STRUCTURAL DIVERSIFICATION AND ECO-FRIENDLY SYNTHESIS OF PHENYTOIN ANALOGS
DOI:
https://doi.org/10.22159/ajpcr.2026v19i3.57389Keywords:
Phenytoin, Schiff Base, Hybrid Molecules, Voltage-gated sodium channels, PEGylationAbstract
Phenytoin is a traditional antiepileptic drug of the hydantoin class, universally employed for seizure control in generalized tonic–clonic and focal seizures. Although effective, phenytoin is plagued by limitations such as low aqueous solubility, dose-dependent pharmacokinetics, and toxicity following chronic administration. These limitations have prompted the synthesis of several hydantoin analogs to enhance therapeutic effects, pharmacokinetics, and drug selectivity. This review focuses on chemically modified phenytoin derivatives, prepared using methods such as N-substitution, para-aryl functionalization, and heterocyclic hybridization, among others. Structural alteration was examined in their literature-cited pharmacological activities. Classical and advanced synthetic methods like microwave-assisted synthesis, solvent-free grinding, ultrasound irradiation, and continuous flow chemistry were also assessed for efficacy, sustainability, and yield of the product. Derivatives including mephenytoin, fosphenytoin, Schiff bases, and hybrid molecules incorporating thiazole, quinazolinone, and imidazole showed improved anticonvulsant, anti-inflammatory, antioxidant, antimicrobial, and anticancer activity. PEGylation and prodrug formation (e.g., Fosphenytoin) improved delivery and solubility profiles. Modern green synthesis techniques, particularly microwave and solvent-free reactions, significantly reduce reaction times while minimizing the environmental footprint. These methods not only enhanced synthetic efficiency but also benefited sustainable medicinal chemistry practices. Structural modification of the phenytoin has given rise to derivatives possessing better pharmacological profiles and broader therapeutic uses. The incorporation of green and highly efficient synthesis routes presents an exciting avenue for future drug discovery. Phenytoin continues to be a useful template in the field of medicinal chemistry, with continued application in the design of safer, better anticonvulsant drugs.
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1. Raj T, Sylvia A, Chidambaranathan S, Nirmala P. A prospective study of drug utilization pattern of anti-epileptic drugs and their adverse effects in a tertiary care hospital. Henry Daniel. Int J Curr Pharm Res. 2018;10(4):50-3.
2. Sarma P, Bhattacharyya A. Models of epilepsy used in antiepileptic drug discovery: A review. J Pharm Pharm Sci. 2014 Oct;6:1-7.
3. Wadghane S, Bhor R, Shinde G, Kolhe M, Pooja R. A review on the some biological activities of the hydantoin derivatives. J Drug Deliv Ther. 2023 Jan 15;13(1):171-8. doi: 10.22270/jddt.v13i1.5904
4. Guerrab W, Lgaz H, Kansiz S, Mague JT, Dege N, Ansar M, et al. Synthesis of a novel phenytoin derivative: Crystal structure, Hirshfeld surface analysis and DFT calculations. J Mol Struct. 2020 May 15;1205:127630. doi: 10.1016/j.molstruc.2019.127630
5. Cho S, Kim SH, Shin D. Recent applications of hydantoin and thiohydantoin in medicinal chemistry. Eur J Med Chem. 2019 Feb 15;164:517-45. doi: 10.1016/j.ejmech.2018.12.066, PMID 30622025
6. Sarkar A, Santra S, Kundu SK, Hajra A, Zyryanov GV, Chupakhin ON, et al. A decade update on solvent and catalyst-free neat organic reactions: A step forward towards sustainability. Green Chem. 2016;18(16): 4475-525.
7. Katre SD. Microwaves in organic synthetic chemistry – a greener approach to environmental protection: An overview. Int J Chem Sci. 2007;5(2):489–501.
8. Pal R, Singh K, Paul J, Khan SA, Naim MJ, Akhtar MJ. Overview of chemistry and therapeutic potential of non-nitrogen heterocyclics as anticonvulsant agents. Current Neuropharmacology. 2022;20(8):1519- 53.
9. Bialer M. Chemical properties of antiepileptic drugs (AEDs). Adv Drug Deliv Rev. 2012 Jul 1;64(10):887-95. doi: 10.1016/j.addr.2011.11.006, PMID 22210279
10. Vardanyan R, Hruby V. Synthesis of Essential Drugs. Netherlands: Elsevier; 2006 Mar 10.
11. McCleane GJ. Intramuscular fosphenytoin reduces neuropathic pain: A randomized, double-blind, placebo-controlled, crossover study. Analgesia. 1999 Jan 1;4(4):479-82.
12. Vatannavaz L, Sabounchei SJ, Sedghi A, Karamian R, Farida SH, Rahmani N. Synthesis, characterization, theoretical study and biological activity studies of the mercury (II) complexes of 5-methyl- 5-(4-nitrophenyl)-hydantoin. J Chin Chem Soc. 2021 Nov;68(11): 2140-50. doi: 10.1002/jccs.202100135
13. Ohashi T, Takahashi S, Nagamachi T, Yoneda K, Yamada H. A new method for 5-(4-hydroxyphenyl) hydantoin synthesis. Agric Biol Chem. 1981 Apr 1;45(4):831-8.
14. Khirallah SM, Ramadan HM, Shawky A, Qahl SH, Baty RS, Alqadri N, et al. Development of novel 1,3-disubstituted-2- thiohydantoin analogues with potent anti-inflammatory activity; In vitro and in silico assessments. Molecules. 2022 Sep 23;27(19):6271. doi: 10.3390/molecules27196271, PMID 36234810
15. Abida MD, Tauquir Alam M, Asif M. Study of some hydantion derivatives as anticonvulsant agents. Prog Chem Biochem Res. 2020;3(2):93-104. doi: 10.33945/SAMI/PCBR.2020.2.2
16. Konnert L, Lamaty F, Martinez J, Colacino E. Recent advances in the synthesis of hydantoins: The state of the art of a valuable scaffold. Chem Rev. 2017 Dec 13;117(23):13757-809. doi: 10.1021/acs. chemrev.7b00067, PMID 28644621
17. Cherneva E, Buyukliev R, Shivachev B, Rusew R, Bakalova A. A new synthetic route for preparation of 5-methyl-5-benzylhydantoin: X-ray analysis and theoretical calculations. Molbank. 2025 Jan 22;2025(1):M1956. doi: 10.3390/M1956
18. Tchekalarova J, Todorov P, Rangelov M, Stoyanova T, Todorova N. Additive anticonvulsant profile and molecular docking analysis of 5,5’-diphenylhydantoin Schiff bases and phenytoin. Biomedicines. 2023 Oct 27;11(11):2912. doi: 10.3390/biomedicines11112912, PMID 38001914
19. Kalník M, Gabko P, Bella M, Koóš M. The Bucherer-Bergs multicomponent synthesis of hydantoins-excellence in simplicity. Molecules. 2021 Jun 30;26(13):4024. doi: 10.3390/molecules26134024, PMID 34209381
20. Banerjee S, Periyasamy S, Muthukumaradoss K, Deivasigamani P, Saravanan V. Revolutionizing organic synthesis through green chemistry: Metal-free, bio-based, and microwave-assisted methods. Front Chem. 2025;13:1656935. doi: 10.3389/fchem.2025.1656935, PMID 40832566
21. Chetry AB. Mechanochemistry: A new frontier in chemical synthesis. J Chem Res. 2025 May;49(3):299. doi: 10.1177/17475198251339299
22. Ahmad S, Jaiswal R, Yadav R, Verma S. Recent advances in green chemistry approaches for pharmaceutical synthesis. Sustain Chem One World. 2024 Dec 1;4:100029. doi: 10.1016/j.scowo.2024.100029
23. Kappe CO, Stadler A. Microwave-assisted organic synthesis. 2nd ed. Weinheim: Wiley-VCH; 2013.
24. Nagar MK, Waghmare KR, Dhabale PN, Chanekar PD, Bhatia S. Microwave assisted synthesis and characterization of phenytoin. Asian J Res Chem. Apr 2011;4(4):619-20.
25. Wenger LE, Hanusa TP. Synthesis without solvent: Consequences for mechanochemical reactivity. Chem Commun (Camb). 2023;59(96):14210-22. doi: 10.1039/D3CC04929A, PMID 37953718
26. Jin Z, Yan C, Chu H, Huang Q, Wang Z. Synthesis of benzoin under supramolecular catalysis involving cyclodextrins in water: Application for the preparation of the antiepileptic drug phenytoin. RSC Adv. 2022;12(17):10460-6. doi: 10.1039/D1RA09062C, PMID 35424977
27. Pagola S. Outstanding advantages, current drawbacks, and significant recent developments in mechanochemistry: A perspective view. Crystals. 2023 Jan 10;13(1):124. doi: 10.3390/cryst13010124
28. Siddique M, Rashid R, Ali A. Fundamentals of acoustic cavitation, ultrasound-assisted processes, and sonochemistry. In: In Modeling and Simulation of Sonogr-Processes. Netherlands: Elsevier; 2025 Jan 1. p. 3-17. doi: 10.1016/B978-0-443-23651-8.00001-2
29. Safari J, Naeimi H, Ghanbari MM, Sabzi Fini O. Preparation of phenytoin derivatives under solvent-free conditions using microwave irradiation. Russ J Org Chem. 2009 Mar 1;45(3):477-9. doi: 10.1134/ S1070428009030270
30. Yang B, Zhai X, Mei R, Wang P, Mei Y. An improved ultrasound-assisted synthesis of phenytoin suitable for undergraduate education. Ultrason Sonochem. 2025 Jan 1;112:107207. doi: 10.1016/j. ultsonch.2024.107207, PMID 39718079
31. Baxendale IR, Brocken L, Mallia CJ. Flow chemistry approaches directed at improving chemical synthesis. Green Process Synth. 2013 Jun 1;2(3):211-30. doi: 10.1515/gps-2013-0029
32. Buglioni L, Raymenants F, Slattery A, Zondag SD, Noël T. Technological innovations in photochemistry for organic synthesis: Flow chemistry, high-throughput experimentation, scale-up, and photoelectrochemistry. Chem Rev. 2021 Aug 10;122(2):2752-906. doi: 10.1021/acs.chemrev.1c00332, PMID 34375082
33. Longstreet AR, McQuade DT. Organic reaction systems: Using microcapsules and microreactors to perform chemical synthesis. Acc Chem Res. 2013 Feb 19;46(2):327-38.
34. Ganesh KN, Zhang D, Miller SJ, Rossen K, Chirik PJ, Kozlowski MC, et al. Green chemistry: A framework for a sustainable future. ACS Omega. 2021 Jun 15;6(25):16254-8. doi: 10.1021/acsomega.1c03011, PMID 34235294
35. Sheldon RA. Metrics of green chemistry and sustainability: Past, present, and future. ACS Sustainable Chem Eng. 2018 Jan 2;6(1): 32-48. doi: 10.1021/acssuschemeng.7b03505
36. Kurul F, Doruk B, Topkaya SN. Principles of green chemistry: Building a sustainable future. Discov Chem. 2025 Apr 7;2(1):68. doi: 10.1007/ s44371-025-00152-9
37. Elbarki A, Guerrab W, Laabaissi T, Benhiba F, Rouifi Z, Oudda H, et al. Chemical, electrochemical and theoretical studies of 3-methyl-5, 5’-diphenylimidazolidine-2, 4-dione as corrosion inhibitor for mildsteel in HCl solution. Chem Data Collect. 2020 Aug 1;28:100454. doi: 10.1016/j.cdc.2020.100454
38. Guerrab W, Akrad R, Ansar M, Taoufik J, Mague JT, Ramli Y. 3-methyl-5, 5-diphenylimidazolidine-2, 4-dione. IUCrData. 2017 Oct 28;2(10):x171534. doi: 10.1107/S2414314617015346
39. Al-Nuzal SM, Al-Dulaimi MF, Hassan AT. Synthesis and spectrometric study of some nucleophilic reactions of the antiepileptic molecule; 5, 5-diphenyl imidazolidine-2,4-dione. J Univ Anbar Pure Sci. 2018 Jan 1;12(1):38-53.
40. Guerrab W, Mague JT, Ramli Y. Synthesis and crystal structure of 3-octyl-5, 5-diphenylimidazolidine-2, 4-dione, C23H28N2O2. Z Kristallogr - New Cryst Struct. 2020 Oct 27;235(6):1425-7. doi: 10.1515/ncrs-2020-0347
41. Han L, Wang P, Wang Y, Zhao Q, Zheng F, Dou Z, et al. Rapid discovery of the potential toxic compounds in Polygonum multiflorum by UHPLC/Q-orbitrap-MS-based metabolomics and correlation analysis. Front Pharmacol. 2019 Apr 16;10:329. doi: 10.3389/fphar.2019.00329, PMID 31057397
42. Hulshoff A, Renema J, Roseboom H, Loriaux B, Rook B. Gas chromatographic alkylation studies of phenytoin, mephenytoin and primidone: Investigation of butylated derivatives. J Pharm Biomed Anal. 1983 Jan 1;1(2):169-79. doi: 10.1016/0731-7085(83)80024-7, PMID 16867815
43. Gordos J, Schäublin J, Spring P. Micro-determination of plasma diphenylhydantoin by gas-liquid chromatography. J Chromatogr. 1977 Mar 1;143(2):171-81. doi: 10.1016/S0378-4347(00)81822-8, PMID 838829
44. Hutt AJ, Hadley MR, Tan SC. Enantiospecific analysis: Applications in bioanalysis and metabolism. Eur J Drug Metab Pharmacokinet. 1994 Sep;19(3):241-51. doi: 10.1007/BF03188927, PMID 7867667
45. Buchwald AL. Mephenytoin overdose--phenytoin poisoning incognito? Case report and mephenytoin/phenytoin comparison. J Toxicol Clin Toxicol. 2000 Jan 1;38(7):781-5. doi: 10.1081/CLT-100102392, PMID 11192466
46. Kupferberg HJ, Yonekawa W. The metabolism of 3-methyl-5-ethyl- 5-phenylhydantoin (mephenytoin) to 5-ethyl-5-phenylhydantoin (nirvanol) in mice in relation to anticonvulsant activity. Drug Metab Dispos. 1975 Jan 1;3(1):26-9. doi: 10.1016/S0090-9556(25)05616-8
47. Bettio L, Bankar G, Dubé CM, Nelkenbrecher K, Filipovic M, Singh S, et al. The pharmacokinetic and pharmacodynamic relationship of clinically used antiseizure medications in the maximal electroshock seizure model in rodents. Int J Mol Sci. 2025 Jul 22;26(15):7029. doi: 10.3390/ijms26157029, PMID 40806162
48. Kappe CO. Recent advances in the Biginelli dihydropyrimidine synthesis. New tricks from an old dog. Acc Chem Res. 2000 Dec 19;33(12): 879-88. doi: 10.1021/ar000048h, PMID 11123887
49. Nageshwaran S, Ledingham D, Wilson HC, Dickenson A, editors. Drugs in Neurology. Oxford: Oxford University Press; 2017 Jan 26.
50. Fujii J, Higashi A, Inotsume N, Matsuda I, Nakano M. Studies on pharmacokinetics of ethotoin in epileptic children and adolescents using a stable isotope. Rinshoyakuri/Japanese Clin Pharmacol Ther. 2001 Mar 31;32(2):59-64.
51. Troupin AS, Friel P, Lovely MP, Wilensky AJ. Clinical Pharmacology of mephenytoin and ethotoin. Ann Neurol. 1979 Nov;6(5):410-4. doi: 10.1002/ana.410060506, PMID 42344
52. Porcheddu A, Charnay C, Delogu F, Colacino E. From solution-based nonconventional activation methods to mechanochemical procedures: The hydantoin case. In: Nontraditional Activation Methods in Green and Sustainable Applications. Netherlands: Elsevier; 2021 Jan 1. p. 421-52. doi: 10.1016/B978-0-12-819009-8.00003-7
53. Schneider H, Janz D, Gardner-Thorpe C, Meinardi H, Sherwin AL, editors. Clinical pharmacology of anti-epileptic drugs. In: Workshop on the Determination of Anti-Epileptic Drugs in Body Fluid II (WODADIBOF II) Held in Bethel, Bielefeld, Germany, 24-25 May, 1974. Berlin: Springer Science+Business Media; 1974.
54. Johannessen SI. Pharmacokinetics of anti-epileptic drugs and their clinical significance. Behav Neurol. 1990;3(1):1-11. doi: 10.3233/ BEN-1990-31S102, PMID 24487080
55. Di L, Kerns EH. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization. United States: Academic Press; 2015 Dec 17.
56. Elati CR, Gangula S, Naredla A, Ashok S, Bhattacharya A, Bandichhor R. Novel synthesis of fosphenytoin: Anti-convulsant prodrug. Synth Commun. 2008 Aug 18;38(17):2950-7.
57. Agrawal S, Gaikwad S, Patel R, Shinde L, Deshmukh A. Synthesis and formulation development of phenytoin by inclusion complexation. Indian J Pharm Sci. 2021 Sep 1;83(5):955-62. doi: 10.36468/ pharmaceutical-sciences.848
58. Noval M, Seung H, Armahizer M. Evaluation of fosphenytoin therapeutic drug monitoring in the neurocritical care unit. Drugs R D. 2020 Mar;20(1):17-22. doi: 10.1007/s40268-019-00292-1, PMID 31925752
59. Martinho J, Simão AY, Barroso M, Gallardo E, Rosado T. Determination of antiepileptics in biological samples-a review. Molecules. 2024 Oct 2;29(19):4679. doi: 10.3390/molecules29194679, PMID 39407608
60. Knapp LE, Kugler AR. Clinical experience with fosphenytoin in adults: Pharmacokinetics, safety, and efficacy. J Child Neurol. 1998 Oct;13 Suppl 1(1 Suppl):S15-8; discussion S30-2. doi: 10.1177/0883073898013001051, PMID 9796747
61. Popławska M, Borowicz KK, Czuczwar SJ. The safety and efficacy of fosphenytoin for the treatment of status epilepticus. Expert Rev Neurother. 2015 Sep 2;15(9):983-92. doi: 10.1586/14737175.2015.1074523, PMID 26289487
62. Mahdizade Ari M, Dashtbin S, Ghasemi F, Shahroodian S, Kiani P, Bafandeh E, et al. Nitrofurantoin: Properties and potential in treatment of urinary tract infection: A narrative review. Front Cell Infect Microbiol. 2023 Jul 27;13:1148603. doi: 10.3389/fcimb.2023.1148603, PMID 37577377
63. Ji W, Li CL, Chen H, Yu ZX, Liao X. A newly designed heterodiene and its application to construct six-membered heterocycles containing an N-O bond. Chem Commun (Camb). 2019;55(80):12012-5. doi: 10.1039/C9CC05694G, PMID 31538167
64. Choudhary U, Kumar V, Dwivedi T, Ahmed W, Vishavjeet V, Rathi J, et al. Study of anticonvulsant drug (phenytoin) along with synthesis and pharmacological effect. Int J Med Sci Pharm Res. 2022 Dec 15;8(4): 13-5. doi: 10.22270/ijmspr.v8i4.52
65. Zeb A, Ali H, Khan JZ, Shah FA, Alattar A, Alanazi FE. In silico molecular docking and molecular dynamic simulation of transferrin coated phenytoin loaded SLNs with molecular targets of epilepsy. PLOS One. 2025 Jun 20;20(6):e0325772. doi: 10.1371/journal. pone.0325772, PMID 40540445
66. Poupaert JH, Cavalier R, Claesen MH, Dumont PA. Absolute configuration of the major metabolite of 5, 5-diphenylhydantoin, 5-(4’-hydroxyphenyl)-5-phenylhydantoin. J Med Chem. 1975 Dec;18(12):1268-71. doi: 10.1021/jm00246a024, PMID 1195283
67. Arboix M, Pantarotto C. Determination of 5, 5-diphenylhydantoin and its major metabolites in biological specimens by gas chromatography and selected ion-monitoring. Chromatographia. 1982 Aug;15(8): 509-13. doi: 10.1007/BF02260285
68. Ieiri I, Goto W, Hirata K, Toshitani A, Imayama S, Ohyama Y, et al. Effect of 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, major metabolites of phenytoin, on the occurrence of chronic-gingival hyperplasia: In vivo and In vitro study. Eur J Clin Pharmacol. 1995 Nov;49(1-2):51-6. doi: 10.1007/BF00192358, PMID 8751021
69. Muccioli GG, Fazio N, Scriba GK, Poppitz W, Cannata F, Poupaert JH, et al. Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4- diones as fatty acid amide hydrolase inhibitors templates. J Med Chem. 2006 Jan 12;49(1):417-25. doi: 10.1021/jm050977k, PMID 16392827
70. Abd Elhady H, El Desoky S, Al-Shareef HF, El-mekawy R. Synthesis, reactions, and applications of hydantoin and 2-thiohydantoin derivatives. Acta Pol Pharm Drug Res. 2019 Dec 29;76(6):971-86. doi: 10.32383/appdr/112124
71. Errayes A, Darwish M, Alzaedi A. Chemical synthesis strategies for thiohydantoin derivatives: A comprehensive review. Mediterr J Chem. 2025 Sep 29;15(2):241-55.
72. Kobyłka K, Żuchowski G, Tejchman W, Zborowski KK. Synthesis, spectroscopy, and theoretical calculations of some 2-thiohydantoin derivatives as possible new fungicides. J Mol Model. 2019 Sep; 25(9):268. doi: 10.1007/s00894-019-4146-9, PMID 31446500
73. González MT, Ariza JL, Pino F, Villanova RG. Derivatives of 2-thiohydantoin as spectrophotometric analytical reagents. Talanta. 1978 Jun 1;25(6):331-7. doi: 10.1016/0039-9140(78)80137-4, PMID 18962269
74. Khodair AI, Bakare SB, Awad MK, Al-Issa SA, Nafie MS. Design, synthesis, and computational explorations of novel 2-thiohydantoin nucleosides with cytotoxic activities. J Heterocycl Chem. 2022 Apr;59(4):664-85. doi: 10.1002/jhet.4405
75. Arani NM, Safari J. A rapid and efficient ultrasound-assisted synthesis of 5,5-diphenylhydantoins and 5,5-diphenyl-2-thiohydantoins. Ultrason Sonochem. 2011 Mar 1;18(2):640-3. doi: 10.1016/j. ultsonch.2010.09.001, PMID 20920873
76. Siopa F, Perry MJ, Francisco AP, Afonso CA. Batch and continuoussynthesis of 5, 5-diphenylhydantoin, an active pharmaceutical ingredient. J Chem Educ. 2025 Jul 15;102(8):3491-6. doi: 10.1021/acs. jchemed.4c01286
77. Sagratella S. Characterization of the in vitro antiepileptic activity of new and old anticonvulsant drugs. General Pharmacology: The Vascular System. 1998;30(2):153-60.
78. Castel-Branco MM, Alves GL, Figueiredo IV, Falcão AC, Caramona MM. The maximal electroshock seizure (MES) model in the preclinical assessment of potential new antiepileptic drugs. Methods Find Exp Clin Pharmacol. 2009;31(2):101-6. doi: 10.1358/ mf.2009.31.2.1338414, PMID 19455265
79. Murtaza S, Akhtar MS, Aslam A, Riaz T, Kousar N. Schiff bases of 2, 4-dihydroxybenzaldehyde as potential anticonvulsant compounds; in vivo and docking studies. Acta Poloniae Pharmaceutica. 2017;74(6):1717-28.
80. Mallesha L, Mohana KN, Veeresh B. Synthesis and biological activities of Schiff bases of gabapentin with different aldehydes and ketones: a structure–activity relationship study. Medicinal Chemistry Research. 2012;21(1):1-9.
81. Batra N, Batra S, Nagori BP. Design, synthesis and evaluation of Schiff bases &thiazolidinone derivatives for anticonvulsant activity. J Appl Pharm Sci. 2014 Jan 30;4(1):105-12. doi: 10.7324/JAPS.2014.40118
82. Pal R, Kumar B, Akhtar MJ, Chawla PA. Voltage gated sodium channel inhibitors as anticonvulsant drugs: A systematic review on recent developments and structure activity relationship studies. Bioorg Chem. 2021 Oct 1;115:105230. doi: 10.1016/j.bioorg.2021.105230, PMID 34416507
83. Meijer JW, Meinardi H, Binnie CD. The development of antiepileptic drugs. In: Discoveries in Pharmacology-Volume 1-Nervous System and Hormones. Vol. 247. Netherlands: Elsevier Science; 2022 Sep 9.
84. Eichelbaum M, Kroemer HK, Fromm MF. Impact of P450 genetic polymorphism on the first-pass extraction of cardiovascular and neuroactive drugs. Adv Drug Deliv Rev. 1997 Sep 15;27(2-3):171-99. doi: 10.1016/S0169-409X(97)00042-2, PMID 10837557
85. Donnelly DM, Meegan MJ, Katritzky AR. Comprehensive heterocyclic chemistry. Ed. AR Katrizky. N.-Y.: Pergamon Press. 1984;4:657.
86. Allah AE, Guerrab W, Mague JT, Ramli Y. Novel approach to the synthesis of alkylated phenytoin scaffold. Moroccan J Heterocycl Chem. 2024 Nov 1;23(1):27-36.
87. Deodhar M, Sable P, Bhosale A, Juvale K, Dumbare R, Sakpal P. Synthesis and evaluation of phenytoin derivatives as anticonvulsant agents. Turkish Journal of Chemistry 2009;33(3):367-73.
88. Yaari Y, Selzer ME, Pincus JH. Phenytoin: Mechanisms of its anticonvulsant action. Ann Neurol. 1986 Aug;20(2):171-84. doi: 10.1002/ana.410200202, PMID 2428283
89. Barton ME, Klein BD, Wolf HH, White HS. Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res. 2001 Dec 1;47(3):217-27. doi: 10.1016/S0920- 1211(01)00302-3, PMID 11738929
90. Poupaert JH, Vandervorst D, Guiot P, Moustafa MM, Dumont P. Structure-activity relationships of phenytoin-like anticonvulsant drugs. J Med Chem. 1984 Jan;27(1):76-8. doi: 10.1021/jm00367a015, PMID 6690687
91. Patocka J, Wu Q, Nepovimova E, Kuca K. Phenytoin-an anti-seizure drug: Overview of its chemistry, pharmacology and toxicology. Food Chem Toxicol. 2020 Aug 1;142:111393. doi: 10.1016/j. fct.2020.111393, PMID 32376339
92. Debnath S, Kannadasan M, Ghosh S, Ghosh NS, Chakraborty R, Sen S. Antiepileptic activity of the hydroalcoholic extract of Erythrina fusca lour bark against the animal models of mes, ptx and ptz induced epileptic seizure models. Int J Chem Res. 2010 Jan 1;1:6-10.
93. Wankhede S, Badule A, Chaure S, Damahe A, Damahe M, Porwal O. Challenges and strategies in prodrug design: A comprehensive review. J Adv Sci Res. 2025 Jun 30;16(6):1-20. doi: 10.55218/JASR.2025160601
94. Lamssane H, Haoudi A, Thiruvalluvar AA, Hökelek T, Varadharajan V, Chakroune S, et al. N-alkylated 5,5-diphenylhydantoin derivatives: Synthesis, X-ray, spectroscopic characterization, Hirshfeld surface analysis, DFT, molecular docking, molecular dynamics simulations, and cholesterol oxidase binding affinity estimation. ACS Omega. 2025 Jul 7;10(27):29267-84. doi: 10.1021/acsomega.5c02215, PMID 40686988
95. Prabhu G, Basavaprabhu N, Narendra N, Vishwanatha TM, Sureshbabu VV. Amino acid chlorides: A journey from instability and racemization toward broader utility in organic synthesis including peptides and their mimetics. Tetrahedron. 2015 May 13;71(19):2785- 832. doi: 10.1016/j.tet.2015.03.026
96. Rasmussen JK, Heilmann SM, Krepski LR, Smith HK, Katritzky AR, Sakizadeh K. Poly (2-imidazolin‐5‐ones)-a new class of heterocyclic polymers. J Polym Sci A Polym Chem. 1986 Nov;24(11):2739-47. doi: 10.1002/pola.1986.080241103
97. Kadam A, Jangam S, Oswal R. Application of green chemistry principle in synthesis of phenytoin and its biogical evaluation as anticonvulsant agents. J Chem. 2011;8(S1):S47-52. doi: 10.1155/2011/159430
98. Kar S, Sanderson H, Roy K, Benfenati E, Leszczynski J. Green chemistry in the synthesis of pharmaceuticals. Chem Rev. 2021 Dec 15;122(3):3637-710. doi: 10.1021/acs.chemrev.1c00631, PMID 34910451
99. Ahsan H, Islam SU, Ahmed MB, Lee YS, Sonn JK. Significance of green synthetic chemistry from a pharmaceutical perspective. Curr Pharm Des. 2020 Dec 1;26(45):5767-82. doi: 10.2174/1381612826666 200928160851, PMID 32988346
100. Gupta P, Mahajan A. Green chemistry approaches as sustainable alternatives to conventional strategies in the pharmaceutical industry. RSC Adv. 2015;5(34):26686-705. doi: 10.1039/C5RA00358J
101. Gupta M, Tripp J. Phenytoin. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2025 Jan.
102. Botros S, Khalil NA, Naguib BH, El-Dash Y. Synthesis and anticonvulsant activity of new phenytoin derivatives. European journal of medicinal chemistry. 2013;60:57-63.
103. Sari SP, Salma SNK, Rianti A. Monitoring of anticonvulsant drug side effects in outpatients with epilepsy. Int J Appl Pharm. 2018 Dec 1;10(1):303-6. doi: 10.22159/ijap.2018.v10s1.67
104. Melkani I, Kumar B, Pandeynk NK, Singh S, Baghel DS, Sudhakar K. Therapeutic impact of nanomedicine for the treatment of neuropathic pain: Principle, prospective and future. Int J App Pharm. 2024; 16(5):46-58.
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