Synthesis and evaluation of 1,2,3,4-tetrahydro-1-acridone analogues as potential dual inhibitors for amyloid-beta and tau aggregation

Amyloid-beta (A beta) and tau protein are two crucial hallmarks in Alzheimer's disease (AD). Their aggregation forms are thought to be toxic to the neurons in the brain. A series of new 1,2,3,4-tetrahydro-1-acridone analogues were designed, synthesized, and evaluated as potential dual inhibitors for A beta and tau aggregation. In vitro studies showed that compounds 25-30 (20 mu M) with N-methylation of the quinolone ring effectively inhibited A beta(1-)(42) aggregation by 84.7%-99.5% and tau aggregation by 71.2%-101.8%. Their structure-activity relationships are discussed. In particular, 30 could permeate the blood-brain barrier, bind to A beta(1-)(42) and tau, inhibit A beta(1-)(42) beta-sheets formation, and prevent tau aggregation in living cells.