| Title : Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer's disease - Wang_2016_Eur.J.Med.Chem_123_282 |
| Author(s) : Wang ZM , Cai P , Liu QH , Xu DQ , Yang XL , Wu JJ , Kong LY , Wang XB |
| Ref : Eur Journal of Medicinal Chemistry , 123 :282 , 2016 |
| Abstract : A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Abeta interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu2+-induced Abeta1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 muM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Abeta1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy. |
| ESTHER : Wang_2016_Eur.J.Med.Chem_123_282 |
| PubMedSearch : Wang_2016_Eur.J.Med.Chem_123_282 |
| PubMedID: 27484514 |
Wang ZM, Cai P, Liu QH, Xu DQ, Yang XL, Wu JJ, Kong LY, Wang XB (2016)
Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer's disease
Eur Journal of Medicinal Chemistry
123 :282
Wang ZM, Cai P, Liu QH, Xu DQ, Yang XL, Wu JJ, Kong LY, Wang XB (2016)
Eur Journal of Medicinal Chemistry
123 :282