Design, Synthesis, and Biological Evaluation of Scutellarein Carbamate Derivatives as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease
Sang, ZP; Qiang, XM; Li, Y; Wu, B; Zhang, H; Zhao, MG; Deng, Y
A series of scutellarein carbamate derivatives were designed and synthesized based on the multitarget-directed drug design strategy for treatment of Alzheimer's disease. Their acetylcholinesterase and butyrylcholinesterase inhibitory activities, antioxidant activities, metals chelation, and neuroprotective effects against hydrogen peroxide-induced PC12 cell injury were evaluated in vitro. The preliminary results indicated that compound 7b exhibited good inhibitory potency toward AChE and BuChE with IC50 values of 1.2 ± 0.03 μm and 22.1 ± 0.15 μm, respectively, possessed the strong antioxidant potency (10.3 trolox equivalents), as well as acted as a selective metal chelator and neuroprotective agent. Furthermore, 7b could improve memory impairment induced by scopolamine, ethanol, and sodium nitrite using the step-down passive avoidance task in vivo and could remarkably decrease the activity of acetylcholinesterase in mice brain. This study indicated that 7b could be considered as a potential multitarget agent against AD.
AChE inhibitors; Alzheimer's disease; antioxidant; metal chelator; neuroprotective effects; scutellarein carbamates; synthesis; 1 piperidinecarboxylic acid 4 (5,6,7 trihydroxy 4 oxo 4h benzopyran)phenyl ester; 1 pyrrolidinecarboxylic acid 4 (5,6,7 trihydroxy 4 oxo 4h benzopyran)phenyl ester; 4 (phenylmethyl) 1 piperidinecarboxylic acid 4 (5,6,7 trihydroxy 4 oxo 4h benzopyran)phenyl ester; 4 morpholinecarboxylic acid 4 (5,6,7 trihydroxy 4 oxo 4h benzopyran)phenyl ester; alcohol; carbamic acid derivative; cholinesterase inhibitor; donepezil; hydrogen peroxide; n ethyl n methylcarbamic acid 4 (5,6,7 trihydroxy 4 oxo 4h benzopyran)phenyl ester; n,n bis(1 methylethyl)carbamic acid 4 (5,6,7 trihydroxy 4 oxo 4h benzopyran)phenyl ester; n,n diethylcarbamic acid 4 (5 hydroxy 6,7 dimethoxy 4 oxo 4h benzopyran)phenyl ester; n,n diethylcarbamic acid 4 (5,6,7 trihydroxy 4 oxo 4h benzopyran)phenyl ester; n,n diethylcarbamic acid 4 (5,6,7 trimethoxy 4 oxo 4h benzopyran)phenyl ester; n,n diethylcarbamic acid 4 [5,6,7 tris(acetyloxy) 4 oxo 4h benzopyran]phenyl ester; n,n diethylcarbamic acid 4 [6,7 bis(acetyloxy) 4 oxo 4h benzopyran]phenyl ester; n,n dimethylcarbamic acid 4 (5,6,7 trihydroxy 4 oxo 4h benzopyran)phenyl ester; neuroprotective agent; nootropic agent; rivastigmine; scopolamine; scutellarein; sodium nitrite; trolox C; unclassified drug; acetylcholinesterase; antioxidant; apigenin; carbamic acid derivative; chelating agent; cholinesterase; cholinesterase inhibitor; neuroprotective agent; scutellarein; Alzheimer disease; animal experiment; animal model; animal tissue; antioxidant activity; Article; carbon nuclear magnetic resonance; cell survival; cell viability; chelation; cholinesterase inhibition; controlled study; dose response; drug design; drug megadose; drug potency; drug synthesis; electrospray mass spectrometry; female; IC50; in vitro study; in vivo study; learning; male; memory; memory disorder; metal binding; mouse; neuroprotection; nonhuman; oxidative stress; PC12 cell line; pharmacophore; priority journal; proton nuclear magnetic resonance; rat; step-down passive avoidance test; stoichiometry; Alzheimer disease; animal; brain; chemistry; drug design; drug effects; human; metabolism; molecularly targeted therapy; Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Apigenin; Brain; Butyrylcholinesterase; Carbamates; Chelating Agents; Cholinesterase Inhibitors; Drug Design; Female; Humans; Male; Memory; Mice; Molecular Targeted Therapy; Neuroprotective Agents; PC12 Cells; Rats