New racemic annulated pyrazolo[1,2- b ]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease

摘要

Abstract A novel series of tacrine-like compounds 7a-u possessing a fused pyrazolo[1,2- b ]phthalazine structure were designed and synthesized as potent and selective inhibitors of AChE. The in-vitro biological assessments demonstrated that several compounds had high anti-AChE activity at nano-molar level. The more promising compound 7l with IC 50 of 49?nM was 7-fold more potent than tacrine and unlike tacrine, it was highly selective against AChE over BuChE. The cell-based assays against hepatocytes (HepG2) and neuronal cell line (PC12) revealed that 7l had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H 2 O 2 -induced damage in PC12?cells. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation. The advantages including synthetic accessibility, high potency and selectivity, low toxicity, adjunctive neuroprotective and Aβ aggregation inhibitory activity, make this compound as a new multifunctional lead for Alzheimer's disease drug discovery. Graphical abstract A series of tacrine-like compounds 7a-u were designed and synthesized as potent AChE inhibitors with high selectivity, low toxicity on hepatocytes, neuroprotective and β-amyloid aggregation inhibitory activity. Display Omitted Highlights ? A series of tacrine-modified compounds were synthesized as potent AChE inhibitors. ? Several compounds had high anti-AChE activity at nano-molar level. ? The 2-methoxyphenyl derivative 7l was 7-fold more potent than tacrine. ? Compound 7l had lower toxicity on HepG2 cells compared to tacrine. ? Compound 7l had significant neuroprotective and Aβ aggregation inhibitory activities.