Synthesis, molecular modeling, and AChE/BChE inhibitory activity of novel phthalonitriles

This study investigated the synthesis, structural characterisation, and inhibitory effects on acetylcholinesterase and butyrylcholinesterase enzymes of novel phthalonitrile derivatives that could be considered potential therapeutic agents for the treatment of Alzheimer's disease. Alzheimer's disease is a neurodegenerative disorder characterised by progressive memory loss and cognitive dysfunction, and supporting the cholinergic system plays a significant role in current symptomatic treatment approaches. In this context, phthalonitrile derivatives with potential biological activity were synthesised via Claisen-Schmidt condensation and Debus-Radziszewski reactions. The structures of the compounds obtained were confirmed using various spectroscopic methods, and their inhibitory activities on AChE and BChE enzymes were then evaluated under in vitro conditions. The findings revealed that all synthesised compounds exhibited significant inhibitory effects at low nanomolar levels against both enzymes. Specifically, compound B4, which contains an imidazole ring, showed the highest inhibitory activity on both acetylcholinesterase and butyrylcholinesterase, with a stronger effect than the reference compound tacrine. Furthermore, molecular docking studies supported the finding that compound B4 demonstrated high binding affinity to the active sites of both enzymes and formed strong enzyme-ligand interactions. These results suggest that phthalonitrile derivatives, particularly compound B4, are promising candidates for the development of novel cholinesterase inhibitors for Alzheimer's disease.