H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Bioorg Chem. 2022 Feb;119:105506. doi: 10.1016/j.bioorg.2021.105506. Epub 2021 Nov 23.
Diabetes mellitus is a chronic metabolic disorder with increasing prevalence and long-term complications. The aim of this study was to identify α-glucosidase inhibitory compounds with potential anti-hyperglycemic activity. For this purpose, a series of new clioquinol derivatives 2a-11a was synthesized, and characterized by various spectroscopic techniques. The enzyme inhibitory activities of the resulting derivatives were assessed using an in-vitro mechanism-based assay. All the tested compounds 2a-11a of the series showed a significant α-glucosidase inhibition with IC values 43.86-325.81 µM, as compared to the standard drug acarbose 1C: 875.75 ± 2.08 µM. Among them, compounds 4a, 5a, 10a, and 11a showed IC values of 105.51 ± 2.41, 119.24 ± 2.37, 99.15 ± 2.06, and 43.86 ± 2.71 µM, respectively. Kinetic study of the active analogues showed competitive, non-competitive, and mixed-type inhibitions. Furthermore, the molecular docking study was performed to elucidate the binding interactions of most active analogues with the various sites of α-glucosidase enzyme. The results indicate that these compounds have the potential to be further studied as new anti-diabetic agents.
糖尿病是一种慢性代谢紊乱疾病，其患病率不断增加，并伴有长期并发症。本研究旨在寻找具有潜在抗高血糖活性的α-葡萄糖苷酶抑制化合物。为此，我们合成了一系列新的氯碘羟喹衍生物 2a-11a，并通过各种光谱技术对其进行了表征。采用基于酶机制的体外测定法评估了所得衍生物的酶抑制活性。与标准药物阿卡波糖 1C：875.75 ± 2.08 μM 相比，该系列的所有测试化合物 2a-11a 均表现出显著的α-葡萄糖苷酶抑制作用，IC 值为 43.86-325.81 μM。其中，化合物 4a、5a、10a 和 11a 的 IC 值分别为 105.51 ± 2.41、119.24 ± 2.37、99.15 ± 2.06 和 43.86 ± 2.71 μM。对活性类似物的动力学研究表明，这些类似物具有竞争性、非竞争性和混合抑制作用。此外，还进行了分子对接研究，以阐明最活跃类似物与α-葡萄糖苷酶各种结合位点的结合相互作用。结果表明，这些化合物具有作为新型抗糖尿病药物进一步研究的潜力。
