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<p>In the present study, a series of structurally diverse vanillin sulfonate derivatives (<b>1–9</b>) were synthesized and evaluated as potential α-glucosidase inhibitors through integrated in vitro, in vivo, and in silico approaches. The target compounds were obtained via sulfonation and subsequent functional modification of the vanillin scaffold and were fully characterized using standard spectroscopic techniques. Enzyme inhibition assays demonstrated that several derivatives exhibited strong α-glucosidase inhibitory activity, with inhibitory constants significantly lower than that of the reference drug, indicating enhanced potency. The synthesized compounds showed notable α-glucosidase inhibitory activity, with compounds <b>8</b> (IC<sub>50</sub> = 7.8 ± 2.2&#xa0;µM), <b>6</b> (IC<sub>50</sub> = 10.2 ± 1.1&#xa0;µM), and <b>5</b> (IC<sub>50</sub> = 13.4 ± 1.9&#xa0;µM) exhibiting stronger activity than acarbose (IC<sub>50</sub> = 28.3 ± 1.2&#xa0;µM), indicating their potential as promising antidiabetic candidates. To the best of our knowledge, this study represents the first in vivo evaluation of vanillin sulfonate derivatives for antihyperglycemic activity. Selected lead compounds were further evaluated in an oral carbohydrate tolerance model, where they produced a significant reduction in postprandial blood glucose levels without observable acute toxicity. Molecular docking and dynamic simulation studies supported the experimental findings by revealing stable binding interactions within the catalytic pocket of α-glucosidase, including hydrogen bonding and π–π stacking with key active-site residues. Density functional theory (DFT) calculations further clarified the electronic properties, frontier molecular orbitals, and reactivity descriptors of the most active derivatives, correlating electronic parameters with inhibitory performance. Collectively, these results identify vanillin sulfonates as promising lead structures for the development of new α-glucosidase inhibitors and support their further optimization as potential antidiabetic agents.</p>

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Synthesis and evaluation of vanillin-based sulfonates as potent α-glucosidase inhibitors through in vitro, in vivo, and in silico approaches

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月25日

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  • Manel Essid,
  • Ehsan Ullah Mughal,
  • Nafeesa Naeem,
  • Aneela Shaheen Cheema,
  • Bushra Shakoor,
  • Ishtiaq Ahmed,
  • Charlene Marais,
  • Amina Sadiq,
  • Samar Y. Al Nami,
  • Aisha Hossan

摘要

In the present study, a series of structurally diverse vanillin sulfonate derivatives (1–9) were synthesized and evaluated as potential α-glucosidase inhibitors through integrated in vitro, in vivo, and in silico approaches. The target compounds were obtained via sulfonation and subsequent functional modification of the vanillin scaffold and were fully characterized using standard spectroscopic techniques. Enzyme inhibition assays demonstrated that several derivatives exhibited strong α-glucosidase inhibitory activity, with inhibitory constants significantly lower than that of the reference drug, indicating enhanced potency. The synthesized compounds showed notable α-glucosidase inhibitory activity, with compounds 8 (IC50 = 7.8 ± 2.2 µM), 6 (IC50 = 10.2 ± 1.1 µM), and 5 (IC50 = 13.4 ± 1.9 µM) exhibiting stronger activity than acarbose (IC50 = 28.3 ± 1.2 µM), indicating their potential as promising antidiabetic candidates. To the best of our knowledge, this study represents the first in vivo evaluation of vanillin sulfonate derivatives for antihyperglycemic activity. Selected lead compounds were further evaluated in an oral carbohydrate tolerance model, where they produced a significant reduction in postprandial blood glucose levels without observable acute toxicity. Molecular docking and dynamic simulation studies supported the experimental findings by revealing stable binding interactions within the catalytic pocket of α-glucosidase, including hydrogen bonding and π–π stacking with key active-site residues. Density functional theory (DFT) calculations further clarified the electronic properties, frontier molecular orbitals, and reactivity descriptors of the most active derivatives, correlating electronic parameters with inhibitory performance. Collectively, these results identify vanillin sulfonates as promising lead structures for the development of new α-glucosidase inhibitors and support their further optimization as potential antidiabetic agents.