The Synthesis and Biological Activity of Series of New Polyfunctional Pyrroles with the Potential to Modulate Neuronal Viability

The polyfunctional pyrrole 3,5-dichloro-1H-pyrrole-2,4-dicarbaldehyde (2) was reacted with malononitrile and Meldrum’s acid in a regioselective manner to yield derivatives (4, 5, 6, 8, 9, and 10). Compound 8 was isolated and its structure was characterised by crystallography and 1 and 2D-¹H, ¹³C-NMR spectroscopy. The biological effects of these derivatives were evaluated on differentiated SH-SY5Y human neuroblastoma cells, under control conditions and following Aβ exposure as an in vitro model of Alzheimer’s disease. MTT assays were performed to assess neuronal viability, and Annexin V staining was used to quantify apoptosis. Compounds 2 and 8 significantly increased cell viability in control differentiated neurons, suggesting a neurotrophic or protective effect. However, in Aβ-treated cells, all tested compounds, namely 5, 6, 8 and 2, reduced viability, indicating a possible interaction between our derivatives and Aβ-induced neurotoxicity. These findings reveal that certain polyfunctional pyrrole derivatives can differentially modulate neuronal survival depending on the cellular environment. This suggests that the neuronal cell death induced by Aβ in Alzheimer’s patients can be enhanced in the presence of those compounds. Since pyrrole scaffolds are present both in biologically essential molecules and in various environmental compounds, this dual action suggests their potential relevance in understanding the mechanisms of neurodegeneration and highlights the need for further mechanistic and translational studies to explore their impact on neurodegenerative disorders, including Alzheimer’s.