Ghasemi Mehran, Mahdavi Mohammad, Dehghan Maryam, Eftekharian Mohammadreza, Mojtabavi Somayeh, Faramarzi Mohammad Ali, Iraji Aida, Al-Harrasi Ahmed
Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P. O. Box 33, Nizwa, Oman.
Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
Sci Rep. 2025 Jan 13;15(1):1871. doi: 10.1038/s41598-024-83917-z.
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 IC 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 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.
糖尿病，尤其是2型糖尿病，是一项日益严峻的全球健康挑战，其特征是由于胰岛素抵抗导致慢性高血糖。控制这种疾病的一种治疗方法是抑制α-葡萄糖苷酶，该酶参与碳水化合物消化，以降低餐后血糖水平。在本研究中，合成了一系列硫代氨基脲连接的喹啉-哌嗪衍生物，并评估了它们的α-葡萄糖苷酶抑制活性，以确定用于管理2型糖尿病的新药物。构效关系（SAR）分析表明，芳环上取代基的性质和位置对抑制效力有显著影响。在合成的衍生物中，2,5-二甲氧基苯基取代物（7j）表现出最有效的活性，IC值为50.0 µM，与标准药物阿卡波糖相比有15倍的改善。动力学研究确定化合物7j为竞争性抑制剂，K值为32 µM。分子对接模拟表明化合物7j与α-葡萄糖苷酶活性位点之间存在关键相互作用，而分子动力学模拟证实了酶-配体复合物的稳定性，这体现在低RMSD值和RMSF值上。
