Dual‐Target‐Directed Ligand Displaying Selective Butyrylcholinesterase Inhibitory and Neurite Promoting Activities as a Potential Therapeutic for Alzheimer's Disease

Abstract

AbstractNovel small molecules were synthesized in the quest to search for multi‐target directed ligand for Alzheimer's disease. From the preliminary synthesis, ethyl 4‐((cyclohexylmethyl)amino)‐3‐nitrobenzoate (2 h) showed good butyrylcholinesterase (BChE) inhibitory activity. Modifications carried out on compound 2 h by removing the nitro group resulted in the identification of ethyl 4‐((cyclohexylmethyl)amino)benzoate (3 h) as a selective and potent BChE inhibitor (IC50=0.735 μM; BChE selectivity>100‐fold over acetylcholinesterase (AChE)). Furthermore, compound 3 h was shown to be able to promote neurite outgrowth in SH‐SY5Y cells. No significant cytotoxicity was exhibited by compound 3 h, up till the highest concentration tested (25 μM). The compound was also predicted to have good permeability across the lipid infused bilayer, indicating its potential to cross the blood‐brain barrier. These results warrant further investigations on compound 3 h as a potential treatment for Alzheimer's disease.