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

• Published in: Bioorganic chemistry Vol. 122; p. 105760
• Main Authors: Wu, Dirong, Chen, Jiao, Luo, Keke, Li, Hui, Liu, Ting, Li, Li, Dai, Zeqin, Li, Yongjun, Zhao, Yonglong, Fu, Xiaozhong
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.05.2022; Elsevier
• Subjects: Acetylcholinesterase - metabolism; AChE inhibitors; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Amino Acids; Amyloid beta-Peptides - metabolism; Animals; Antioxidants; Antioxidants - pharmacology; Apigenin; Biochemistry & Molecular Biology; Carbamates - therapeutic use; Chemistry; Chemistry, Organic; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Drug Design; Glucuronates; Life Sciences & Biomedicine; Mice; multifunctional anti-AD agents; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Physical Sciences; Rats; Science & Technology; Scutellarin; Structure-Activity Relationship; Scutellarin; Antioxidants; Alzheimer’s disease; multifunctional anti-AD agents; AChE inhibitors; OXIDATIVE STRESS; NEUROTOXICITY; PEPTIDE; STRATEGIES; ACETYLCHOLINESTERASE; ANTIOXIDANT; INDUCED COGNITION IMPAIRMENT; HYPOTHESIS; INHIBITORS; Alzheimers disease; BRAIN
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105760

[Display omitted] •Scutellarin and scutellarein derivatives were designed as potential multifunctional agents for the treatment of AD.•6 h exhibited the most potent inhibition potency against AChE and against self and Cu2+ induced Aβ1-42 aggregation.•6 h exhibited more potent protective activity against oxidative damage by improving the relevant detection indicators.•6 h exhibited optimal Papp AP–BL desirable direct uptake values in hCMEC/D3 cell monolayer and hPepT1-MDCK cell lines.•6 h could ameliorate the learning and memory impairment by increasing ACh levels and alleviating damage of hippocampal tissue. 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 IC50 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 Cu2+-induced Aβ1–42 aggregation (89.17% and 86.19% inhibition) but also induced disassembly of self- and Cu2+-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.