Synthesis of 4-substituted benzyl-2-triazole-linked-tryptamine-paeonol derivatives and evaluation of their selective inhibitions against butyrylcholinesterase and monoamine oxidase-B

Cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors are being used and developed to treat Alzheimer's disease (AD), a major type of dementia patients. Fifteen 4-substituted benzyl-2-triazole-linked-tryptamine-paeonol derivatives were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase-A (MAO-A), and [sbnd]B (MAO-B). Compound 896 was the most potent BChE inhibitor (IC₅₀ = 0.13 μM) with the selectivity index (SI) value of >769.23 for BChE over AChE. Compound 897 was the most potent selective MAO-B inhibitor (IC₅₀ = 0.73 μM; SI = 20.45 for MAO-B over MAO-A). The meta-CF₃ substituent of 896 increased BChE inhibitory activity and the para-CF₃ substituent of 897 increased MAO-B inhibitory activity. Compound 896 was a reversible noncompetitive BChE inhibitor (K_i = 0.171 μM) and 897 was a reversible competitive MAO-B inhibitor (K_i = 0.237 μM). Compound 896 had a lower binding energy (−13.75 kcal/mol) to BChE than 897 (−11.29 kcal/mol), and 897 had a lower binding energy to MAO-B (−11.31 kcal/mol) than that to MAO-A (−6.72 kcal/mol). Little cytotoxicity was observed for 896 and 897 to normal cells (MDCK) and human neuroblastoma cells (SH-SY5Y). This study suggested that 896 and 897 are therapeutic candidates for various neurodegenerative disorders such as AD.