Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093, Istanbul, Turkey.
Mol Divers. 2019 Aug;23(3):625-638. doi: 10.1007/s11030-018-9897-1. Epub 2018 Dec 4.
In the present study, 14 novel naphthyridine-11-amine derivatives were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 12-(4-Fluorophenyl)-1,2,3,4,7,8,9,10-octahydrodibenzo[b,g][1, 8]naphthyridin-11-amine (4a) was found to be the most potent AChE inhibitor with IC value of 0.091 µM, and 12-(2,3-dimethoxyphenyl)-1,2,3,4,7,8,9,10-octahydrodibenzo[b,g][1,8]naphthyridin-11-amine (4h) exhibited the strongest inhibition against BuChE with IC value of 0.182 µM. Additionally, hepatocellular carcinoma (HepG2) cell cytotoxicity assay for the synthesized compounds was investigated and the results showed negligible cell death. Log P values of the synthesized compounds were also calculated using ChemSketch program. Moreover, the blood-brain barrier (BBB) permeability of the potent AChE inhibitor (4a) was assessed by the widely used parallel artificial membrane permeability assay (PAMPA-BBB). The results showed that 4a is capable of crossing the BBB.
在本研究中，合成了 14 种新型的萘啶-11-胺衍生物，并评估了它们对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的抑制作用。发现 12-(4-氟苯基)-1,2,3,4,7,8,9,10-八氢二苯并[b,g][1,8]萘啶-11-胺（4a）是最有效的 AChE 抑制剂，IC 值为 0.091 µM，而 12-(2,3-二甲氧基苯基)-1,2,3,4,7,8,9,10-八氢二苯并[b,g][1,8]萘啶-11-胺（4h）对 BuChE 的抑制作用最强，IC 值为 0.182 µM。此外，还对合成化合物进行了肝细胞癌（HepG2）细胞细胞毒性试验，结果显示细胞几乎没有死亡。还使用 ChemSketch 程序计算了合成化合物的 Log P 值。此外，还通过广泛使用的平行人工膜透过性测定法（PAMPA-BBB）评估了有效的 AChE 抑制剂（4a）对血脑屏障（BBB）的透过性。结果表明，4a 能够穿透 BBB。
