Short Communication
Design of pyrrolidine-2, 5-dione Schiff’s base derivatives as GABAA inhibitors for antiepileptic activity
Balsam A. Abodabous, Suaad M. Abuskhuna, Nisreen H. Meiqal, and Omran N.R. Fhaid
Abstract :
Succinimide derivatives are an essential class of compounds with diverse pharmacological applications. Different derivatives of succinimide as Schiff’s base were designed for good inhibitory activity against the human GABAA receptor. Compounds that inhibit GABAA are effective as anti-epileptic agents. Virtual screening methods, such as chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, play key roles in drug discovery and development, and molecular docking was used. ADMET properties and drug likeliness of all investigated compounds were predicted by Swiss ADMET software. A higher binding affinity and interactions have been observed with the designed compounds compared to the standard compounds (phenobarbital and flumazenil).
References
1. Alan Aitken R, Dheirya KS. The solid-state structures of cyclic NH carboximides. Crystals. 2020; 10(7): 606. doi: 10.3390/cryst10070606
2. Shivam AM, Deepika T, Panda D, Rahul R, Akhilesh KV. Visible light-promoted metal and oxidant-free stereo-selective synthesis of functionalized succinimides from aza-1,6-enynes. RSC Sustainability. 2025; 3: 592-598. doi: 10.1039/dsu00753k
3. Saba Z, Muhammad H, Mirza WB. Synthesis, crystal structure, anti-cancer, anti-inflammatory, anti-oxidant, and quantum chemical studies of 4-(pyrrolidine-2,5-dione-1-yl) phenol. Journal of Molecular Structure. 2021; 1224: 129267. doi: 10.1016/ j.molstruc. 2020.129267
4. Zefeng Z, Jiangxin Y, Xiaotong Ji, Meng N, Kaiwen K, Haifa Q, Xiaohui Z. Research progress in biological activities of succinimide derivatives. Bioorganic Chemistry. 2021; 108: 104557. doi: 10.1016/j.bioorg.2020.104557
5. Arun K, Anjali K, Prabhakar KV, Mano G, Girish Ch, Umesh K, Ashok KY, Deepak K. An insight into recent developments in imidazole-based heterocyclic compounds as anticancer agents: Synthesis, SARs, and mechanism of actions. European Journal of Medicinal Chemistry. 2024; 280: 15.116896. doi: 10.1016/j.ejmech.2024.116896
6. Daniele RB, Laura VB, du VF, Rita DCV, Anelize D, Mariana Z, et al. Antispasmodic activity of a series of cyclic imides (phthalimides) derivatives. Naunyn-Schmiedeberg's Archives of Pharmacology. 2026; 399(2): 2337-2352. doi: 1007/s00210-025-04515
7. Błażej G, Dariusz MP, Łukasz SZ. Succinimide derivatives as acetylcholinesterase inhibitors: In silico and in vitro Studies. Current Issues of Molecular Biology. 2024; 46(6): 5117-5130. doi: 10.3390/cimb46060307
8. Sultan DYA, Dakhil ZM, Ali AA. Antibacterial, antifungal, and antitumor properties of 2, 5-pyrrolidinedione derivatives. Chemistry Africa. 2023; 6: 2933-2944. doi: 10.1007/s42250-023-00710-7
9. Muhammad IQ, Sami U, Umer R, Abdul S, Mater HM, Saif UKK, Muhammad MA. N-phenyl and N-benzyl substituted succinimide: Preclinical evaluation for their antihypertensive effect and underlying mechanism. European Journal of Pharmacology. 2024; 964(5): 176195. doi: 10.1016/j.ejphar.2023.176195
10. Aeyaz AB, Nitin T, Iqubal S, Runjhun T. Structure-activity relationship (SAR) and antibacterial activity of pyrrolidine-based hybrids: A review. Journal of Molecular Structure. 2023; (1283)5: 135175. doi: 10.1016/j. molstruc.2023.135175
11. Xin L, Yifang Ch, Yu W, Zhifu X, Ju P, Jixiang Ch. Design, synthesis, and antifungal activity of novel amide derivatives containing a pyrrolidine moiety as potential succinate dehydrogenase inhibitor. Molecular Diversity. 2024; 28(2): 805-816. doi: 10.1007/s11030-023-10622-w
12. Krzysztof K, Sabina R, Jolanta O. Synthesis and anticonvulsant activity of new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2, 5-diones. Bioorganic and Medicinal Chemistry Letters. 2011; 21(19): 5800-5803. doi: 10.1016/j.bmcl.2011.07.118
13. Rakhi Y, Dilkhush M, Kavita S, Rajdeep T, Yogesh Y, Ram S. Recent advances in the synthesis of new benzothiazole-based anti-tubercular compounds. RSC Advances. 2023; 13: 21890-21925. doi: 10.1039/d3ra03862a
14. Braja GH, Vandana SP, Sanjeey KD, Suchitra D, Mahendra PD, Dharmendra S, et al. Bile acid amides derived from chiral amino alcohols: Novel antimicrobials and antifungals. Bioorganic and Medicinal Chemistry Letters. 2004; (14)3: 773-777. doi: 10.1016/j.bmcl.2003.11.018
15. Farshid H, Elham J. Cyclic imide derivatives: As promising scaffold for the synthesis of antimicrobial agents. Journal of Research in Medical Sciences. 2018; 23: 53. doi: 10.4103/jrms.JRMS.539.17
16. Patil MM, Rajput SS. Succinimide: Synthesis, reaction, and biological activity. International Journal of Pharmacy and Pharmaceutical Sciences. 2014; 6(11): 8-14. doi: Nil.
17. Gallo AT, Hulse GK. Pharmacological uses of flumazenil in benzodiazepine use disorders: A systematic review of limited data. Journal of Psychopharmacology. 2021; 35(3): 211-220. doi: 10.1177/02698811209813
18. Alharati SH, Elbakay JAM, Hermann A, Gbaj AM. Polycystic ovary syndrome: Molecular modeling study on potential Lepidium sativum bioactive compounds in modulating kiss-1 gene function. Mediterranean Journal of Medical Research. 2025; 2(3): 129-140. doi: 10.5281/zenodo.17069661
19. Ieban NA, Gbaj HA, Gbaj MA, Hermann A, Gbaj AM. Immune profile score of modified Tremelimumab with CTLA-4 could enhance immunotherapy using molecular docking. Mediterranean Journal of Medicine and Medical Sciences. 2026; 2(1): 40-50. doi: 10.5281/zenodo.18667523
20. Hoque F, Nahar N, Annie FS, Rahim A, Hossain MK, Abdul Rahman MN, et al. Synthesis, characterization, and complexation of Schiff base ligand p-anisalcefuroxime with Cu2+ and Fe2+ ions; antimicrobial and docking analysis with PBP2xto study pharmacokinetic parameters. Mediterranean Journal of Pharmacy and Pharmaceutical Sciences. 2025; 5(1): 48-64. doi: 10.5281/zenodo.14647651
21. Sherif FM. Pharmacological profile of the GABA-transaminase inhibitor vigabatrin. World Journal of Pharmacy and Pharmaceutical Sciences. 2015; 4(7): 139-148. doi: 10.20959/wjpps20157-4561
22. Daina A, Michielin O, Zoete V. Swiss ADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 2017; 7: 42717. doi: 10.1038/srep42717
23. Guan L, Yang H, Cai Y, Sun L, Di P, Li W, et al. ADMET-score - A comprehensive scoring function for evaluation of chemical drug likeness. Medicinal Chemistry Communications. 2019; 10(1): 148-157. doi: 10.1039/c8md00472b
24. Yang H, Lou C, Sun L, Li J, Cai Y, Wang Z, et al. ADMET SAR 2.0: Web-service for prediction and optimization of chemical ADMET properties. Bioinformatics. 2019; 35(6):1067-1069. doi: 10.1093/bioinformatics/bty707
25. Tian S, Wang J, Li Y, Li D, Xu L, Hou T. The application of in silico drug-likeness predictions in pharmaceutical research. Advanced Drug Delivery Reviews. 2015; 86: 2-10. doi: 10.1016/j.addr.2015.01.009
Citation :
Abodabous et al. Design of pyrrolidine-2,5-dione Schiff’s base derivatives as GABAA inhibitors for antiepileptic activity. Mediterr J Pharm Pharm Sci. 2026; 6(2): 36-43. [Article number: 251]. https://doi.org/10.5281/zenodo.20170915