Alzheimer's disease (AD) is becoming a serious threat to life expectancy for elderly people. A hot area of treatments for AD is to develop dual binding site acetylcholinesterase (AChE) inhibitors that simultaneously interact with both the catalytic and peripheral anionic sites of the enzyme. These compounds may act as disease-modifying agents with multiple functions, not only improving cognition of AD patients by elevating acetylcholine levels, but also interfering with β-amyloid (Aβ) aggregation and delaying Aβ-elicited pathological process. Thus, the novel promising dual binding site AChE inhibitors reported in recent years are the focus of this review. Here, we first introduce the action mechanism of dual binding site AChE inhibitors, and then summarize the main classes of dimeric or hybrid compounds, along with the pharmacological profile of the most active candidates for AD therapy. In addition, combined with our preceding studies on (-)-meptazinol-based bivalents, the rational design strategy and structure-activity relationship of dual binding site AChE inhibitors are discussed. The current challenges and development trends are also proposed.

Contents
1 Introduction
2 The action mechanism of dual binding site AChEIs
3 Dual binding site AChE inhibitors
3.1 Homodimers
3.2 Heterodimers
3.3 Dual binding site AChEIs with additional functions
4 Conclusions and outlook