Design-Driven Discovery of 3,5-disubstituted hydantoin-Based Anticonvulsants Supported by In-Vivo and In-Silico Studies
Keywords:
N-methylurea, Glyoxal, 1-methyl-imidazolidine-2,4-dione, indole-3-aldehyde, hydantoin bearing indole, anti-convulsant activity, docking studiesAbstract
Abstract
A variety of imidazolidine-2,4-dione (hydantoin) derivatives 5a–5g with an indole moiety were created and produced utilizing the proper techniques. Every synthetic substance was examined both physically and spectrally. Overall, the compounds produced good yields. Wistar albino rats were used to test the compounds' in-vivo anticonvulsant activity utilizing maximum electroshock (MES) and pentylenetetrazole (PTZ) techniques in comparison to the common medication phenytoin. Compounds 5c and 5d showed notable action. To predict an anticonvulsant effect, molecular docking tests using AutoDock software showed that compounds 5b, 5c, and 5d have a strong binding interaction at the voltage-gated sodium channel protein target (PDB ID-3RVY) in comparison to the conventional ligand phenytoin. Both in-vivo anticonvulsant activity and in-silico molecular docking investigations indicated that compounds electron-withdrawing nitro group compounds had significant anticonvulsant activity and strong binding affinity respectively at target site.
Downloads
References
1. Wadghane et al., A Review on the Some Biological Activities of the Hydantoin Derivatives, Journal of Drug Delivery & Therapeutics. 2023; 13(1):171-178.
2. Gawas PP, Ramakrishna B, Veeraiah N, Nutalapati V. Multifunctional hydantoins: recent advances in optoelectronics and medicinal drugs from Academia to the chemical industry. Journal of Materials Chemistry C. 2021; 9(46): 16341-16377.
3. Padwa A, Bur SK. The domino way to heterocycles.Tetrahedron. 2007; 63(25): 5341-5378.
4. Peerzada MN, Hamel E, Bai R, Supuran CT, Azam A. Deciphering the key heterocyclic scaffolds in targeting microtubules, kinases and carbonic anhydrases for cancer drug development. Pharmacology & Therapeutics. 2021; 225: 107860.
5. Brunton L, Parker K, Blumenthal D, et al. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. New York: The McGraw-Hill; 2008.
6. Lingappa M, Guruswamy V, Bantal V. Synthesis and characterization of 4-amino-4H-1,2,4-triazole derivatives: Anticonvulsant activity. Current Chemistry Letters. 2021; 10(1): 33-42.
7. Laure Konnert, FrédéricLamaty, Jean Martinez, EvelinaColacino. Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold. Chemical Reviews, American Chemical Society, 2017, 117 (23), pp.13757-13809.
8. Ee-Zhen Chin et al., Synthesis and Characterization of Amino Acid-Derived Hydantoins,Malaysian Journal of Chemistry, 2021, Vol. 23(2), 19-25.
9. Konnert L, Lamaty F, Martinez J, Colacino E. Recent advances in the synthesis of hydantoins: the state of the art of a valuable scaffold. Chemical Reviews. 2017; 117(23): 13757-13809.
10. Baccolini, G.; Boga, C.; Delpivo, C.; Micheletti, G. Facile Synthesis of Hydantoins and Thiohydantoins in Aqueous Solution. Tetrahedron Lett.2011; 52, 1713−1717.
11. B. Gilles, A.A.A.Q. Abed, D.E. Claes, K. Izet, J.N. Hans, V.C. Serge, S. Morris, C. Tom, Synthesis and evaluation of thiazolidinedione and dioxazaborocane analogues as inhibitors of AI-2 quorum sensing in Vibrio harveyi, Bioorg. Med. Chem. 21 (2013) 660-667.
12. Kumar KS, Rao AL, Rao MB. Design, synthesis, biological evaluation and molecular docking studies of novel 3-substituted-5-[(indol-3-yl) methylene]-thiazolidine-2, 4-dione derivatives.Heliyon. 2018 Sep 1;4(9).
13. E.R. Alexander, E.J. Underhill, Studies on the mechanism of the mannich reaction. I. Ethylmalonic acid, a methynyl compound, J. Am. Chem. Soc. 17 (1949) 4014-4019.
14. S.K. Jiwane, V.K. Singh, K.P. Namdeo, S.K. Prajapati, Synthesis of some novel 2,4-thiazolidinedione derivatives and their biological screening as antidiabetic agents, Asian J. Chem. 21 (2009) 5068-5072.
15. Enoch, O.C.; Ezeonu, C.F. Comparative Study of LD50 Determination of Bisphenol A in Albino Wistar Rats Using Different Method. Asian Sci. Bul 2024, 2(1), 92-98.
16. Raj A, Nair NS, Nisha AR, Sujith S, Divya C, Shankar R. Determination of the median lethal dose of indoxacarb pesticide in Wistar rat. Journal of Veterinary and Animal Sciences. 2023;54(2):510-5.
17. Singh RB, Das N, Singh GK, Singh SK, Zaman K. Synthesis and pharmacological evaluation of 3-[5-(aryl-[1, 3, 4] oxadiazole-2-yl]-piperidine derivatives as anticonvulsant and antidepressant agents. Arabian Journal of Chemistry. 2020 May 1;13(5):5299-311.
18. Fakhrioliaei A, Abedinifar F, SalehiDarjani P, Mohammadi-Khanaposhtani M, Larijani B, Ahangar N, Mahdavi M. Hybridization of the effective pharmacophores for treatment of epilepsy: design, synthesis, in vivo anticonvulsant activity, and in silico studies of phenoxyphenyl-1, 3, 4-oxadiazole-thio-N-phenylacetamid hybrids. BMC chemistry. 2023 Jul 17;17(1):80.
19. Dehestani L, Ahangar N, Hashemi SM, Irannejad H, Masihi PH, Shakiba A, Emami S. Design, synthesis, in vivo and in silico evaluation of phenacyltriazolehydrazones as new anticonvulsant agents. Bioorganic chemistry. 2018 Aug 1;78:119-29.
20. Singh RB, Das N, Singh GK, Singh SK, Zaman K. Synthesis and pharmacological evaluation of 3-[5-(aryl-[1,3,4] oxadiazole-2-yl]-piperidine derivatives as anticonvulsant and antidepressant agents. Arabian Journal of Chemistry. 2020 May 1;13(5):5299-311.
21. Botros S, Khalil NA, Naguib BH, El-Dash Y. Synthesis and anticonvulsant activity of new phenytoin derivatives. European journal of medicinal chemistry. 2013 Feb 1;60:57-63.
22. Khirallah SM, Ramadan HM, Shawky A, Qahl SH, Baty RS, Alqadri N, Alsuhaibani AM, Jaremko M, Emwas AH, Saied EM. Development of novel 1, 3-disubstituted-2-thiohydantoin analogues with potent anti-inflammatory activity; in vitro and in silico assessments.Molecules. 2022; 27(19): 6271.
23. Das D, Kumar A, Guruprasad R, Mahapatra DK. Molecular Docking and Density Function Theory (DFT) Studies of some 4-(2-Chloroacetamido) Benzoic Acid Derivatives as Local Anesthetics. Molecular Modeling. 2017:1-5.
24. Hompoonsup S. Identification and Transcriptional Characterization of Novel Inhibitors of NAv1. 7 and TRKB: King's College London; 2018.
25. Karumanchi SK, Atmakuri LR, Mandava VB, Rajala S. Synthesis and hypoglycemic and anti-inflammatory activity screening of novel substituted 5-[morpholino (phenyl) methyl]-thiazolidine-2, 4-diones and their molecular docking studies. Turkish Journal of Pharmaceutical Sciences. 2019 Dec;16(4):380-391.
Published
How to Cite
Issue
Section
Copyright (c) 2025 Alekhya Dandamudi
This work is licensed under a Creative Commons Attribution 4.0 International License.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.