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Memantine derived compounds as potent in vitro inhibitors of urease: Repurposing of memantine, sonication assisted derivatization and in vitro enzyme inhibition, kinetics and molecular docking studies

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Abstract

The phenyl-substituted thiourea derivatives (2-21) of memantine (1) were synthesized through a sonication-assisted single-step chemical reaction. Urease inhibition and cytotoxicity against 3T3 mouse fibroblast cells were also performed. The synthesized compounds were characterized using UV/VIS, FT-IR, 1H-NMR, 13C-NMR (BB, DEPT-90, DEPT-135), and mass spectrometric techniques. All of these compounds were found to be new, except 2, 14, 17, and 21. These compounds showed good activity against the urease (IC50 = 36.5 ± 0.20 to 5.6 ± 0.30 µM) while acetohydroxamic acid (AHA) was used as a standard (IC50 = 20.43 ± 0.43 µM). Compounds 6, 7, 12, and 20 were found to be the most potent urease inhibitors. Among all compounds, 5, 7, 11, 16, and 17-21 were found to be toxic against 3T3 mouse fibroblast cells, doxorubicin (IC50 = 0.1 ± 0.002 µM) was used as a standard. Urease inhibition activity of the parent drug memantine (1) was also evaluated and interestingly to the best of our knowledge we are reporting the repurposing of memantine as a urease inhibitor for the first time. (IC50 = 44.3 ± 0.52 µM). Memantine was also found to be noncytotoxic against 3T3 normal cells. The kinetics and molecular docking studies were performed for potent urease inhibitors 6, 7, 12, and 20. These compounds exhibited enhanced interaction with the active site residues of the urease in a competitive manner (Ki = 4.1-8.6 µM). Among these, compounds 6 and 12 from this library have the potential to be studied as anti-ulcer agents.

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Acknowledgements

We are thankful to Miss Kiran Fida (Cell Culture Facility Manager at the Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi) for conducting the cytotoxicity assay.

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Author notes

  1. These authors contributed equally: Waseem Shehzad, Majid Khan

Authors and Affiliations

  1. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Waseem Shehzad, Majid Khan, Hina Siddiqui & M. Iqbal Choudhary

  2. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    M. Iqbal Choudhary

  3. Department of Biochemistry, King Abdulaziz University, Jeddah, 21452, Saudi Arabia

    M. Iqbal Choudhary

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  1. Waseem Shehzad
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Shehzad, W., Khan, M., Siddiqui, H. et al. Memantine derived compounds as potent in vitro inhibitors of urease: Repurposing of memantine, sonication assisted derivatization and in vitro enzyme inhibition, kinetics and molecular docking studies. Med Chem Res 32, 525–541 (2023). https://doi.org/10.1007/s00044-023-03020-2

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