Multi-target drug design of anti-Alzheimer's disease based on tacrine.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with concealed onset, which is characterized by damage of cholinergic system, deposition and accumulation of β-amyloid protein (Aβ) and Neurofibrillary tangles. Because cholinergic system plays a key role in the process of brain memory, cholinergic system has become one of the important targets in anti-AD research. In view of the complicated pathological characteristics of AD, the multi-target directed ligands (MTDLs) that can act on multiple targetsis considered to be an effective treatment strategy at present. Tacrine, as the first acetylcholinesterase (AChE) inhibitor, has been discontinued because of its hepatotoxicity, but its core structure is simple and easy to modify. By using tacrine to target the catalytic active site (CAS), the tacrine-based MTDLs can act on both CAS and peripheral anion site (PAS) of AChE so as to serve as a dual-site AChE inhibitor. Additionally, the tacrine-based MTDLs can also be designed on the basis of other theories of AD, for example, introducing functional moieties to modulate the formation of β-amyloid (Aβ), oxidation resistance or metal chelation. In this paper, the research progress of tacrine-based MTDLs is summarized.