Synthesis and Biological Evaluation of Amino Acid Based Mutual Amide Prodrugs of Phenytoin as Anticonvulsant Agents

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: 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: 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: 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: 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.