Dual-target-directed ligand displaying selective butyrylcholinesterase inhibitory and neurite promoting activities as a potential therapeutic for alzheimer's disease

Novel 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.