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

Autor: Aboul-Enein MN; Department of Medicinal and Pharmaceutical Chemistry, Medicinal Chemistry Group, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), Dokki, Giza, Egypt., El-Azzouny AA; Department of Medicinal and Pharmaceutical Chemistry, Medicinal Chemistry Group, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), Dokki, Giza, Egypt., Amin KM; Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Cairo University, Cairo, Egypt., Aboutabl ME; Department of Medicinal and Pharmaceutical Chemistry, Pharmacology Group, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), Dokki, Giza, Egypt., Abo-Elmagd MI; Department of Medicinal and Pharmaceutical Chemistry, Medicinal Chemistry Group, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), Dokki, Giza, Egypt.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2018 Dec; Vol. 351 (12), pp. e1800269. Date of Electronic Publication: 2018 Nov 21.
DOI: 10.1002/ardp.201800269
Abstrakt: 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 (ED 50  = 0.0012 mmol/kg), Xd (ED 50  = 0.002 mmol/kg), Xf (ED 50  = 0.004 mmol/kg), IXj (ED 50  = 0.0047 mmol/kg), Xl (ED 50  = 0.0076 mmol/kg), and Xi (ED 50  = 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 ED 50 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.
(© 2018 Deutsche Pharmazeutische Gesellschaft.)
Databáze: MEDLINE
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