Design, synthesis, and biological evaluation of novel 2-acetylphenol-rivastigmine hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease

• Published in: Medicinal chemistry research 2022-06, Vol.31 (6), p.1035-1048
• Main Authors: Deng, Cong, Mi, Jing, Zhou, Yi, Li, Xinjuan, Liu, Zhengwei, Sang, Zhipei, Li, Hui
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amine oxidase (flavin-containing); Antioxidants; Biochemistry; Biological activity; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Blood-brain barrier; Chelation; Hybrids; Hydrogen peroxide; Inorganic Chemistry; Medicinal Chemistry; Neurodegenerative diseases; Neuroprotection; Original Research; Permeability; Pharmacology/Toxicology; Pheochromocytoma cells; Rivastigmine
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-022-02899-7

Herein, a series of 2-acetylphenol-rivastigmine hybrids were rationally designed as multifunctional agents for the treatment of AD through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c was a pseudo-irreversible and selective hu AChE inhibitor (IC 50  = 8.7 μM). Compound 3c was also a significant antioxidant with ORAC value of 1.2 eq . Moreover, compound 3c showed potent MAO-B inhibitory activity with IC 50 values of 2.9 μM. In addition, compound 3c displayed selective metal chelation property. Furthermore, compound 3c showed significant neuroprotective effect on H 2 O 2 -induced PC12 cells injury. More importantly, compound 3c displayed favorable drug-like property and good blood brain barrier permeability in vitro. Thus, compound 3c was a promising multifunctional agent in vitro for the treatment of AD, deserving for further investigations. Graphical abstract