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Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease

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...

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Autores principales: Guo, Jie, Xu, Airen, Cheng, Maojun, Wan, Yang, Wang, Rikang, Fang, Yuanying, Jin, Yi, Xie, Sai-Sai, Liu, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124477/
https://www.ncbi.nlm.nih.gov/pubmed/35611357
http://dx.doi.org/10.2147/DDDT.S354879
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author Guo, Jie
Xu, Airen
Cheng, Maojun
Wan, Yang
Wang, Rikang
Fang, Yuanying
Jin, Yi
Xie, Sai-Sai
Liu, Jing
author_facet Guo, Jie
Xu, Airen
Cheng, Maojun
Wan, Yang
Wang, Rikang
Fang, Yuanying
Jin, Yi
Xie, Sai-Sai
Liu, Jing
author_sort Guo, Jie
collection PubMed
description 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 (IC(50)=0.28 µM to eeAChE; IC(50)=0.34 µM to hAChE; IC(50)=2.81 µM to hMAO-B; IC(50)=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.
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spelling pubmed-91244772022-05-23 Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease Guo, Jie Xu, Airen Cheng, Maojun Wan, Yang Wang, Rikang Fang, Yuanying Jin, Yi Xie, Sai-Sai Liu, Jing Drug Des Devel Ther Original Research 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 (IC(50)=0.28 µM to eeAChE; IC(50)=0.34 µM to hAChE; IC(50)=2.81 µM to hMAO-B; IC(50)=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. Dove 2022-05-18 /pmc/articles/PMC9124477/ /pubmed/35611357 http://dx.doi.org/10.2147/DDDT.S354879 Text en © 2022 Guo et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Guo, Jie
Xu, Airen
Cheng, Maojun
Wan, Yang
Wang, Rikang
Fang, Yuanying
Jin, Yi
Xie, Sai-Sai
Liu, Jing
Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease
title Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease
title_full Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease
title_fullStr Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease
title_full_unstemmed Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease
title_short Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease
title_sort design, synthesis and biological evaluation of new 3,4-dihydro-2(1h)-quinolinone-dithiocarbamate derivatives as multifunctional agents for the treatment of alzheimer’s disease
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124477/
https://www.ncbi.nlm.nih.gov/pubmed/35611357
http://dx.doi.org/10.2147/DDDT.S354879
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