title: Synthesis, molecular modeling studies and anticonvulsant activity of certain (1-(benzyl (aryl) amino) cyclohexyl) methyl esters.
abstract: A series of (1-(benzyl (aryl) amino) cyclohexyl) methyl esters 7a-n were prepared and screened for their anticonvulsant profile. Screening of these esters 7a-n and their starting alcohols 6a and 6b revealed that compound 7k was the most potent one in the scPTZ screening test with an ED50value of 0.0056mmol/kg being about 10- and 164-fold more potent than phenobarbital (ED50=0.056mmol/kg) and ethosuximide (ED50=0.92mmol/kg) as reference drugs, respectively. Meanwhile, in the MES test, compounds 7b and 7k at doses 0.0821mmol/kg and 0.0334mmol/kg, exerted 66% and 50% protection of the tested mice, respectively, compared with diphenylhydantoin, which exerted 100% protection at dose 0.16mmol/kg. In the neurotoxicity screen test, almost all esters 7a-n did not show any minimal motor impairment at the maximum administrated dose. The anticonvulsant effectiveness of esters 7a-n was higher than their corresponding alcohols 6a and 6b. Compounds 7b and 7k exhibited pronounced anticonvulsant activity devoid of neurotoxicity in minimal motor impairment test and hepatotoxicity in the serum enzyme activity assay. 3D pharmacophore model using Discovery Studio 2.5 programs showed high fit value. The obtained experimental results of sc-PTZ activity of compounds 7a-n was consistent with the molecular modeling study.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr University for Science & Technology, 6th of October City, Egypt.
authors.forename: Walaa Hamada
authors.initials: WH
authors.lastname: Abd-Allah
authors.affiliation: Medicinal and Pharmaceutical Chemistry Department, Pharmacology Group, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), 33 El Bohouth St., P.O. 12622, Dokki, Giza, Egypt.
authors.forename: Mona Elsayed
authors.initials: ME
authors.lastname: Aboutabl
authors.affiliation: Medicinal and Pharmaceutical Chemistry Department, Medicinal Chemistry Group, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), 33 El Bohouth St., P.O. 12622, Dokki, Giza, Egypt. Electronic address: mnaboulenein@yahoo.com.
authors.forename: Mohamed Nabil
authors.initials: MN
authors.lastname: Aboul-Enein
authors.affiliation: Medicinal and Pharmaceutical Chemistry Department, Medicinal Chemistry Group, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), 33 El Bohouth St., P.O. 12622, Dokki, Giza, Egypt.
authors.forename: Aida Abdel Sattar
authors.initials: AA
authors.lastname: El-Azzouny
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use* / Q000633:toxicity; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use* / Q000633:toxicity; D004195:Disease Models, Animal; D015195:Drug Design; D004827:Epilepsy; D004951:Esterification; D008297:Male; D008745:Methylation; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D001593:Benzyl Compounds; D010433:Pentylenetetrazole
keywords: 1-(Benzyl (aryl) amino) cyclohexyl) methyl esters; Anticonvulsants; Epilepsy; Molecular modeling