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

In Alzheimer's disease, neurons slowly degenerate due to the accumulation of misfolded amyloid ß and tau proteins. In our research, we performed extended studies directed at amyloid ß and tau aggregation inhibition using in cellulo (Escherichia coli model of protein aggregation), in silico, and in vitro 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 18, which exhibited a unique profile of biological activity. This compound was the most potent and balanced dual aggregation inhibitor (Aß42 inhibition (inh.) 80.0%, tau inh. 68.3% in 10 µM), with previously reported in vitro inhibitory activity against hBuChE, hBACE1, and Aß (hBuChE IC50 = 5.74 µM; hBACE1 IC50 = 41.6 µM; Aß aggregation (aggr.) inh. IC50 = 3.09 µM). In docking studies for both proteins, we tried to explain the different structural requirements for the inhibition of Aß vs tau. Moreover, docking and kinetic studies showed that compound 18 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.