Indazole derivatives as selective inhibitors of butyrylcholinesterase with effective blood-brain-barrier permeability profile

• Published in: Medicinal chemistry research Vol. 33; no. 2; pp. 298 - 307
• Main Authors: Tobuse, Asuka Joy, Law, Christine Shing Wei, Thy, Chun Keng, James, Jason Jonah, Chee, Chin Fei, Yeong, Keng Yoon
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2024; Springer Nature B.V
• Subjects: Alzheimer's disease; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Blood; Brain; Cholinesterase; Drug development; Hydrophobicity; Inorganic Chemistry; Medicinal Chemistry; Molecular docking; Neurodegenerative diseases; Original Research Article; Permeability; Pharmacology/Toxicology; Toxicity testing; Blood-brain-barrier; Enzyme inhibition; Alzheimer’s disease; Indazoles; Cholinesterase
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-023-03179-8

Alzheimer’s disease (AD) is a chronic disease that is multifactorial. Its underlying cause and mechanisms are yet to be fully understood and numerous research are underway to develop more effective drug candidates. This research explores the synthesis of an indazole-containing novel drug targeting AD, particularly by inhibiting cholinesterase activity. Among the 17 indazole derivatives synthesized in this study, compound 4q was demonstrated to have potent and selective butyrylcholinesterase (BChE) inhibitory activity. Molecular docking simulations revealed that the binding of 4q with BChE was through hydrophobic and polar interactions. It was also found to easily permeate through the blood-brain-barrier via an in vitro model and is non-toxic when tested against SH-SY5Y cells.