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Design, synthesis, molecular docking and pharmacological evaluation of some thiadiazole based nipecotic acid derivatives as a potential anticonvulsant and antidepressant agents

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Abstract

In our continuous effort to develop novel antiepileptic drug, a new series of nipecotic acid derivatives having1,3,4-thiadiazole nucleus were designed and synthesized. This study aims to improve the lipophilicity of nipecotic acid by attaching some lipophilic anchors like thiadiazole and substituted aryl acid derivatives. In our previous study, we noticed that the N-substituted oxadiazole derivative of nipecotic acid exhibited significant antiepileptic activity in the rodent model. The synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, Mass, and elemental analysis. The anticonvulsant activity was evaluated by using the maximal electroshock-induced seizure model in rats (MES) and the subcutaneous pentylenetetrazol (scPTZ) test in mice. None of the compounds were found to be active in the MES model whereas compounds (TN2, TN9, TN12, TN13, and TN15) produced significant protection against the scPTZ-induced seizures model. The compounds showing antiepileptic activity were additionally evaluated for antidepressant activity by using the forced swim test, 5-hydroxytryptophan (5-HTP)-induced head twitch test, and learned helplessness test. All the molecules that showed anticonvulsant activity (TN2, TN9, TN12, TN13, and TN15), also exerted significant antidepressant effects in the animal models. The selected compounds were subjected to different toxicity studies. Compounds were found to have no neurotoxicity in the rota-rod test and devoid of hepatic and renal toxicity in 30 days repeated oral toxicity test. Further, a homology model was developed to perform the in-silico molecular docking and dynamics studies which revealed the similar binding of compound TN9 within the active binding pocket and were found to be the most potent anti-epileptic agent. The market expectation for newly developed antiepileptic thiadiazole-based nipecotic acid derivatives is significant, driven by their potential to offer improved therapeutic outcomes and reduced side effects, addressing a critical need in epilepsy treatment. These innovative compounds hold promise for meeting the demand for more effective and safer antiepileptic medications.

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Acknowledgements

We thank to all our authors for their valuable suggestions and support. Authors are also thankful to CIF, IIT-BHU, Varanasi, India for providing NMR.

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Authors did not receive any specific financial support from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, Bihar, 824236, India

    Gireesh Kumar Singh & Bindu Kumari

  2. Department of Pharmaceutical Science, SSMPS, Assam University, Silchar, Assam, 788151, India

    Nirupam Das

  3. Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, 786004, India

    Kamaruz Zaman

  4. Department of Neurology, All India Institute of Medical Sciences, Deoghar, Jharkhand, 814142, India

    Pratibha Prasad

  5. Institute of Pharmacy, Harischandra P.G. College, Bawanbeegha, Azamgarh Road, Varanasi, 221002, India

    Ravi Bhushan Singh

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Contributions

RBS, KZ and GKS designed the research study; RBS has synthesized compounds and performed the spectral analysis; RBS and GKS performed pharmacological activity; ND performed the in-silico study. RBS, ND and GKS wrote the paper. PP critically revised the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Ravi Bhushan Singh.

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Singh, G.K., Kumari, B., Das, N. et al. Design, synthesis, molecular docking and pharmacological evaluation of some thiadiazole based nipecotic acid derivatives as a potential anticonvulsant and antidepressant agents. 3 Biotech 14, 71 (2024). https://doi.org/10.1007/s13205-023-03897-1

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