Design, synthesis and evaluation of novel scutellarin and scutellarein-N,N-bis-substituted carbamate-l-amino acid derivatives as potential multifunctional therapeutics for Alzheimer's disease.

In this study, we designed, synthesized and evaluated a series of scutellarin and scutellarein-N,N-bis-substituted carbamate-l-amino acid derivatives as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds containing scutellarein as the parent nucleus (6a-l) had good inhibitory activity against acetyl cholinesterase (AChE), with compound 6 h exhibiting the most potent inhibition of electric eel AChE and human AChE enzymes with IC values of 6.01 ± 1.66 and 7.91 ± 0.49 μM, respectively. In addition, compound 6 h displayed not only excellent inhibition of self- and Cu-induced Aβ aggregation (89.17% and 86.19% inhibition) but also induced disassembly of self- and Cu-induced Aβ fibrils (84.25% and 78.73% disaggregation). Moreover, a neuroprotective assay demonstrated that pre-treatment of PC12 cells with 6 h significantly decreased lactate dehydrogenase levels, increased cell viability, enhanced expression of relevant apoptotic proteins (Bcl-2, Bax, and caspase-3) and inhibited RSL3 induced PC12 cell ferroptosis. Furthermore, hCMEC/D3 and hPepT1-MDCK cell line permeability assays indicated that 6 h would have optimal blood-brain barrier and intestinal absorption characteristics. The in vivo experimental data suggested that 6 h ameliorated learning and memory impairment in mice by decreasing AChE activity, increasing ACh levels and alleviating pathological damage of hippocampal tissue cells. These multifunctional properties highlight compound 6 h as a promising candidate for development as a multifunctional drug against AD.