Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended , , and Kinetic Studies of Multifunctional Anti-Alzheimer's Agents.

In Alzheimer's disease, neurons slowly degenerate due to the accumulation of misfolded amyloid β and tau proteins. In our research, we performed extended studies directed at amyloid β and tau aggregation inhibition using ( model of protein aggregation), , and kinetic studies. We tested our library of 1-benzylamino-2-hydroxyalkyl multifunctional anti-Alzheimer's agents and identified very potent dual aggregation inhibitors. Among the tested derivatives, we selected compound , which exhibited a unique profile of biological activity. This compound was the most potent and balanced dual aggregation inhibitor (Aβ inhibition (inh.) 80.0%, tau inh. 68.3% in 10 μM), with previously reported inhibitory activity against BuChE, BACE1, and Aβ (BuChE IC = 5.74 μM; BACE1 IC = 41.6 μM; Aβ aggregation (aggr.) inh. IC = 3.09 μM). In docking studies for both proteins, we tried to explain the different structural requirements for the inhibition of Aβ vs tau. Moreover, docking and kinetic studies showed that compound could inhibit the amyloid aggregation process at several steps and also displayed disaggregating properties. These results may help to design the next generations of dual or selective aggregation inhibitors.