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 Aβ -induced cell death and biologically specific activities involved in anti-Aβ aggregation, anti-AChE, and antioxidant effects. The proposed compounds, except compounds and , could protect SK-N-SH cells at the IC of anti-Aβ aggregation with cell viability values ranging from 63.05% ± 2.70% to 87.90% ± 3.26%. Compounds , , and demonstrated striking relationships between the %viability of SK-N-SH cells and IC values of anti-Aβ aggregation and antioxidants. No significant potency of all synthesized compounds against AChE was found. Among them, compound showed the strongest anti-Aβ and antioxidant properties with IC values of 3.18 ± 0.87 and 28.18 ± 1.40 μM, respectively. The docking data on the monomeric Aβ peptide of compound 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 , 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 . In light of our findings, compounds and appeared as potentially intriguing lead compounds for new therapeutic approaches to Alzheimer's disease. More in vivo testing will be revealed in due course.