Synthesis, in vivo anticonvulsant testing, and molecular modeling studies of new nafimidone derivatives

An estimated 50 million people suffer epilepsy worldwide and 30% of the cases do not respond to current antiepileptic drugs (AEDs). Here, we report synthesis and anticonvulsant screening of new derivatives of nafimidone, a well‐known member of (arylakyl)azole anticonvulsants. The compounds showed pr...

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Bibliographic Details
Published in:Drug development research 2019-08, Vol.80 (5), p.606-616
Main Authors: Acar, Mustafa F., Sari, Suat, Dalkara, Sevim
Format: Article
Language:English
Subjects:
(arylalkyl)azole
Administration, Oral
Animal models
Animals
Anticonvulsants
Anticonvulsants - chemical synthesis
Anticonvulsants - chemistry
Anticonvulsants - pharmacology
Antiepileptic agents
Benzodiazepines
Binding sites
Biocompatibility
Brain
Chemical synthesis
Computer simulation
Cornea
Derivatives
Disease Models, Animal
Dose-Response Relationship, Drug
Drugs
Electroshock - adverse effects
Epilepsy
esterification
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
In vivo methods and tests
Injections, Intraperitoneal
Male
Mice
Models, Molecular
Molecular docking
Molecular Docking Simulation
Molecular modelling
Molecular Structure
Naphazoline - analogs & derivatives
Naphazoline - chemistry
Oral administration
Permeability
Rats
Receptors, GABA-A - chemistry
Receptors, GABA-A - metabolism
Seizures
Seizures - drug therapy
Seizures - etiology
Seizures - metabolism
Structure-Activity Relationship
Toxicity
γ-Aminobutyric acid
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Summary:An estimated 50 million people suffer epilepsy worldwide and 30% of the cases do not respond to current antiepileptic drugs (AEDs). Here, we report synthesis and anticonvulsant screening of new derivatives of nafimidone, a well‐known member of (arylakyl)azole anticonvulsants. The compounds showed promising protection against maximal electroshock (MES)‐induced seizures in mice and rats when administered via intraperitoneal (ip) and oral route. Especially, 5b, 5c, and 5i displayed outstanding activity in rats in MES test when given ip (ED50: 16.0, 15.8, and 11.8 mg/kg, respectively). Additionally, 5l was active against 6 Hz and corneal‐kindled mice models. Behavioral toxicity of the compounds was very low and their therapeutic indexes were high compared to some currently available AEDs. A number of pharmaceutically relevant descriptors and properties were predicted for the compounds in silico in comparison with a set of known drugs. Favorable results were obtained such as good blood–brain barrier permeability and high oral absorption, as well as drug‐likeness. 5l was found to show affinity to the benzodiazepine binding site of A‐type GABA receptor via molecular docking simulations.
ISSN:0272-4391
1098-2299
DOI:10.1002/ddr.21538