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Published on:November 2022
Indian Journal of Pharmaceutical Education and Research, 2022; 57(1):xx-xx
Original Article | doi:

Design, Synthesis and Molecular Docking Studies of (S)-1-(2-(substituted benzylamino)-3- methylbutanoyl)pyrrolidin-2-one analogues as GABA Mediated Anticonvulsant agents

Authors and affiliation (s):

Obaid Afzal1, Gopal Prasad Agrawal2, Ghadah Rashed Ghazi Alotaibi3, Raid Saleh Ali Shatat4, Habibullah Khalilullah5, Zabih Ullah6, Mohammad Rashid7, Ahmed F Elkirdasy8, Benson Mathai K9,*

1Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, SAUDI ARABIA.

2Institute of Pharmaceutical Research, GLA University, Mathura-Delhi Road, Chaumuhan, Mathura, INDIA.

3Clinical Pharmacist, Al Nahdi Medical Company, SAUDI ARABIA.

4Riyadh ELM University, Riyadh, KSA.

5Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University, KSA.

6Department of Pharmaceutical Sciences, College of Dentistry and Pharmacy, Buraydah Colleges, Alqassim, SAUDI ARABIA.

7Department of Pharmaceutical Chemistry and Pharmacognosy, College of Dentistry and Pharmacy, Buraydah Colleges, Al-Qassim, SAUDI ARABIA.

8Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, University of Sadat City, EGYPT.

9Department of Pharmacology, Dr. Joseph Mar Thoma Institute of Pharmaceutical Sciences and Research, Kattanam, Alappuzha, Kerala, INDIA.


Background: Epilepsy is a deep rooted, partially curable brain illness that affects all individuals irrespective of ages and genders. Despite the discovery of various innovative antiepileptic drugs (AEDs), selectivity and toxicity issues remain. Materials and Methods: A series of (S)-1-(2-(substituted benzylamino)-3-methylbutanoyl)pyrrolidin-2-one analogues (5a-r) were synthesized and evaluated for their anticonvulsant activity. The analogues were screened by two gold standard methods, i.e., electroshock (MES) and chemoshock (scPTZ) seizure tests. In addition, the rotarod method was used to test motor impairment in all synthetic analogues for acute neurotoxicity. The paper also reports ADME prediction of all the 18 synthesized compounds, with each parameter discussed in detail. Furthermore, the GABA-A target protein was used in molecular docking experiments. Results: In the MES model, compounds 5e, 5h, 5k, 5l, 5o, and 5r were identified to be the most effective, while compounds 5j, 5k, 5l, 5o, and 5r were the most active against the scPTZ model. The majority of the synthesized analogues passed the neurotoxicity test, according to the findings. ADME prediction of the compounds exhibited good agreement with the in vivo outcomes. The results of molecular docking showed important interactions with TYR 62, ASN 85, ARG 114, ARG 129, and MET 115 at the active site of GABA-A and the results showed good agreement with in vivo results. Conclusion: The findings of the study indicated some of the compounds possessed excellent anticonvulsant activity without noticeable neurotoxicity. These compounds can be investigated further for the formation of newer/novel anticonvulsant agents.

Keywords: Pyrrolidine, Anticonvulsant activity, Molecular Docking, GABA-A, Toxicity, ADME prediction.



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The Official Journal of Association of Pharmaceutical Teachers of India (APTI)
(Registered under Registration of Societies Act XXI of 1860 No. 122 of 1966-1967, Lucknow)

Indian Journal of Pharmaceutical Education and Research (IJPER) [ISSN-0019-5464] is the official journal of Association of Pharmaceutical Teachers of India (APTI) and is being published since 1967.


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