstract: A series of twenty two ( E )- N- cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S -(2 E )- N -(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5 ) (ED50 MES = 42.56, ED50 scPTZ = 58.38, ED50 6-Hz 44 mA = 42.27 mg/kg tested in mice after intraperitoneal ( i.p .) administration); R, S -(2 E )-3-(4-chlorophenyl)- N -(1-hydroxybutan-2-yl)prop-2-enamide (6 ) (ED50 MES = 53.76, ED50 scPTZ = 90.31, ED50 6-Hz 44 mA = 92.86 mg/kg mice, i.p .); and R, S -(2 E )-3-(4-chlorophenyl)- N -(2-hydroxypropyl)prop-2-enamide (11 ) (ED50 MES = 55.58, ED50 scPTZ = 102.15, ED50 6-Hz 44 mA = 51.27 mg/kg mice, i.p .). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives.