This study involved designing, synthesizing, and evaluating the protective potential of compounds on microglial cells (BV-2 cells) and neurons (SH-SY5Y cells) against cell death induced by Aβ_1–42. It aimed to identify biologically specific activities associated with anti-Aβ aggregation and understand their role in oxidative stress initiation and modulation of proinflammatory cytokine expression. Actively designed compounds CE5, CA5, PE5, and PA5 showed protective effects on BV-2 and SH-SY5Y cells, with cell viability ranging from 60.78 ± 2.32% to 75.38 ± 2.75% for BV-2 cells and 87.21% ± 1.76% to 91.55% ± 1.78% for SH-SY5Y cells. The transformation from ester in CE5 to amide in CA5 resulted in significant antioxidant properties. Molecular docking studies revealed strong binding of CE5 to critical Aβ aggregation regions, disrupting both intra- and intermolecular formations. TEM assessment supported CE5's anti-Aβ aggregation efficacy. Structural variations in PE5 and PA5 had diverse effects on IL-1β and IL-6, suggesting further specificity studies for Alzheimer's disease. Log P values suggested potential blood–brain barrier permeation for CE5 and CA5, indicating suitability for CNS drug development. In silico ADMET and toxicological screening revealed that CE5, PA5, and PE5 have favorable safety profiles, while CA5 shows a propensity for hepatotoxicity. According to this prediction, coumarin triazolyl derivatives are likely to exhibit mutagenicity. Nevertheless, CE5 and CA5 emerge as promising lead compounds for Alzheimer's therapeutic intervention, with further insights expected from subsequent in vivo studies.

In this investigation, a number of phenoxyindole derivatives were designed, synthesized, and tested for their neuroprotective ability on SK-N-SH cells against Aβ₄₂-induced cell death and biologically specific activities involved in anti-Aβ 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-Aβ 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-Aβ aggregation and antioxidants. No significant potency of all synthesized compounds against AChE was found. Among them, compound 5 showed the strongest anti-Aβ and antioxidant properties with IC₅₀ values of 3.18 ± 0.87 and 28.18 ± 1.40 μM, respectively. The docking data on the monomeric Aβ 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.

Coumarin-based molecular hybrids provide a framework for examining how structural changes influence cellular responses. This study compared four hybrids and three reference compounds across ten human cancer cell lines, with the lead hybrid also tested in non-cancerous Beas-2B cells, followed by functional assays and quantitative expression proteomics in HT-29 cells. Of 70 compound–cell-line combinations, the ferulic ester hybrid (FEC) was the only compound to yield a reproducibly measurable IC₅₀ within the primary screening range, reaching 42.8 ± 4.7 µM in HT-29 cells. Replacing the ferulic moiety or the ester linkage reduced activity within this series. HCT116 cells did not reach 50% inhibition at up to 100 µM. Basal PPARγ abundance did not consistently explain sensitivity across the panel. FEC reduced metabolic activity and colony formation, whereas annexin V/propidium iodide analysis showed a smaller apoptotic response. Proteomics identified coordinated decreases in DNA replication and translation proteins and a modest increase in endoplasmic reticulum protein-folding enzymes. These findings support a structure-dependent and cell-context-dependent antiproliferative response despite moderate potency.