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新型 3,4-二氢-2(1H )-喹啉酮二硫代氨基甲酸酯衍生物的设计、合成和生物学评价
Authors Guo J, Xu A, Cheng M, Wan Y, Wang R, Fang Y, Jin Y, Xie SS, Liu J
Received 6 January 2022
Accepted for publication 10 May 2022
Published 18 May 2022 Volume 2022:16 Pages 1495—1514
DOI https://doi.org/10.2147/DDDT.S354879
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Tin Wui Wong
Background: Alzheimer’s disease (AD) belongs to neurodegenerative disease, and the increasing number of AD patients has placed a heavy burden on society, which needs to be addressed urgently. ChEs/MAOs dual-target inhibitor has potential to treat AD according to reports.
Purpose: To obtain effective multi-targeted agents for the treatment of AD, a novel series of hybrid compounds were designed and synthesized by fusing the pharmacophoric features of 3,4-dihydro-2 (1H )-quinolinone and dithiocarbamate.
Methods: All compounds were evaluated for their inhibitory abilities of ChEs and MAOs. Then, further biological activities of the most promising candidate 3e were determined, including the ability to cross the blood-brain barrier (BBB), kinetics and molecular model analysis, cytotoxicity in vitro and acute toxicity studies in vivo.
Results: Most compounds showed potent and clear inhibition to AChE and MAOs. Among them, compound 3e was considered to be the most effective and balanced inhibitor to both AChE and MAOs (IC50=0.28 μM to eeAChE; IC50=0.34 μM to hAChE; IC50=2.81 μM to hMAO-B; IC50=0.91 μM to hMAO-A). In addition, 3e showed mixed inhibition of hAChE and competitive inhibition of hMAO-B in the enzyme kinetic studies. Further studies indicated that 3e could penetrate the BBB and showed no toxicity on PC12 cells and HT-22 cells when the concentration of 3e was lower than 12.5 μM. More importantly, 3e lacked acute toxicity in mice even at high dose (2500 mg/kg, P.O.).
Conclusion: This work indicated that compound 3e with a six-carbon atom linker and a piperidine moiety at terminal position was a promising candidate and was worthy of further study.
Graphical Abstract:
Keywords: Alzheimer’s disease, cholinesterase, monoamine oxidase, 3,4-dihydro-2(1H )-quinolinone, dithiocarbamate