Design, synthesis, and biological evaluation of novel tryptanthrin derivatives as selective acetylcholinesterase inhibitors for the treatment of Alzheimer's disease

Two novel series of tryptanthrin (TRYP) derivatives were designed and synthesized as multifunctional agents for the treatment of Alzheimer’s disease (AD). Inhibition assay against cholinesterase (ChE) indicated that these derivatives can act as acetylcholinesterase (AChE) inhibitors with selectivity over butyrylcholinesterase (BuChE). Among them, n1 exhibited the most excellent ChE inhibitory potency (AChE, IC50 = 12.17 ± 1.50 nM; BuChE, IC50 = 6.29 ± 0.48 μΜ; selectivity index = 517). Molecular docking studies indicated that compound n1 can interact with amino acid residues in the catalytic active site and peripheral anionic site of AChE and the molecular dynamics (MD) simulation studies demonstrated that the AChE–n1 complex had good stability. N1 also exhibited anti-amyloid-β (Aβ) aggregation (63.48% ± 1.02%, 100 μΜ) and anti-neuroinflammation activity (NO, IL-1β, TNF-α; IC50 = 2.13 ± 0.54 μΜ, 2.21 ± 0.37 μΜ, 2.47 ± 0.07 μΜ, respectively), and n1 had neuroprotective and metal-chelating properties. Further studies indicated n1 had proper blood–brain barrier permeability in the Parallel artificial membrane permeation assay. In vivo studies found that n1 effectively improved learning and memory impairment in scopolamine-induced AD mouse models. Nissl staining of mice hippocampal tissue sections revealed that n1 restored neuronal cells in the hippocampus CA3 and CA1 regions. These findings suggested that n1 can be a promising compound for further development of multifunctional agents for AD treatment.