Synthesis, molecular modeling studies, and anticonvulsant evaluation of novel 1‐((2‐hydroxyethyl)(aryl)amino)‐N‐substituted cycloalkanecarboxamides and their acetate esters

A series of 1‐((2‐hydroxyethyl)(aryl)amino)‐N‐substituted cycloalkanecarboxamides IXa–l and their acetate esters Xa–l were designed and synthesized as new anticovulsant agents. The evaluation of the anticonvulsant effect was performed in vivo by subcutaneous pentylenetetrazole (scPTZ) and maximal el...

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Bibliographic Details
Published in:Archiv der Pharmazie (Weinheim) 2018-12, Vol.351 (12), p.e1800269-n/a
Main Authors: Aboul‐Enein, Mohamed N., El‐Azzouny, Aida A., Amin, Kamilia M., Aboutabl, Mona E., Abo‐Elmagd, Mai I.
Format: Article
Language:English
Subjects:
1‐[(2‐hydroxyethyl)(aryl)amino]‐N‐substituted cycloalkanecarboxamides
acetate esters
Animals
anticonvulsants
Anticonvulsants - chemical synthesis
Anticonvulsants - chemistry
Anticonvulsants - pharmacology
Anticonvulsants - toxicity
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Design
Drug-Related Side Effects and Adverse Reactions - etiology
epilepsy
Mice
Models, Molecular
molecular modeling studies
Molecular Structure
Neurotoxicity
Neurotoxicity Syndromes - etiology
Pentylenetetrazole - administration & dosage
Seizures - drug therapy
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Summary:A series of 1‐((2‐hydroxyethyl)(aryl)amino)‐N‐substituted cycloalkanecarboxamides IXa–l and their acetate esters Xa–l were designed and synthesized as new anticovulsant agents. The evaluation of the anticonvulsant effect was performed in vivo by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) tests in mice. Further, neurotoxicity, hepatotoxicity, and acute toxicity were determined. All the new candidates displayed 100% anticonvulsant activity in the scPTZ screen in the dose range of 0.0057–0.283 mmol/kg. The most potent compounds in the scPTZ screen were Xh (ED50 = 0.0012 mmol/kg), Xd (ED50 = 0.002 mmol/kg), Xf (ED50 = 0.004 mmol/kg), IXj (ED50 = 0.0047 mmol/kg), Xl (ED50 = 0.0076 mmol/kg), and Xi (ED50 = 0.008 mmol/kg). They exhibited higher fold activity in the anticonvulsant potential than the gold standards, phenobarbital and ethosuximide. Compound Xf was active in both scPTZ and MES screens. It showed ED50 of 0.016 mmol/kg in MES screen. In the neurotoxicity screens, none of the test compounds displayed any minimal motor impairment at the maximum administered dose. The 3D pharmacophore model using Biova 1 Discovery Studio 2016 programs exhibited high fit value. The anticonvulsant evaluation results were compatible with the molecular modeling study. The 1,1‐disubstituted cycloalkane congeners, 1‐((2‐hydroxyethyl)(aryl)amino)‐N‐substituted cycloalkanecarboxamides IXa–l and their acetate esters Xa–l, were synthesized and in vivo tested for anticonvulsant activity. The most potent compounds in the scPTZ screen exhibited higher anticonvulsant potential than the gold standards, phenobarbital and ethosuximide.
ISSN:0365-6233
1521-4184
DOI:10.1002/ardp.201800269