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<p>Diabetes mellitus, particularly type 2 diabetes, is a growing global health challenge characterized by chronic hyperglycemia due to insulin resistance. One therapeutic approach to managing this condition is the inhibition of α-glucosidase, an enzyme involved in carbohydrate digestion, to reduce postprandial blood glucose levels. In this study, a series of thiosemicarbazide-linked quinoline-piperazine derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity, to identify new agents for type 2 diabetes management. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the aryl ring significantly impacted the inhibitory potency. Among the synthesized derivatives, the 2,5-dimethoxy phenyl substitution (<b>7j</b>) exhibited the most potent activity with an IC<sub>50</sub> value of 50.0 µM, demonstrating a 15-fold improvement compared to the standard drug acarbose. Kinetic studies identified compound <b>7j</b> as a competitive inhibitor, with a <i>K</i><sub><i>i</i></sub> value of 32 µM. Molecular docking simulations demonstrated key interactions between compound <b>7j</b> and the active site of α-glucosidase, while molecular dynamics simulations confirmed the stability of the enzyme-ligand complex, reflected in low RMSD and RMSF values.</p>

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Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月13日

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  • Mehran Ghasemi,
  • Mohammad Mahdavi,
  • Maryam Dehghan,
  • Mohammadreza Eftekharian,
  • Somayeh Mojtabavi,
  • Mohammad Ali Faramarzi,
  • Aida Iraji,
  • Ahmed Al-Harrasi

摘要

Diabetes mellitus, particularly type 2 diabetes, is a growing global health challenge characterized by chronic hyperglycemia due to insulin resistance. One therapeutic approach to managing this condition is the inhibition of α-glucosidase, an enzyme involved in carbohydrate digestion, to reduce postprandial blood glucose levels. In this study, a series of thiosemicarbazide-linked quinoline-piperazine derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity, to identify new agents for type 2 diabetes management. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the aryl ring significantly impacted the inhibitory potency. Among the synthesized derivatives, the 2,5-dimethoxy phenyl substitution (7j) exhibited the most potent activity with an IC50 value of 50.0 µM, demonstrating a 15-fold improvement compared to the standard drug acarbose. Kinetic studies identified compound 7j as a competitive inhibitor, with a Ki value of 32 µM. Molecular docking simulations demonstrated key interactions between compound 7j and the active site of α-glucosidase, while molecular dynamics simulations confirmed the stability of the enzyme-ligand complex, reflected in low RMSD and RMSF values.