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 dis-ease (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 IC50 values of 6.01 +/- 1.66 and 7.91 +/- 0.49 mu M, respectively. In addition, compound 6 h displayed not only excellent inhibition of self-and Cu2+-induced A beta(1-42) aggregation (89.17% and 86.19% inhibition) but also induced disassembly of self-and Cu2+-induced A beta 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.

Automated summary

In this study, a series of scutellarin derivatives were designed, synthesized, and evaluated as multifunctional therapeutic agents for Alzheimer's disease. One of the compounds, 6h, showed potent inhibition of acetyl cholinesterase and Aβ aggregation, as well as neuroprotective effects and optimal blood-brain barrier and intestinal absorption characteristics. The in vivo experiments further demonstrated its potential in improving learning and memory impairment. These findings highlight compound 6h as a promising multifunctional drug candidate against Alzheimer's disease.