Aryldiazoquinoline based multifunctional small molecules for modulating Aβ₄₂ aggregation and cholinesterase activity...

Research continues to find a breakthrough for the treatment of Alzheimer's Disease (AD) due to its complicated pathology. Presented herein is a novel series of arydiazoquinoline molecules investigated for their multifunctional properties against the factors contributing to Alzheimer's disease (AD). The inhibitory properties of fourteen closely related aryldiazoquinoline derivatives have been evaluated for their inhibitory effect on Aβ₄₂ peptide aggregation. Most of these molecules inhibited Aβ₄₂ fibrillation by 50-80%. Selected molecules were also investigated for their binding behaviour to preformed Aβ₄₀ aggregates indicating a nanomolar affinity. In addition, these compounds were further investigated as cholinesterase inhibitors. Interestingly, some of the compounds turned out to be moderate in vitro inhibitors for AChE activity with IC₅₀ values in low micro molar range. The highest anti-AChE activity was shown by compound labelled as 2a with an IC₅₀ value of 6.2 μM followed by 2b with IC₅₀ value of 7.0 μM. In order to understand the inhibitory effect, binding of selected molecules to AChE enzyme was studied using molecular docking. In addition, cell toxicity studies using Neuro2a cells were performed to assess their effect on neuronal cell viability which suggests that these molecules possess a non-toxic molecular framework. Overall, the study identifies a family of molecules that show good in vitro anti-Aβ-aggregation properties and moderately inhibit cholinesterase activity.