Li_2018_Eur.J.Med.Chem_148_238

A series of novel tacrine-phenolic acid dihybrids and tacrine-phenolic acid-ligustrazine trihybrids were synthesized, characterized and screened as novel potential anti-Alzheimer drug candidates. These compounds showed potent inhibition activity towards cholinesterases (ChEs), among of them, 9i was the most potent one towards acetylcholinesterase (eeAChE, IC50=3.9nM; hAChE, IC50=65.2nM). 9i could also effectively block beta-amyloid (Abeta) self-aggregation with an inhibition ratio of 47% at 20muM. In addition, its strong anti-oxidation activity could protect PC12cells from CoCl2-damage in the experimental condition while no neurotoxicity. Furthermore, its hepatotoxicity was lower than tacrine in vitro and in vivo. Kinetic and molecular modeling studies revealed that 9i worked in a mixed-type way, could interact simultaneously with catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Therefore, 9i was a promising multifunctional candidate for the treatment of AD.