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<p>Considering the global incidence of diabetes, developing new compounds to lower blood sugar levels has become increasingly crucial. As a result, there has been a growing focus on the synthesis of&#xa0;α-glucosidase inhibitors in recent years. This study investigated design, synthesis, and effects of novel 5-aryl pyrazole-glucose hybrids as α-glucosidase inhibitors. Thirteen derivatives from this class of compounds were synthesized, demonstrating superior in vitro inhibitory effects (IC<sub>50</sub> values ranging from 0.5 to 438.6 µM, compared to acarbose at 750.0 µM). Among them, compound <b>8g</b> (IC<sub>50</sub> =&#xa0;0.5 µM) was selected for further investigations and the kinetic studies revealed that it is a competitive inhibitor (<i>K</i><sub>i</sub> =&#xa0;0.46 µM). Fluorescence assays indicated changes in the fluorescence intensity, while thermodynamic analyses suggested that compound <b>8g</b> promoted a transition of the enzyme into an unfolded state. Furthermore, in vivo studies demonstrated that <b>8g</b> effectively reduced blood sugar levels in rats at doses comparable to acarbose. Molecular docking studies revealed that this compound interacted with the enzyme’s active site, and molecular dynamics simulations showed that pharmacophores engaged in various interactions with the enzyme.</p>

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Design, synthesis, and investigation of novel 5-arylpyrazole-glucose hybrids as α-glucosidase inhibitors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月22日

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  • Roshanak Hariri,
  • Mina Saeedi,
  • Somayeh Mojtabavi,
  • Simin Alizadeh,
  • Ahmad Ebadi,
  • Mohammad Ali Faramarzi,
  • Mohsen Amini,
  • Mohammad Sharifzadeh,
  • Mahmood Biglar,
  • Tahmineh Akbarzadeh

摘要

Considering the global incidence of diabetes, developing new compounds to lower blood sugar levels has become increasingly crucial. As a result, there has been a growing focus on the synthesis of α-glucosidase inhibitors in recent years. This study investigated design, synthesis, and effects of novel 5-aryl pyrazole-glucose hybrids as α-glucosidase inhibitors. Thirteen derivatives from this class of compounds were synthesized, demonstrating superior in vitro inhibitory effects (IC50 values ranging from 0.5 to 438.6 µM, compared to acarbose at 750.0 µM). Among them, compound 8g (IC50 = 0.5 µM) was selected for further investigations and the kinetic studies revealed that it is a competitive inhibitor (Ki = 0.46 µM). Fluorescence assays indicated changes in the fluorescence intensity, while thermodynamic analyses suggested that compound 8g promoted a transition of the enzyme into an unfolded state. Furthermore, in vivo studies demonstrated that 8g effectively reduced blood sugar levels in rats at doses comparable to acarbose. Molecular docking studies revealed that this compound interacted with the enzyme’s active site, and molecular dynamics simulations showed that pharmacophores engaged in various interactions with the enzyme.