Hirbod Kimia, Jalili-Baleh Leili, Nadri Hamid, Ebrahimi Seyed Esmaeil Sadat, Moradi Alireza, Pakseresht Bahar, Foroumadi Alireza, Shafiee Abbas, Khoobi Mehdi
Department of Medical Chemistry, School of Pharmacy, International Campus, Tehran University of Medical Science, Tehran, Iran.
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Iran J Basic Med Sci. 2017 Jun;20(6):631-638. doi: 10.22038/IJBMS.2017.8830.
To investigate the efficiency of a novel series of coumarin derivatives bearing benzoheterocycle moiety as novel cholinesterase inhibitors.
Different 7-hydroxycoumarin derivatives were synthesized via Pechmann or Knoevenagel condensation and conjugated to different benzoheterocycle (8-hydroxyquinoline, 2-mercaptobenzoxazole or 2-mercaptobenzimidazole) using dibromoalkanes 3a-m: Final compounds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by Ellman's method. Kinetic study of AChE inhibition and ligand-protein docking simulation were also carried out for the most potent compound 3b.
Some of the compounds revealed potent and selective activity against AChE. Compound 3b containing the quinoline group showed the best activity with an IC value of 8.80 μM against AChE. Kinetic study of AChE inhibition revealed the mixed-type inhibition of the enzyme by compound 3b. Ligand-protein docking simulation also showed that the flexibility of the hydrophobic five carbons linker allows the quinoline ring to form π-π interaction with Trp279 in the PAS.
We suggest these synthesized compounds could become potential leads for AChE inhibition and prevention of AD symptoms.
研究一系列带有苯并杂环部分的新型香豆素衍生物作为新型胆碱酯酶抑制剂的效率。
通过Pechmann或Knoevenagel缩合反应合成不同的7-羟基香豆素衍生物，并使用二溴代烷烃3a-m将其与不同的苯并杂环（8-羟基喹啉、2-巯基苯并恶唑或2-巯基苯并咪唑）共轭：采用Ellman法对最终化合物进行乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）活性评估。对最有效的化合物3b还进行了AChE抑制动力学研究和配体-蛋白质对接模拟。
部分化合物对AChE显示出强效且选择性的活性。含喹啉基团的化合物3b表现出最佳活性，对AChE的IC值为8.80 μM。AChE抑制动力学研究表明化合物3b对该酶具有混合型抑制作用。配体-蛋白质对接模拟还显示，疏水的五个碳原子连接子的灵活性使喹啉环能够与PAS中的Trp279形成π-π相互作用。
我们认为这些合成化合物可能成为抑制AChE和预防AD症状的潜在先导物。
