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

Q3 Psychology

Central nervous system agents in medicinal chemistry Pub Date : 2021-01-01 DOI:10.2174/1871524920666201109152344

Sampada Jangam, Meenakshi Deodhar, Sagar Wankhede

{"title":"Synthesis and Biological Evaluation of Amino Acid Based Mutual Amide Prodrugs of Phenytoin as Anticonvulsant Agents.","authors":"Sampada Jangam, Meenakshi Deodhar, Sagar Wankhede","doi":"10.2174/1871524920666201109152344","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":9799,"journal":{"name":"Central nervous system agents in medicinal chemistry","volume":"21 1","pages":"53-72"},"PeriodicalIF":0.0000,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Central nervous system agents in medicinal chemistry","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/1871524920666201109152344","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Psychology","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文本刊更多论文

苯妥英抗惊厥药氨基酸互酰胺前药的合成及生物学评价。

背景:苯妥英(5,5-二苯基苯妥英)水溶性差，导致口服有效性不完全。与口服和肌肉注射苯妥英相关的其他问题是胃刺激和注射部位的炎症。目的:利用甘氨酸、l -色氨酸、l -赖氨酸和牛磺酸等氨基酸合成苯妥英互酰胺前药。方法:采用傅立叶变换红外(FTIR)、质子核磁共振(1H NMR)、质谱等方法对前体药物进行合成和表征。通过测定溶解度、最大波长、分配系数(log P)、电离常数(pKa)、比(α)和摩尔旋转(μ)、折射率(n)、比折射率(RS)和摩尔折射率(RM)进行物理和光谱表征。结果:溶解度和对数P值测定结果表明，苯妥英前药可通过口服和肠外给药，最大限度地减少了苯妥英相关的局限性。对25 ~ 30 g体重的白化小鼠进行最大电击(MES)和士的宁诱发癫痫试验，发现4b和4d在最大电击和士的宁诱发癫痫试验中具有显著的抗惊厥活性。对体重280 ~ 300 g的雄性Sprague Dawley大鼠的肝脏、肠黏膜和血浆样品进行了4b和4d的体外酶解研究，其中苯妥英在220 nm下于10.13 ~ 10.68 min洗脱。结论:以氨基酸为基础的互前药策略是提高苯妥英的溶解度和抗惊厥活性的一种有前景的方法，可用于开发抗惊厥药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Central nervous system agents in medicinal chemistry Psychology-Neuropsychology and Physiological Psychology

CiteScore

2.10

自引率

0.00%

发文量

期刊介绍： Central Nervous System Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new central nervous system agents. Containing a series of timely in-depth reviews written by leaders in the field covering a range of current topics, Central Nervous System Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in the field.