7- O -galloyltricetiflavan (GTF), a natural flavonoid, is known to exert anti-oxidation and neuroprotective activity, which are related to the prevention of Alzheimer’s disease (AD). In this study, three series of GTF hybrids have been designed, synthesized and evaluated as multifunctional agents for treatment AD. The biological assays indicated that most of them showed strong inhibitory effect on self-induced β -amyloid (A β ) aggregation, and a significant ability to inhibit ChEs. Among them, compound A15 exhibited best inhibition of A β aggregation (78.81% at 20 μM), potent AChE inhibitory potencies (IC 50 , 0.56 μM), and compound C4 presented the highest ability to inhibit BuChE (IC 50 , 5.77 μM). Furthermore, kinetic, molecular modeling and molecular dynamics studies revealed that A15 and C4 could interact with the catalytic active site of AChE and BuChE, respectively. In addition, compounds A15 and C4 could cross the blood–brain barrier in vitro. More importantly, A15 and C4 also showed excellent neuroprotective activities against H 2 O 2 -induced human neuroblastoma SH-SY5Y cells damage and nearly no toxicity on SH-SY5Y cells. All of these outstanding in vitro results indicated A15 and C4 as the leading structure worthy of further investigation.
A new series of N-aryltacrine derivatives were designed and synthesized as cholinesterase inhibitors by the late-stage modification of tacrine, using the palladium-catalyzed Buchwald–Hartwig cross-coupling reaction. In vitro inhibition assay against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) demonstrated that most of the synthesized compounds had potent AChE inhibitory activity with negative inhibition of BuChE. Among them, N-(4-(trifluoromethyl)phenyl)-tacrine (3g) and N-(4-methoxypyridin-2-yl)-tacrine (3o) showed the most potent activity against AChE (IC50 values of 1.77 and 1.48 μM, respectively). The anti-AChE activity of 3g and 3o was 3.5 times more than that of tacrine (IC50 value of 5.16 μM). Compound 3o also displayed anti-BuChE activity with an IC50 value of 19.00 μM. Cell-based assays against HepG2 and SH-SY5Y cell lines revealed that 3o had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H2O2-induced damage in SH-SY5Y cells. The advantages including synthetic accessibility, high potency, low toxicity, and adjunctive neuroprotective activity make compound 3o a new promising multifunctional candidate for the treatment of Alzheimer’s disease.
危险品化学品经营许可证（带存储）