Additive Anticonvulsant Profile and Molecular Docking Analysis of 5,5'-Diphenylhydantoin Schiff Bases and Phenytoin

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2023 Nov 25

PMID 38001914

Authors

Jana Tchekalarova

Petar Todorov

Miroslav Rangelov

Tsveta Stoyanova

Nadezhda Todorova

Affiliations

Soon will be listed here.

Abstract

Four 5,5'-diphenylhydantoin Schiff bases possessing different aromatic species (-) were recently synthesized and characterized using spectroscopic and electrochemical tools. The present study aimed to ascertain the anticonvulsant activity of the novel phenytoin derivatives , , , and , containing different electron-donor and electron-acceptor groups, and their possible mechanism of action. The exhibited the highest potency to suppress the seizure spread with ED = 8.29 mg/kg, comparable to phenytoin (ED = 5.96 mg/kg). While did not produce neurotoxicity and sedation, it decreased locomotion and stereotypy compared to control. When administered in combination, the four Schiff bases decreased the phenytoin ED by more than 2× and raised the protective index by more than 7× (phenytoin+). The strongest correlation between in-vivo and docking study results was found for ligands' interaction energies with kappa and delta receptors. These data, combined with the worst interaction energies of our ligands with the mu receptor, suggest that the primary mechanism of their action involves the kappa and delta receptors, where the selectivity to the kappa receptor leads to higher biological effects. Our findings suggest that the four Schiff bases might be promising candidates with potential applications as a safe and effective adjuvant in epilepsy.

Citing Articles

Schiff Bases: A Captivating Scaffold with Potential Anticonvulsant Activity.

Sahu R, Shah K Mini Rev Med Chem. 2024; 24(18):1632-1650.

PMID: 38629363 DOI: 10.2174/0113895575302197240408121537.

Small Schiff Base Molecules-A Possible Strategy to Combat Biofilm-Related Infections.

Coanda M, Limban C, Nuta D Antibiotics (Basel). 2024; 13(1).

PMID: 38247634 PMC: 10812491. DOI: 10.3390/antibiotics13010075.

References

Pandeya S, Raja A, Stables J . Synthesis of isatin semicarbazones as novel anticonvulsants--role of hydrogen bonding. J Pharm Pharm Sci. 2003; 5(3):266-71. View

Pepin M, Yue S, Roberts E, Wahlestedt C, Walker P . Novel "restoration of function" mutagenesis strategy to identify amino acids of the delta-opioid receptor involved in ligand binding. J Biol Chem. 1997; 272(14):9260-7. DOI: 10.1074/jbc.272.14.9260. View

Zhang M, Liang Y, Li H, Liu M, Wang Y . Design, synthesis, and biological evaluation of hydantoin bridged analogues of combretastatin A-4 as potential anticancer agents. Bioorg Med Chem. 2017; 25(24):6623-6634. DOI: 10.1016/j.bmc.2017.10.045. View

Suzuki T, Saito Y, Nishihara K . Kinetics of diphenylhydantoin disposition in man. Chem Pharm Bull (Tokyo). 1970; 18(2):405-11. DOI: 10.1248/cpb.18.405. View

Singh N, Cheve G, Ferguson D, McCurdy C . A combined ligand-based and target-based drug design approach for G-protein coupled receptors: application to salvinorin A, a selective kappa opioid receptor agonist. J Comput Aided Mol Des. 2006; 20(7-8):471-93. DOI: 10.1007/s10822-006-9067-x. View

Clayton C, Bruchas M, Lee M, Chavkin C . Phosphorylation of the mu-opioid receptor at tyrosine 166 (Tyr3.51) in the DRY motif reduces agonist efficacy. Mol Pharmacol. 2009; 77(3):339-47. PMC: 2835424. DOI: 10.1124/mol.109.060558. View

Barton M, Klein B, Wolf H, White H . Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res. 2001; 47(3):217-27. DOI: 10.1016/s0920-1211(01)00302-3. View

Fenalti G, Giguere P, Katritch V, Huang X, Thompson A, Cherezov V . Molecular control of δ-opioid receptor signalling. Nature. 2014; 506(7487):191-6. PMC: 3931418. DOI: 10.1038/nature12944. View

Unverferth K, Engel J, Hofgen N, Rostock A, Gunther R, Lankau H . Synthesis, anticonvulsant activity, and structure-activity relationships of sodium channel blocking 3-aminopyrroles. J Med Chem. 1998; 41(1):63-73. DOI: 10.1021/jm970327j. View

10.

Yaari Y, Selzer M, PINCUS J . Phenytoin: mechanisms of its anticonvulsant action. Ann Neurol. 1986; 20(2):171-84. DOI: 10.1002/ana.410200202. View

11.

Putnam T, Merritt H . EXPERIMENTAL DETERMINATION OF THE ANTICONVULSANT PROPERTIES OF SOME PHENYL DERIVATIVES. Science. 1937; 85(2213):525-6. DOI: 10.1126/science.85.2213.525. View

12.

Han J, Zhang J, Nazarova A, Bernhard S, Krumm B, Zhao L . Ligand and G-protein selectivity in the κ-opioid receptor. Nature. 2023; 617(7960):417-425. PMC: 10172140. DOI: 10.1038/s41586-023-06030-7. View

13.

Wu H, Wacker D, Mileni M, Katritch V, Han G, Vardy E . Structure of the human κ-opioid receptor in complex with JDTic. Nature. 2012; 485(7398):327-32. PMC: 3356457. DOI: 10.1038/nature10939. View

14.

Alkahtani H, Alanazi M, Aleanizy F, Alqahtani F, Alhoshani A, Alanazi F . Synthesis, anticancer, apoptosis-inducing activities and EGFR and VEGFR2 assay mechanistic studies of 5,5-diphenylimidazolidine-2,4-dione derivatives: Molecular docking studies. Saudi Pharm J. 2019; 27(5):682-693. PMC: 6598223. DOI: 10.1016/j.jsps.2019.04.003. View

15.

Jonas H, Aiello D, Schepmann D, Diana P, Wunsch B . Synthesis of 8-aminomorphans with high KOR affinity. Eur J Med Chem. 2022; 230:114079. DOI: 10.1016/j.ejmech.2021.114079. View

16.

Krall R, PENRY J, White B, KUPFERBERG H, SWINYARD E . Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia. 1978; 19(4):409-28. DOI: 10.1111/j.1528-1157.1978.tb04507.x. View

17.

Alachkar A, Ojha S, Sadeq A, Adem A, Frank A, Stark H . Experimental Models for the Discovery of Novel Anticonvulsant Drugs: Focus on Pentylenetetrazole-Induced Seizures and Associated Memory Deficits. Curr Pharm Des. 2020; 26(15):1693-1711. DOI: 10.2174/1381612826666200131105324. View

18.

Varia S, Stella V . Phenytoin prodrugs V: In vivo evaluation of some water-soluble phenytoin prodrugs in dogs. J Pharm Sci. 1984; 73(8):1080-7. DOI: 10.1002/jps.2600730814. View

19.

Labute P . The generalized Born/volume integral implicit solvent model: estimation of the free energy of hydration using London dispersion instead of atomic surface area. J Comput Chem. 2008; 29(10):1693-8. DOI: 10.1002/jcc.20933. View

20.

Fadhil I, Schmidt R, Walpole C, Carpenter K . Exploring deltorphin II binding to the third extracellular loop of the delta-opioid receptor. J Biol Chem. 2004; 279(20):21069-77. DOI: 10.1074/jbc.M311468200. View