Key Chemotypes for the Rational Design of Dual AChE/BACE-1 Inhibitors

2025-05-06

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DOI：10.2174/0109298673350086250310080327

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A classical one-drug-one-target approach is ineffective against diseases with a multi-factorial pathogenesis, such as Alzheimer's disease (AD). On the other hand, multi-target approaches can provide a higher level of pharmacological interference which can better affect the disease network. Acetylcholinesterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (beta-secretase, BACE-1), glycogen synthase kinase 3 beta (GSK-3 beta), monoamine oxidases (MAOs), metal ions in the brain, N-methyl-D-aspartate (NMDA) receptor, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), and phosphodiesterases (PDEs) are the main major targets of this network whose connection are still far from being fully understood. Aware of this limitation, we herein focus on the main chemotypes employed for AChE/BACE-1 targeting. These include mostly bioactive compounds based on chalcones, triazines, triazoles, piperidines, and flavonoids.

Keywords:

Acetylcholinesterase

beta-secretase-1

Alzheimer's disease

multi-targeted ligands

structure-activity

relationships

homeostasis

Key Chemotypes for the Rational Design of Dual AChE/BACE-1 Inhibitors

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