Dual inhibition of BChE and Aβ42 aggregation by novel 2-phenylbenzofuran derivatives as a multitarget approach to Alzheimer’s disease

Alzheimer’s disease (AD) is a complex neurodegenerative disorder involving multiple pathogenic mechanisms, requiring therapies targeting different pathways. In this study, five 2-phenylbenzofurans (8–12) were designed, synthesized via the Wittig reaction, and evaluated as potential multi-target agents for AD. All compounds selectively inhibited butyrylcholinesterase (BChE, IC50 = 5.1–45.8 µM), with compounds 8 and 12 showing the highest activity, better than the reference compound. All compounds also exhibited significant antioxidant activity in the ABTS assay (EC50 = 10.65–27.02 µM), with compound 12 displaying the highest antioxidant capacity, outperforming the reference standard. Both compounds act as mixed-type BChE inhibitors and were non-cytotoxic in SH-SY5Y neuroblastoma cells at their active concentrations. Moreover, they significantly decreased intracellular reactive oxygen species levels induced by H2O2, with compound 12 demonstrating highest potency. Thioflavin-T assay proved that both compounds effectively interfere with Aβ42 aggregation, with compound 12 showing the strongest anti-amyloid activity. The biological findings were further supported by computational studies, with molecular docking providing insight into BChE binding and ADMET analysis predicting favourable pharmacokinetic properties. Preliminary telomere analyses further suggested protection against oxidative stress-induced chromosomal damage. Overall, compound 12 emerges as the most promising molecule for further optimization as a multitarget therapeutic agent for AD.