Synthesis and biological evaluation of berberine-thiophenyl hybrids as multi-functional agents: Inhibition of acetylcholinesterase, butyrylcholinesterase, and Aβ aggregation and antioxidant activity.
A series of berberine-thiophenyl hybrids were designed, synthesised, and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and β-amyloid (Aβ) aggregation and as antioxidants. Among these hybrids, compounds 4f and 4i, berberine linked with o-methylthiophenyl and o-chlorothiophenyl by a 2-carbon spacer, were observed to be potent inhibitors of AChE, with IC50 values of 0.077 and 0.042 μM, respectively. Of the tested compounds, 4i was also the most potent inhibitor of BuChE, with an IC50 value of 0.662 μM. Kinetic studies and molecular modelling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives. The biological studies also demonstrated that these hybrids displayed interesting activities, including Aβ aggregation inhibition and antioxidant properties.
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Tao
T
Su
Shishun
S
Xie
Hui
H
Wei
Jun
J
Yan
Ling
L
Huang
Xingshu
X
Li
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry; D001599:Berberine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006861:Hydrogen Peroxide / Q000737:chemistry; D007700:Kinetics; D062105:Molecular Docking Simulation; D010636:Phenols / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013438:Sulfhydryl Compounds / Q000737:chemistry*
C587143:9-o-(2-(o-methyl)thiophenyl)ethyl-berberine bromide; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D010636:Phenols; D013438:Sulfhydryl Compounds; D001599:Berberine; C042983:thiophenol; D006861:Hydrogen Peroxide; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
Alzheimer’s disease; Antioxidants; Inhibitors of AChE; berberine–thiophenyl hybrids; β-Amyloid aggregation