Synthesis, molecular modeling studies and anticonvulsant activity of certain (1-(benzyl (aryl) amino) cyclohexyl) methyl esters. 2017

Walaa Hamada Abd-Allah, and Mona Elsayed Aboutabl, and Mohamed Nabil Aboul-Enein, and Aida Abdel Sattar El-Azzouny
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr University for Science & Technology, 6th of October City, Egypt.

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 ED50 value 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.

UI MeSH Term Description Entries
D008297 Male Males
D008745 Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. (From Stedman, 25th ed) Methylations
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D009043 Motor Activity Body movements of a human or an animal as a behavioral phenomenon. Activities, Motor,Activity, Motor,Motor Activities
D010433 Pentylenetetrazole A pharmaceutical agent that displays activity as a central nervous system and respiratory stimulant. It is considered a non-competitive GAMMA-AMINOBUTYRIC ACID antagonist. Pentylenetetrazole has been used experimentally to study seizure phenomenon and to identify pharmaceuticals that may control seizure susceptibility. Leptazole,Pentamethylenetetrazole,Pentetrazole,Cardiazol,Corasol,Corazol,Corazole,Korazol,Korazole,Metrazol,Metrazole,Pentazol,Pentylenetetrazol
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004827 Epilepsy A disorder characterized by recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Epilepsy classification systems are generally based upon: (1) clinical features of the seizure episodes (e.g., motor seizure), (2) etiology (e.g., post-traumatic), (3) anatomic site of seizure origin (e.g., frontal lobe seizure), (4) tendency to spread to other structures in the brain, and (5) temporal patterns (e.g., nocturnal epilepsy). (From Adams et al., Principles of Neurology, 6th ed, p313) Aura,Awakening Epilepsy,Seizure Disorder,Epilepsy, Cryptogenic,Auras,Cryptogenic Epilepsies,Cryptogenic Epilepsy,Epilepsies,Epilepsies, Cryptogenic,Epilepsy, Awakening,Seizure Disorders
D004951 Esterification The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. Esterifications
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000927 Anticonvulsants Drugs used to prevent SEIZURES or reduce their severity. Anticonvulsant,Anticonvulsant Drug,Anticonvulsive Agent,Anticonvulsive Drug,Antiepileptic,Antiepileptic Agent,Antiepileptic Agents,Antiepileptic Drug,Anticonvulsant Drugs,Anticonvulsive Agents,Anticonvulsive Drugs,Antiepileptic Drugs,Antiepileptics,Agent, Anticonvulsive,Agent, Antiepileptic,Agents, Anticonvulsive,Agents, Antiepileptic,Drug, Anticonvulsant,Drug, Anticonvulsive,Drug, Antiepileptic,Drugs, Anticonvulsant,Drugs, Anticonvulsive,Drugs, Antiepileptic

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