Dual-target ligand discovery for Alzheimer's disease: triphenylphosphoranylidene derivatives as inhibitors of acetylcholinesterase and β-amyloid aggregation.

Alzheimer disease (AD) is one of the major neurodegenerative diseases that could not be prevented or completely cured and may lead to death. Here, we target AChE and β-amyloid proteins. Synthesising new triphenylphosphporanylidene derivatives based on the surveyed literature and testing their biological activity revealed promising results especially for the acetyl triphenylphosphoranylidene derivative , which showed good inhibitor activity against AChE enzyme with IC in the nanomolar range (97.04 nM); on the other hand, it showed poor selectivity for AChE versus butyrylcholinesterase but with some futural structural modification, this selectivity can be improved. showed MMP-2 IC of 724.19 nM and Aβ aggregation IC of 302.36 nM. A kinetic study demonstrated that compound uncompetitively inhibited AChE. Moreover, derivative showed low cytotoxicity, good behavioural studies including Y-maze and passive avoidance tests with activity similar to that of donepezil. Finally, studies for predict its good penetration into BBB and good binding affinity in the AChE binding site.