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; Pakistan Academy of Sciences, 3-Constitution Avenue G-5/2, Islamabad, 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 Jul;100:103879. doi: 10.1016/j.bioorg.2020.103879. Epub 2020 Apr 25.
Inhibition of α-glucosidase enzyme is of prime importance for the treatment of diabetes mellitus (DM). Apart of many organic scaffolds, pyridine based compounds have previously been reported for wide range of bioactivities. The current study reports a series of pyridine based synthetic analogues for their α-glucosidase inhibitory potential assessed by in vitro, kinetics and in silico studies. For this purpose, 2-amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitriles 1-28 were synthesized and subjected to in vitro screening. Several analogs, including 1-3, 7, 9, 11-14, and 16 showed many folds increased inhibitory potential in comparison to the standard acarbose (IC = 750 ± 10 µM). Interestingly, compound 7 (IC = 55.6 ± 0.3 µM) exhibited thirteen-folds greater inhibition strength than the standard acarbose. Kinetic studies on most potent molecule 7 revealed a competitive type inhibitory mechanism. In silico studies have been performed to examine the binding mode of ligand (compound 7) with the active site residues of α-glucosidase enzyme.
抑制α-葡萄糖苷酶对于治疗糖尿病（DM）至关重要。除了许多有机支架外，吡啶类化合物以前也曾被报道具有广泛的生物活性。本研究报道了一系列吡啶类合成类似物，通过体外、动力学和计算研究评估其α-葡萄糖苷酶抑制潜力。为此，合成了 2-氨基-4-芳基-6-（苯硫基）吡啶-3,5-二腈 1-28，并进行了体外筛选。与标准阿卡波糖（IC=750±10µM）相比，包括 1-3、7、9、11-14 和 16 在内的几种类似物显示出多倍增加的抑制潜力。有趣的是，化合物 7（IC=55.6±0.3µM）的抑制强度比标准阿卡波糖强十三倍。对最有效分子 7 的动力学研究表明，它具有竞争性抑制机制。已进行了计算研究，以检查配体（化合物 7）与α-葡萄糖苷酶活性位点残基的结合模式。
