Synthesis and CNS Activity of Phenytoin Derivatives

Rahul      Chauhan; Shweta      Verma; Alankar      Shrivasatava

doi:10.2174/1871524922666220429122141

Abstract

Background: The derivatives of Phenytoin conjugated with various anilines were synthesized. The synthesized derivatives were evaluated for different physicochemical parameters along with log P values using different software programs to discover their ability to cross the blood brain barrier. The pharmacological activities such as antianxiety, skeletal muscle relaxant and anticonvulsant were evaluated by using different models.

Objective: The new Phenytoin derivatives were synthesized and evaluated for different properties to predict CNS activity. The drugs synthesized by chloroacetylation and then different aniline were added to it. The compounds were evaluated for their different CNS activity by using different methods.

Methods: The compounds were synthesized by firstly chloroacetylating the phenytoin and then different substituted anilines were added to it. The compounds were evaluated for antianxiety activity, muscle relaxant activity and anticonvulsant activity by using different models.

Results: The number of derivatives of Phenytoin was synthesized and various physicochemical parameters were optimized which revealed that the compound containing chloro groups such as C2 and C5 exhibited significant potential when compared with the standard drug Diazepam.

Conclusion: It was portrayed that the synthesis, computational studies and evaluation of anticonvulsant, antianxiety and skeletal muscle relaxant activity of new Phenytoin derivatives were carried out. The compounds were productively synthesized and portrayed by molecular docking studies. The compounds also exhibit mild to moderate similarity with respect to standard drug. The synthesized drugs have the potential to be optimized further to engender new scaffolds to treat various CNS disorders.

Keywords: Phenytoin, parameters, CNS activity, blood brain barrier, log P, CNS active.

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[1] 
Kitano, Y.; Usui, C.; Takasuna, K.; Hirohashi, M.; Nomura, M. Increasing-current electroshock seizure test: a new method for assessment of anti- and pro-convulsant activities of drugs in mice. J. Pharmacol. Toxicol. Methods,  1996, 35(1), 25-29.
[http://dx.doi.org/10.1016/1056-8719(95)00115-8] [PMID:  8645877] 
[2] 
Bosch, J.; Roca, T.; Domènech, J.; Suriol, M. Synthesis of water-soluble phenytoin prodrugs. Bioorg. Med. Chem. Lett.,  1999, 9(13), 1859-1862.
[http://dx.doi.org/10.1016/S0960-894X(99)00294-2] [PMID:  10406655] 
[3] 
Safari, J.; Naeimi, H.; Ghanbari, M.; Sabzi Fini, O. SabziFini O.Preparation of phenytoin derivatives under solvent-free conditions using microwave irradiation. Russ. J. Org. Chem.,  2009, 45(3), 477-479.
[http://dx.doi.org/10.1134/S1070428009030270] 
[4] 
Taylor, C.P. Voltage-gated Na+ channels as targets for anticonvulsant,analgesic and neuroprotective drugs. Curr. Pharm. Des.,  1996, (2), 375-379.
[5] 
Sayyah, M.; Nadjafnia, L.; Kamalinejad, M. Anticonvulsant activity and chemical composition of Artemisia dracunculus L. essential oil. J. Ethnopharmacol.,  2004, 94(2-3), 283-287.
[http://dx.doi.org/10.1016/j.jep.2004.05.021] [PMID:  15325732] 
[6] 
Śladowska, K.; Opydo-Chanek, M.; Król, W.; Trybus, W.; Trybus, E.; Kopacz-Bednarska, Anna.; Handzlik, J.; Kieć-Kononowicz, K.; Mazur, L. In-vitro effects of bromoalkylphenytoin derivatives on regulated death, cell cycle and ultra structure of leukemia cells. Anticancer Res.,,  2017, 37(11), 6373-6380.
[PMID:  29061822] 
[7] 
van de Waterbeemd, H.; Camenisch, G.; Folkers, G.; Chretien, J.R.; Raevsky, O.A. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J. Drug Target.,  1998, 6(2), 151-165.
[http://dx.doi.org/10.3109/10611869808997889] [PMID:  9886238] 
[8] 
Kelder, J.; Grootenhuis, P.D.J.; Bayada, D.M.; Delbressine, L.P.C.; Ploemen, J.P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm. Res.,  1999, 16(10), 1514-1519.
[http://dx.doi.org/10.1023/A:1015040217741] [PMID:  10554091] 
[9] 
Kumar, S.; Wahi, A.K.; Singh, R. Synthesis, computational studies and preliminary pharmacological evaluation of 2-[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides as potential antipsychotics. Eur. J. Med. Chem.,  2011, 46(9), 4753-4759.
[http://dx.doi.org/10.1016/j.ejmech.2011.07.028] [PMID:  21824691] 
[10] 
Moriguchi, I.; Hirono, S.; Liu, Q.; Nakagomeand, I.; Matsushita, Y. Simple method of calculatingoctanol/water partition coefficient. Chem. Pharm. Bull. (Tokyo),  1992, 40(1), 127-130.
[http://dx.doi.org/10.1248/cpb.40.127] 
[11] 
Available from: www.molinspiration.com/cgi-bin/properties
[12] 
Parle, M.; Dhamija, I. Anxiolytic potential of tamarindusindica. Ann. Pharm. Pharm. Sci.,  2012, 3(2), 67-71.
[13] 
Sinoriya, P.; Irchhaiya, R.; Sharma, B.; Sahu, G.; Kumar, S. Anticonvulsant and muscle relaxant activity of the ethanolic extract of stems of Dendrophthoefalcata (Linn. F.) in mice. Int. J. Pharmacol.,  2011, 43(6), 713.
[14] 
Suite 700, NW (202)452-1600.NW Suite 700, Washington D C, 2003. 6, pp.
[15] 
Steimer, T. The biology of fear- and anxiety-related behaviors. Dialogues Clin. Neurosci.,  2002, 4(3), 231-249.
[http://dx.doi.org/10.31887/DCNS.2002.4.3/tsteimer] [PMID:  22033741] 
[16] 
Moser, P.C. An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone. Psychopharmacology (Berl.),  1989, 99(1), 48-53.
[http://dx.doi.org/10.1007/BF00634451] [PMID:  2528779] 
[17] 
Pellow, S.; Chopin, P.; File, S.E.; Briley, M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J. Neurosci. Methods,  1985, 14(3), 149-167.
[http://dx.doi.org/10.1016/0165-0270(85)90031-7] [PMID:  2864480] 
[18] 
Mokhtari, S.; Rabiei, Z.; Shahrani, M.; Rafieian-Kopaei, M. The ameliorating effect of beta vulgaris extract on memory and learning im-pairment induced by lesions of the nucleus basalis of meynert in rat. J. Clin. Diagn. Res.,  2017, 11(11), 9-14.
[http://dx.doi.org/10.7860/JCDR/2017/20809.10887] 
[19] 
Swinyard, E.A.; Brown, W.C.; Goodman, L.S. Comparative assays of antiepileptic drugs in mice and rats. J. Pharmacol. Exp. Ther.,  1952, 106(3), 319-330.
[PMID:  13000628] 

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DOI https://dx.doi.org/10.2174/1871524922666220429122141	Print ISSN 1871-5249
Publisher Name Bentham Science Publisher	Online ISSN 1875-6166

Central Nervous System Agents in Medicinal Chemistry

Synthesis and CNS Activity of Phenytoin Derivatives

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