Scutellarein derivatives with histamine H receptor antagonism and cholinesterase inhibitory potency as multi target-directed ligands for possible Alzheimer's disease therapy.

A series of scutellarein 7--amino acid carbamate-4'-cycloalkylamine propyl ether conjugates were designed and synthesized for the first time as multifunctional agents for Alzheimer's disease (AD) therapy. The designed compounds exhibited more balanced and effective multi-target potency. Among them, compound 11l, -Valine carbamate derivative of scutellarein cycloheptylamine ether, exhibited the most potent inhibition of electric eel AChE enzymes and human AChE enzymes, with an IC values of 7.04 μM and 9.73 μM, respectively. Moreover, 11l exhibited more potent HR antagonistic activities than clobenpropit, with an IC value of 1.09 nM. Compound 11l not only displayed excellent inhibition of self- and Cu-induced Aβ aggregation (95.48 % and 88.63 % inhibition, respectively) but also induced the disassembly of self- and Cu-induced Aβ fibrils (80.16 % and 89.30 % disaggregation, respectively). Moreover, 11l significantly reduced tau protein hyperphosphorylation induced by Aβ. It exhibited effective antioxidant activity and neuroprotective potency, and inhibited RSL3-induced PC12 cell ferroptosis. Assays of hCMEC/D3 and hPepT1-MDCK cell line permeability indicated that 11l would have optimal blood-brain barrier permeability and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11l significantly attenuated learning and memory impairment in an AD mouse model. Finally, a pharmacokinetic characterization of 11l indicated favorable druggability and pharmacokinetic properties. Taken together, our results suggest that 11l is a potential candidate for AD treatment and merits further investigation.