Synthesis, molecular modeling studies, and anticonvulsant evaluation of novel 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides and their acetate esters
| Autor: | Kamilia M. Amin, Mohamed Nabil Aboul-Enein, Mona E Aboutabl, Mai I Abo-Elmagd, Aida A. El-Azzouny |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular Drug-Related Side Effects and Adverse Reactions medicine.medical_treatment Pharmaceutical Science 01 natural sciences Medicinal chemistry chemistry.chemical_compound Mice In vivo Seizures Drug Discovery medicine Animals Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Aryl Acute toxicity 0104 chemical sciences 010404 medicinal & biomolecular chemistry Disease Models Animal Ethosuximide Anticonvulsant Drug Design Pentylenetetrazole Phenobarbital Anticonvulsants Neurotoxicity Syndromes Pharmacophore medicine.drug Discovery Studio |
| Zdroj: | Archiv der Pharmazie. 351(12) |
| ISSN: | 1521-4184 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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