Tacrine-hydroxamate derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation

In order to develop multitarget-directed ligands as potential treatments for Alzheimer's disease, twenty-eight new tacrine-hydroxamate derivatives were designed, synthesized, and biologically evaluated. As expected, most of the compounds exhibited inhibitory activities against cholinesterases (ChEs) and histone deacetylase (HDACs). Among the tested compounds, A10 showed not only potent and selective inhibition on AChE at sub-nanomolar potency (AChE_IC50 = 0.12 nM, BChE_IC50 = 361.52 nM) but also potent inhibition on HDAC (IC₅₀ = 0.23 nM). Moreover, A10 exhibited inhibitory activity on Aβ_1-42 self-aggregation as well as disaggregation activity on pre-formed Aβ fibrils. Furthermore, A10 exhibited antioxidant activity and metal chelating properties. Further mechanistic studies demonstrated that A10 is a pan-inhibitor of HDACs and a mixed-type inhibitor for AChE. It shown that A10 is a BBB penetrant by online prediction. Taken together, the results indicate that A10 can serve as a lead compound to develop promising candidate analogs as AD therapeutics.