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

• DOI: 10.1016/j.ijbiomac.2022.07.178
• Publication Date: 2022-07-28T15:21:38Z
• Authors: Jong Min Oh; Yujung Kang; Ji Hyun Hwang; Jeong-Ho Park; Woong-Hee Shin; Seul-Ki Mun; Jong Uk Lee; Sung-Tae Yee; Hoon Kim
• Keywords: 0303 health sciences; Monoamine Oxidase Inhibitors; Molecular Structure; Acetophenones; Triazoles; Tryptamines; 3. Good health; Molecular Docking Simulation; Neuroblastoma; Structure-Activity Relationship; 03 medical and health sciences; Alzheimer Disease; Butyrylcholinesterase; Acetylcholinesterase; Humans; Cholinesterase Inhibitors; Monoamine Oxidase

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 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 (Ki = 0.171 μM) and 897 was a reversible competitive MAO-B inhibitor (Ki = 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.