Synthesis and Biological Evaluation of Amino Acid Based Mutual Amide Prodrugs of Phenytoin as Anticonvulsant Agents.
Phenytoin
amino acid
anticonvulsant
hydrolysis.
mutual prodrug
solubility
Journal
Central nervous system agents in medicinal chemistry
ISSN: 1875-6166
Titre abrégé: Cent Nerv Syst Agents Med Chem
Pays: United Arab Emirates
ID NLM: 101269163
Informations de publication
Date de publication:
2021
2021
Historique:
received:
05
07
2020
revised:
10
10
2020
accepted:
16
10
2020
pubmed:
11
11
2020
medline:
26
10
2021
entrez:
10
11
2020
Statut:
ppublish
Résumé
Phenytoin (5,5-diphenyl hydantoin) has poor water solubility, which results in incomplete oral availability. Other problems associated with the oral and intramuscular administration of phenytoin are gastric irritation and inflammation at the site of injection. The purpose of this study was to synthesize mutual amide prodrugs of phenytoin by using amino acids like glycine, L-tryptophan, L-lysine and taurine. These prodrugs were synthesized and characterized by Fourier Transform Infrared (FTIR), Proton nuclear magnetic resonance (1H NMR) and Mass Spectra. Physical and spectral characterization was performed by determination of solubility, maximum wavelength, partition coefficient (log P), ionization constant (pKa), specific (α) and molar rotation (μ), refractive index (n), specific refraction (RS) and molar refraction (RM). The results obtained from solubility and log P values determination indicated that phenytoin prodrugs can be administered by oral as well as a parenteral route by minimizing the limitations associated with phenytoin. Anticonvulsant activity of prodrugs (4a-4d) was evaluated by using maximal electroshock (MES) and strychnine induced seizure test on albino mice of either sex weighing 25-30 g in which 4b and 4d were found to have significant anticonvulsant activity for MES and strychnine induced seizure test. In vitro enzymatic hydrolysis study of 4b and 4d was performed on liver, intestinal mucosa and plasma sample of male Sprague Dawley rats weighing 280-300 g in which phenytoin was eluted at 10.13 to 10.68 minutes at 220 nm. The results obtained from the present work showed that amino acid-based mutual prodrug strategy can be a promising method to increase the solubility and anticonvulsant activity of phenytoin for the development of anticonvulsant agents.
Sections du résumé
BACKGROUND
BACKGROUND
Phenytoin (5,5-diphenyl hydantoin) has poor water solubility, which results in incomplete oral availability. Other problems associated with the oral and intramuscular administration of phenytoin are gastric irritation and inflammation at the site of injection.
OBJECTIVE
OBJECTIVE
The purpose of this study was to synthesize mutual amide prodrugs of phenytoin by using amino acids like glycine, L-tryptophan, L-lysine and taurine.
METHODS
METHODS
These prodrugs were synthesized and characterized by Fourier Transform Infrared (FTIR), Proton nuclear magnetic resonance (1H NMR) and Mass Spectra. Physical and spectral characterization was performed by determination of solubility, maximum wavelength, partition coefficient (log P), ionization constant (pKa), specific (α) and molar rotation (μ), refractive index (n), specific refraction (RS) and molar refraction (RM).
RESULTS
RESULTS
The results obtained from solubility and log P values determination indicated that phenytoin prodrugs can be administered by oral as well as a parenteral route by minimizing the limitations associated with phenytoin. Anticonvulsant activity of prodrugs (4a-4d) was evaluated by using maximal electroshock (MES) and strychnine induced seizure test on albino mice of either sex weighing 25-30 g in which 4b and 4d were found to have significant anticonvulsant activity for MES and strychnine induced seizure test. In vitro enzymatic hydrolysis study of 4b and 4d was performed on liver, intestinal mucosa and plasma sample of male Sprague Dawley rats weighing 280-300 g in which phenytoin was eluted at 10.13 to 10.68 minutes at 220 nm.
CONCLUSION
CONCLUSIONS
The results obtained from the present work showed that amino acid-based mutual prodrug strategy can be a promising method to increase the solubility and anticonvulsant activity of phenytoin for the development of anticonvulsant agents.
Identifiants
pubmed: 33167845
pii: CNSAMC-EPUB-111290
doi: 10.2174/1871524920666201109152344
doi:
Substances chimiques
Amides
0
Amino Acids
0
Anticonvulsants
0
Prodrugs
0
Phenytoin
6158TKW0C5
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
53-72Informations de copyright
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