Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β 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 beta and tau proteins. In our research, we performed extended studies directed at amyloid beta 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 (A beta 42 inhibition (inh.) 80.0%, tau inh. 68.3% in 10 mu M), with previously reported in vitro inhibitory activity against hBuChE, hBACE1, and A beta (hBuChE IC50 = 5.74 mu M; hBACE1 IC50 = 41.6 mu M; A beta aggregation (aggr.) inh. IC50 = 3.09 mu M). In docking studies for both proteins, we tried to explain the different structural requirements for the inhibition of A beta 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.

Automated summary

The study identified a potent dual aggregation inhibitor for Alzheimer's disease, with compound 18 showing the most balanced and strong inhibitory effects on amyloid beta and tau aggregation. This compound also exhibited inhibitory activity against hBuChE, hBACE1, and A beta, and may provide insight into the design of future generations of aggregation inhibitors.