Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia
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 re...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-83917-z |
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| author | Mehran Ghasemi Mohammad Mahdavi Maryam Dehghan Mohammadreza Eftekharian Somayeh Mojtabavi Mohammad Ali Faramarzi Aida Iraji Ahmed Al-Harrasi |
| author_facet | Mehran Ghasemi Mohammad Mahdavi Maryam Dehghan Mohammadreza Eftekharian Somayeh Mojtabavi Mohammad Ali Faramarzi Aida Iraji Ahmed Al-Harrasi |
| author_sort | Mehran Ghasemi |
| collection | DOAJ |
| description | 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 K i 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. |
| format | Article |
| id | doaj-art-1be5957d000741038c6d14822127654d |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-1be5957d000741038c6d14822127654d2025-01-19T12:21:13ZengNature PortfolioScientific Reports2045-23222025-01-0115111310.1038/s41598-024-83917-zSubstituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemiaMehran Ghasemi0Mohammad Mahdavi1Maryam Dehghan2Mohammadreza Eftekharian3Somayeh Mojtabavi4Mohammad Ali Faramarzi5Aida Iraji6Ahmed Al-Harrasi7Natural and Medical Sciences Research Center, University of NizwaEndocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical SciencesSchool of Chemistry, College of Science, University of TehranStudent Research Committee, Jahrom Univesity of Medical SciencesDepartment of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical SciencesDepartment of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical SciencesStem Cells Technology Research Center, Shiraz University of Medical SciencesNatural and Medical Sciences Research Center, University of NizwaAbstract 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 K i 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.https://doi.org/10.1038/s41598-024-83917-zΑ-glucosidaseDiabetes mellitusThiosemicarbazideQuinoline-piperazine |
| spellingShingle | Mehran Ghasemi Mohammad Mahdavi Maryam Dehghan Mohammadreza Eftekharian Somayeh Mojtabavi Mohammad Ali Faramarzi Aida Iraji Ahmed Al-Harrasi Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia Scientific Reports Α-glucosidase Diabetes mellitus Thiosemicarbazide Quinoline-piperazine |
| title | Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia |
| title_full | Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia |
| title_fullStr | Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia |
| title_full_unstemmed | Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia |
| title_short | Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia |
| title_sort | substituted piperazine conjugated to quinoline thiosemicarbazide as potent α glucosidase inhibitors to target hyperglycemia |
| topic | Α-glucosidase Diabetes mellitus Thiosemicarbazide Quinoline-piperazine |
| url | https://doi.org/10.1038/s41598-024-83917-z |
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