Design, synthesis and biological evaluation of new multi-target scutellarein hybrids for treatment of Alzheimer's disease.

[Display omitted] • Scutellarein derivatives were designed as potential multifunctional agents for the treatment of AD. • 11e displayed excellent inhibition of self- and Cu2+-induced Aβ 1–42 aggregation and induced disassembly of Aβ fibrils. • 11e significantly reduced tau hyperphosphorylation and exhibited good inhibition of platelet aggregation. • 11e exhibited optimal Papp AP–BL desirable direct uptake values in hCMEC/D3 cell monolayer and hPepT1-MDCK cell lines. • 11e could ameliorate the learning and memory impairment by significantly reduced APP and BACE-1 expression. Scutellarein hybrids were designed, synthesized and evaluated as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds 11a–i , containing a 2-hydroxymethyl-3,5,6-trimethylpyrazine fragment at the 7-position of scutellarein, were found to have balanced and effective multi-target potencies against AD. Among them, compound 11e exhibited the most potent inhibition of electric eel and human acetylcholinesterase enzymes with IC 50 values of 6.72 ± 0.09 and 8.91 ± 0.08 μM, respectively. In addition, compound 11e displayed not only excellent inhibition of self- and Cu2+-induced Aβ 1–42 aggregation (91.85% and 85.62%, respectively) but also induced disassembly of self- and Cu2+-induced Aβ fibrils (84.54% and 83.49% disaggregation, respectively). Moreover, 11e significantly reduced tau protein hyperphosphorylation induced by Aβ 25–35 , and also exhibited good inhibition of platelet aggregation. A neuroprotective assay demonstrated that pre-treatment of PC12 cells with 11e 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 11e would have optimal blood–brain barrier and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11e significantly attenuated learning and memory impairment in an AD mice model. Toxicity experiments with the compound did not reveal any safety concerns. Notably, 11e significantly reduced β-amyloid precursor protein (APP) and β-site APP cleaving enzyme-1 (BACE-1) protein expression in brain tissue of scopolamine-treated mice. Taken together, these outstanding properties qualified compound 11e as a promising multi-target candidate for AD therapy, worthy of further studies. [ABSTRACT FROM AUTHOR]