Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 37, Issue 1, Pages 69-85Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2021.1993845
Keywords
Alzheimer's disease; chalcone-vitamin E-donepezil hybrids; multitarget-directed ligands
Funding
- Key Scientific Research Project of Colleges and Universities in Henan Province [20A350006]
- Special Project of Nanyang Normal University [SYKF2020032, 2020QN036, 2020QN045]
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A series of novel chalcone-Vitamin E-donepezil hybrids were designed and synthesized for treating Alzheimer's disease. Compound 17f showed potent enzyme inhibitory activity, antioxidant properties, and anti-aggregation effects, as well as neuroprotective effects in vitro.
A novel series of chalcone-Vitamin E-donepezil hybrids was designed and developed based on multitarget-directed ligands (MTDLs) strategy for treating Alzheimer's disease (AD). The biological results revealed that compound 17f showed good AChE inhibitory potency (ratAChE IC50 = 0.41 mu M; eeAChE IC50 = 1.88 mu M). Both the kinetic analysis and docking study revealed that 17f was a mixed type AChE inhibitor. 17f was also a good antioxidant (ORAC = 3.3 eq), selective metal chelator and huMAO-B inhibitor (IC50 = 8.8 mu M). Moreover, it showed remarkable inhibition of self- and Cu2+-induced A beta (1-42) aggregation with a 78.0 and 93.5% percentage rate at 25 mu M, respectively, and disassembled self-induced and Cu2+-induced aggregation of the accumulated A beta (1-42) fibrils with 72.3 and 84.5% disaggregation rate, respectively. More importantly, 17f exhibited a good neuroprotective effect on H2O2-induced PC12 cell injury and presented good blood-brain barrier permeability in vitro. Thus, 17f was a promising multi-target-directed ligand for treating AD.
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