2. Academic Validation
  3. Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia

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

  • Sci Rep. 2025 Jan 13;15(1):1871. doi: 10.1038/s41598-024-83917-z.
Mehran Ghasemi 1,  Mohammad Mahdavi 2,  Maryam Dehghan 3,  Mohammadreza Eftekharian 4,  Somayeh Mojtabavi 5,  Mohammad Ali Faramarzi 5,  Aida Iraji 6 7,  Ahmed Al-Harrasi 8
Affiliations

Affiliations

  • 1 Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P. O. Box 33, Nizwa, Oman.
  • 2 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
  • 3 School of Chemistry, College of Science, University of Tehran, Tehran, 14155-6455, Iran.
  • 4 Student Research Committee, Jahrom Univesity of Medical Sciences, Jahrom, Iran.
  • 5 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 6 Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. aida.iraji@gmail.com.
  • 7 Department of Persian Medicine, School of Medicine, Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. aida.iraji@gmail.com.
  • 8 Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P. O. Box 33, Nizwa, Oman. aharrasi@unizwa.edu.om.
PMID: 39805968 DOI: 10.1038/s41598-024-83917-z
Abstract

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.

Keywords

Diabetes mellitus; Quinoline-piperazine; Thiosemicarbazide; Α-glucosidase.

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