H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia.
Bioorg Chem. 2020 Jan;94:103195. doi: 10.1016/j.bioorg.2019.103195. Epub 2019 Aug 23.
The current study describes the discovery of novel inhibitors of α-glucosidase and α-amylase enzymes. For that purpose, new hybrid analogs of N-hydrazinecarbothioamide substituted indazoles 4-18 were synthesized and fully characterized by EI-MS, FAB-MS, HRFAB-MS, H-, and C NMR spectroscopic techniques. Stereochemistry of the imine double bond was established by NOESY measurements. All derivatives 4-18 with their intermediates 1-3, were evaluated for in vitro α-glucosidase and α-amylase enzyme inhibition. It is worth mentioning that all synthetic compounds showed good inhibition potential in the range of 1.54 ± 0.02-4.89 ± 0.02 µM for α-glucosidase and for α-amylase 1.42 ± 0.04-4.5 ± 0.18 µM in comparison with the standard acarbose (IC value of 1.36 ± 0.01 µM). In silico studies were carried out to rationalize the mode of binding interaction of ligands with the active site of enzymes. Moreover, enzyme inhibitory kinetic characterization was also performed to understand the mechanism of enzyme inhibition.
本研究描述了新型α-葡萄糖苷酶和α-淀粉酶抑制剂的发现。为此，合成了新的 N-腙基甲硫酰胺取代的吲唑 4-18 的杂合类似物，并通过 EI-MS、FAB-MS、HRFAB-MS、H-和 C NMR 波谱技术进行了全面表征。通过 NOESY 测量确定了亚胺双键的立体化学。所有衍生物 4-18 及其中间体 1-3 均进行了体外α-葡萄糖苷酶和α-淀粉酶抑制活性评价。值得一提的是，所有合成化合物在 1.54±0.02-4.89±0.02µM 范围内对α-葡萄糖苷酶表现出良好的抑制潜力，对α-淀粉酶的抑制活性为 1.42±0.04-4.5±0.18µM，与标准阿卡波糖（IC 值为 1.36±0.01µM）相比。还进行了计算机模拟研究，以合理化配体与酶活性位点结合的模式。此外，还进行了酶抑制动力学特征分析，以了解酶抑制的机制。
