title: NO-donating tacrine derivatives as potential butyrylcholinesterase inhibitors with vasorelaxation activity.
abstract: To search for potent anti-Alzheimer's disease (AD) agents with multifunctional effects, 12 NO-donating tacrine-flurbiprofen hybrid compounds (2a-l) were synthesized and biologically evaluated. It was found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine-flurbiprofen hybrid compounds 1a-c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research.
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors: Yao
authors: Y
authors: Chen
authors: Jianfei
authors: J
authors: Sun
authors: Zhangjian
authors: Z
authors: Huang
authors: Hong
authors: H
authors: Liao
authors: Sixun
authors: S
authors: Peng
authors: Jochen
authors: J
authors: Lehmann
authors: Yihua
authors: Y
authors: Zhang
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D009566:Nitrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D009566:Nitrates; D014665:Vasodilator Agents; D009569:Nitric Oxide; D013619:Tacrine; D005480:Flurbiprofen; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase