Title : Design, synthesis and biological evaluation of novel donepezil-coumarin hybrids as multi-target agents for the treatment of Alzheimer's disease - Xie_2016_Bioorg.Med.Chem_24_1528 |
Author(s) : Xie SS , Lan JS , Wang X , Wang ZM , Jiang N , Li F , Wu JJ , Wang J , Kong LY |
Ref : Bioorganic & Medicinal Chemistry , 24 :1528 , 2016 |
Abstract :
Combining N-benzylpiperidine moiety of donepezil and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activity were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for AChE and BuChE, and clearly selective inhibition to MAO-B. Of these compounds, 5m was the most potent inhibitor for eeAChE and eqBuChE (0.87muM and 0.93muM, respectively), and it was also a good and balanced inhibitor to hChEs and hMAO-B (1.37muM for hAChE; 1.98muM for hBuChE; 2.62muM for hMAO-B). Molecular modeling and kinetic studies revealed that 5m was a mixed-type inhibitor, which bond simultaneously to CAS, PAS and mid-gorge site of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, 5m showed good ability to cross the BBB and had no toxicity on SH-SY5Y neuroblastoma cells. Collectively, all these results suggested that 5m might be a promising multi-target lead candidate worthy of further pursuit. |
PubMedSearch : Xie_2016_Bioorg.Med.Chem_24_1528 |
PubMedID: 26917219 |
Xie SS, Lan JS, Wang X, Wang ZM, Jiang N, Li F, Wu JJ, Wang J, Kong LY (2016)
Design, synthesis and biological evaluation of novel donepezil-coumarin hybrids as multi-target agents for the treatment of Alzheimer's disease
Bioorganic & Medicinal Chemistry
24 :1528
Xie SS, Lan JS, Wang X, Wang ZM, Jiang N, Li F, Wu JJ, Wang J, Kong LY (2016)
Bioorganic & Medicinal Chemistry
24 :1528