An Overview of Tetramethylpyrazine (Ligustrazine) and its Derivatives as Potent Anti-Alzheimer’s Disease Agents

Abstract: Tetramethylpyrazine (TMP), or ligustrazine, is an alkaloid isolated from the Chinese herb Ligusticum wallichii. It is known for its broad-spectrum medicinal properties against several diseases, and various studies have shown that it can modulate diverse biological targets and signaling pathways to produce neuroprotective effects, especially against Alzheimer’s disease (AD). This has attracted significant research attention evaluating TMP as a potent multitarget anti-AD agent. This review compiles the results of studies assessing the neuroprotective mechanisms exerted by TMP as well as its derivatives prepared using a multi-target-directed ligand strategy to explore its multitarget modulating properties. The present review also highlights the work done on the design, synthesis, structure-activity relationships, and mechanisms of some potent TMP derivatives that have shown promising anti-AD activities. These derivatives were designed, synthesized, and evaluated to develop anti-AD molecules with enhanced biological and pharmacokinetic activities compared to TMP. This review article paves the way for the exploration and development of TMP and TMP derivatives as an effective treatment for AD.