Journal
BIOORGANIC CHEMISTRY
Volume 81, Issue -, Pages 512-528Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2018.09.010
Keywords
Coumarin; Dithiocarbamate; Cholinesterase; Monoamine oxidase; Alzheimer's disease
Funding
- Program of the National Natural Science Foundation of China [21807052, 81760622, 31600265]
- Program of Natural Science Foundation of Jiangxi Province of China [20171BAB215064]
- Research Fund for the Doctoral Program of Jiangxi University of Traditional Chinese Medicine [2015BS008]
- Health and Family planning Commission of Jiangxi province [2016A048, 20173013]
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University [07010150001]
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A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 mu M and 0.0089 mu M for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 mu M for hAChE; 0.101 mu M for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold.
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