Design, synthesis, and evaluation of dual-target inhibitors of acetylcholinesterase (AChE) and soluble epoxide hydrolase (sEH) for the treatment of Alzheimer's disease

In this study, a series of tacrine derivatives featuring a triazole linker with sEH fragment were designed, synthesized, and evaluated for Alzheimer's disease treatment. Among them, compound Z43 exhibited best dual inhibitory activity against AChE and sEH (AChE IC₅₀ = 1.7 nM; sEH IC₅₀ = 0.7 nM) and showed low cytotoxicity in HepG2, SMMC7721 and SH-SY5Y cell lines. In addition, Z43 showed high permeability in PAMPA permeability test. Meanwhile, Z43 protected PC12 cells from H₂O₂-induced toxicity. Moreover, in LPS-induced BV-2 cell inflammation model, Z43 significantly reduced the levels of TNF-α, IL-1β, IL-6 and iNOS. Acute toxicity tests also indicated a favorable safety profile. In the scopolamine-induced AD mice model, Z43 markedly improved learning and memory deficits, which was significantly better than tacrine and EC5026. In summary, compound Z43 shows promising potential for further research.