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Design and synthesis of novel parabanic acid derivatives as anticonvulsants. 2020

Mona Elsayed Aboutabl, and Rasha Mohamed Hassan, and Aida Abdel-Sattar El-Azzouny, and Mohamed Nabil Aboul-Enein, and Walaa Hamada Abd-Allah
Medicinal and Pharmaceutical Chemistry Department (Pharmacology Group), Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt.

In this work a set of novel derivatives of parabanic acid 9a-d, 12a-d and 13a-d was synthesized and their anticonvulsant potential was evaluated. All the compounds under investigation exhibited anticonvulsant activity in both scPTZ and MES tests. In phase II anticonvulsant study, the trimethoxy phenyl derivative 9a evoked the highest potency among the tested compounds in scPTZ test. It displayed 1.72- and 17.05-folds activity more than the standard drugs phenobarbital and ethosuximide, respectively. In addition, the margin of safety for compound 9a is better than that of the reference antiepileptic drug ethosuximide. Also, compound 9a was devoid of hepatotoxicity indicated by measurements of serum level of ALT, AST, ALP, albumin and total protein. Furthermore, treatment with compound 9a significantly increased the GABA brain level by 2.56-folds compared to the control value. Additionally, molecular docking was performed on the active site of GABA-AT to clarify the interactions of the most potent compound 9a with the enzyme. In MES test, compound 12a exhibited the most potent activity against electric stimuli-induced seizures with the lowest ED50 = 13.7 mg/kg and protective index >36.5. Both candidates 9a and 12a could be a good starting point to develop new molecules as novel antiepileptic drugs.

UI MeSH Term Description Entries
D008297 Male Males
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
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
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006827 Hydantoins Compounds based on imidazolidine dione. Some derivatives are ANTICONVULSANTS. Hydantoin,Imidazolidine-2,4-Diones,Imidazolidine 2,4 Diones
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
D012640 Seizures Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder." Absence Seizure,Absence Seizures,Atonic Absence Seizure,Atonic Seizure,Clonic Seizure,Complex Partial Seizure,Convulsion,Convulsions,Convulsive Seizure,Convulsive Seizures,Epileptic Seizure,Epileptic Seizures,Generalized Absence Seizure,Generalized Tonic-Clonic Seizures,Jacksonian Seizure,Myoclonic Seizure,Non-Epileptic Seizure,Nonepileptic Seizure,Partial Seizure,Seizure,Seizures, Convulsive,Seizures, Focal,Seizures, Generalized,Seizures, Motor,Seizures, Sensory,Tonic Clonic Seizure,Tonic Seizure,Tonic-Clonic Seizure,Atonic Absence Seizures,Atonic Seizures,Clonic Seizures,Complex Partial Seizures,Convulsion, Non-Epileptic,Generalized Absence Seizures,Myoclonic Seizures,Non-Epileptic Seizures,Nonepileptic Seizures,Partial Seizures,Petit Mal Convulsion,Seizures, Auditory,Seizures, Clonic,Seizures, Epileptic,Seizures, Gustatory,Seizures, Olfactory,Seizures, Somatosensory,Seizures, Tonic,Seizures, Tonic-Clonic,Seizures, Vertiginous,Seizures, Vestibular,Seizures, Visual,Single Seizure,Tonic Seizures,Tonic-Clonic Seizures,Absence Seizure, Atonic,Absence Seizure, Generalized,Absence Seizures, Atonic,Absence Seizures, Generalized,Auditory Seizure,Auditory Seizures,Clonic Seizure, Tonic,Clonic Seizures, Tonic,Convulsion, Non Epileptic,Convulsion, Petit Mal,Convulsions, Non-Epileptic,Focal Seizure,Focal Seizures,Generalized Seizure,Generalized Seizures,Generalized Tonic Clonic Seizures,Generalized Tonic-Clonic Seizure,Gustatory Seizure,Gustatory Seizures,Motor Seizure,Motor Seizures,Non Epileptic Seizure,Non Epileptic Seizures,Non-Epileptic Convulsion,Non-Epileptic Convulsions,Olfactory Seizure,Olfactory Seizures,Partial Seizure, Complex,Partial Seizures, Complex,Seizure, Absence,Seizure, Atonic,Seizure, Atonic Absence,Seizure, Auditory,Seizure, Clonic,Seizure, Complex Partial,Seizure, Convulsive,Seizure, Epileptic,Seizure, Focal,Seizure, Generalized,Seizure, Generalized Absence,Seizure, Generalized Tonic-Clonic,Seizure, Gustatory,Seizure, Jacksonian,Seizure, Motor,Seizure, Myoclonic,Seizure, Non-Epileptic,Seizure, Nonepileptic,Seizure, Olfactory,Seizure, Partial,Seizure, Sensory,Seizure, Single,Seizure, Somatosensory,Seizure, Tonic,Seizure, Tonic Clonic,Seizure, Tonic-Clonic,Seizure, Vertiginous,Seizure, Vestibular,Seizure, Visual,Seizures, Generalized Tonic-Clonic,Seizures, Nonepileptic,Sensory Seizure,Sensory Seizures,Single Seizures,Somatosensory Seizure,Somatosensory Seizures,Tonic Clonic Seizures,Tonic-Clonic Seizure, Generalized,Tonic-Clonic Seizures, Generalized,Vertiginous Seizure,Vertiginous Seizures,Vestibular Seizure,Vestibular Seizures,Visual Seizure,Visual Seizures
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs

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