Wei Mankun, Chai Wei-Ming, Wang Rui, Yang Qin, Deng Zhihong, Peng Yiyuan
Key Laboratory of Small Fuctional Organic Molecule, Ministry of Education and College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China.
Key Laboratory of Small Fuctional Organic Molecule, Ministry of Education and College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China; Key Laboratory of Green Chemistry, Jiangxi Province, Nanchang, Jiangxi 330022, China.
Bioorg Med Chem. 2017 Feb 15;25(4):1303-1308. doi: 10.1016/j.bmc.2016.09.042. Epub 2016 Sep 17.
In this study, eight quinazolinone derivatives were designed and synthesized. Their inhibitory activities on α-glucosidase were assessed in vitro. Two compounds: 2-(4-chlorophenyl)-quinazolin-4(3H)-one (CQ) and 2-(4-bromophenyl)-quinazolin-4(3H)-one (BQ) were found to be potent inhibitors of α-glucosidase with IC values of 12.5±0.1μM and 15.6±0.2μM, respectively. Spectroscopy methods were performed to analyze the inhibitory mechanisms of both compounds on α-glucosidase. The results revealed that they reversibly inhibited α-glucosidase in a non-competitive manner. CQ and BQ could statically quench the fluorescence spectra by formation of an inhibitor-α-glucosidase complex. The interaction between CQ and α-glucosidase depended on hydrogen bonds, electrostatic and hydrophobic force, while the driving force of the binding between BQ and the enzyme was hydrophobic. The docking results showed that BQ was less active than CQ against α-glucosidase because of its weaker interaction with the enzyme. In brief, the quinazolinone derivatives identified in this work were potentially promising candidates for developing as novel anti-diabetic agents.
在本研究中，设计并合成了八种喹唑啉酮衍生物。在体外评估了它们对α-葡萄糖苷酶的抑制活性。发现两种化合物：2-(4-氯苯基)-喹唑啉-4(3H)-酮（CQ）和2-(4-溴苯基)-喹唑啉-4(3H)-酮（BQ）是α-葡萄糖苷酶的有效抑制剂，IC值分别为12.5±0.1μM和15.6±0.2μM。采用光谱学方法分析这两种化合物对α-葡萄糖苷酶的抑制机制。结果表明，它们以非竞争性方式可逆地抑制α-葡萄糖苷酶。CQ和BQ可通过形成抑制剂-α-葡萄糖苷酶复合物静态猝灭荧光光谱。CQ与α-葡萄糖苷酶之间的相互作用取决于氢键、静电和疏水作用力，而BQ与该酶结合的驱动力是疏水作用。对接结果表明，BQ对α-葡萄糖苷酶的活性低于CQ，因为其与该酶的相互作用较弱。简而言之，本研究中鉴定出的喹唑啉酮衍生物有望成为开发新型抗糖尿病药物的潜在候选物。
