Biological evaluation of 7-O-amide hesperetin derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease

A series of 7- O -amide hesperetin derivatives were subjected to multi-target biological evaluation of anti-Alzheimer's disease. Most of the compounds showed good in vitro inhibitory activity against cholinesterase , of which compound 7c (7- O -(4-(morpholinoethyl)-acetamide) hesperetin) was the most effective anti-eqBuChE derivative (IC 50  = 0.28 ± 0.05 μM) and exerted neuroprotective effects. Further biological evaluation found that compounds 4d , 4e and 7c showed strong antioxidant, anti-Aβ self-aggregation and anti-neuroinflammatory activities. Compound 7c could inhibit the expression of iNOS and COX-2 proteins and prevent LPS-induced inflammatory response in BV2 cells. In addition, compound 7c could chelate biometal ions such as Cu 2+ and Zn 2+ . In the vivo study, the MWM test confirmed that compound 7c could improve the cognitive impairment caused by scopolamine . In summary, the above studies have shown that the optimized compound 7c has great development potential as MTDL for the treatment of AD.