Title : The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer's disease - Zhu_2019_Bioorg.Med.Chem.Lett_29_126625 |
Author(s) : Zhu G , Wang K , Shi J , Zhang P , Yang D , Fan X , Zhang Z , Liu W , Sang Z |
Ref : Bioorganic & Medicinal Chemistry Lett , 29 :126625 , 2019 |
Abstract :
A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound TM-14 showed the best eeAChE inhibitory activity with IC(50) value of 2.9 microM, in addition, both kinetic analysis of AChE inhibition and docking study displayed that TM-14 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. Moreover, compound TM-14 was a selective metal chelator and could form 1:1 TM-14-Cu(2+) complex. The structure-active-relationship also indicated that the O-alkylamine fragment remarkably decreased hMAO-B inhibitory activity, compound TM-2 exhibited potent hMAO-B inhibitory activity (IC(50) = 6.8 microM), which was supported by the molecular docking study. More interestingly, compounds TM-14 and TM-2 could cross the blood-brain barrier in vitro. Therefore, the structure-active-relationship of 2-acetylphenol-donepezil hybrids could encourage the development of multifunction agents with selective AChE inhibition or selective MAO-B inhibition for the treatment of Alzheimer's disease. |
PubMedSearch : Zhu_2019_Bioorg.Med.Chem.Lett_29_126625 |
PubMedID: 31444085 |
Zhu G, Wang K, Shi J, Zhang P, Yang D, Fan X, Zhang Z, Liu W, Sang Z (2019)
The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer's disease
Bioorganic & Medicinal Chemistry Lett
29 :126625
Zhu G, Wang K, Shi J, Zhang P, Yang D, Fan X, Zhang Z, Liu W, Sang Z (2019)
Bioorganic & Medicinal Chemistry Lett
29 :126625