Design, Synthesis, and Neuroprotective Activity of Phenoxyindole Derivatives on Antiamyloid Beta (Aβ) Aggregation, Antiacetylcholinesterase, and Antioxidant Activities

In this investigation, a number of phenoxyindole derivatives were designed, synthesized, and tested for their neuroprotective ability on SK-N-SH cells against A beta(42)-induced cell death and biologically specific activities involved in anti-A beta aggregation, anti-AChE, and antioxidant effects. The proposed compounds, except compounds 9 and 10, could protect SK-N-SH cells at the IC50 of anti-A beta aggregation with cell viability values ranging from 63.05% +/- 2.70% to 87.90% +/- 3.26%. Compounds 3, 5, and 8 demonstrated striking relationships between the %viability of SK-N-SH cells and IC50 values of anti-A beta aggregation and antioxidants. No significant potency of all synthesized compounds against AChE was found. Among them, compound 5 showed the strongest anti-A beta and antioxidant properties with IC50 values of 3.18 +/- 0.87 and 28.18 +/- 1.40 mu M, respectively. The docking data on the monomeric A beta peptide of compound 5 demonstrated good binding at regions involved in the aggregation process, and the structural feature made it possible to be a superior radical scavenger. The most effective neuroprotectant belonged to compound 8, with a cell viability value of 87.90% +/- 3.26%. Its unique mechanisms for enhancing the protective impact may serve additional purposes since it demonstrated mild biological-specific effects. In silico prediction of CNS penetration shows strong passive penetration ability across the blood-brain barrier from blood vessels to the CNS for compound 8. In light of our findings, compounds 5 and 8 appeared as potentially intriguing lead compounds for new therapeutic approaches to Alzheimer's disease. More in vivo testing will be revealed in due course.

Automated summary

In this study, several phenoxyindole derivatives were synthesized and tested for their neuroprotective effects on SK-N-SH cells. The compounds showed potential in protecting the cells against A beta-induced cell death and having anti-A beta aggregation and antioxidant activities. Compound 5 exhibited the strongest effects in both anti-A beta aggregation and antioxidant assays, while compound 8 showed the highest cell viability. These compounds have the potential to be novel therapeutic approaches for Alzheimer's disease.