Design, synthesis and evaluation of rivastigmine and curcumin hybrids as site-activated multitarget-directed ligands for Alzheimer's disease therapy.

Abstract A series of novel 2-methoxy-phenyl dimethyl-carbamate derivatives were designed, synthesized and evaluated as site-activated MTDLs based on rivastigmine and curcumin. Most of them exhibited good to excellent AChE and BuChE inhibitory activities with sub-micromolar IC 50 values. Among all the compounds, 6a demonstrated the most potent AChE inhibition with IC 50 value of 0.097 μM, which is about 20-fold than that of rivastigmine. In addition, the three selected compounds 5a , 6a and 6e demonstrated inhibitory activity against Aβ self-aggregation similar to cucurmin in TEM assay, which is obviously different from the weak activity of rivastigmine. Moreover, the hydrolysate of 6a (compound 7 ) also showed potent ABTS + scavenging and moderate copper ion chelating activity in vitro.