Design, synthesis, and biological evaluation of novel xanthone-alkylbenzylamine hybrids as multifunctional agents for the treatment of Alzheimer’s disease

Zhang, Zhipeng; Guo, Jie; Cheng, Maojun; Zhou, Weixin; Wan, Yang; Wang, Rikang; Yuan, Fang; Jin, Yi; Liu, Jing; Xie, Sai‐Sai

doi:10.1016/j.ejmech.2021.113154

Cited by 18 publications

(11 citation statements)

References 38 publications

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“…Thus, AChE has received considerable attention over the past few decades. 11 The crystallographic structure of AChE shows that the enzyme has a deep and narrow gorge which includes two binding active sites: a catalytic active site (CAS) at the bottom of the gorge and a peripheral anion site (PAS) at the entrance of the gorge. A good AChE inhibitor should have a core ring system that binds to PAS and a basic center that interacts with CAS, as well as a linking structure that can connect the two parts.…”

Section: Introductionmentioning

confidence: 99%

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

Guo¹,

Xu²,

Cheng³

et al. 2022

DDDT

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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 (1 H )-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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Section: Introductionmentioning

confidence: 99%

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

Guo¹,

Xu²,

Cheng³

et al. 2022

DDDT

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“…The enzymatic cavity of AChE is characterized by a nearly 20 Å deep narrow gorge, which is composed of two binding sites: the catalytic active site (CAS) at the bottom and the peripheral anionic site (PAS) near the entrance of the gorge. 10 …”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease

et al. 2022

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“…Oxidative stress or high levels of reactive oxygen species (ROS) are prevalent in brain regions of AD where Aβ is deposited. Antioxidant mechanisms have been thus considered as an effective therapeutic strategy in AD to increase the viability of surviving neurons [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Morpholine-Bearing Quinoline Derivatives as Potential Cholinesterase Inhibitors: The Influence of Amine, Carbon Linkers and Phenylamino Groups

Liu

Wang

Liu

2022

IJMS

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A series of novel 4-N-phenylaminoquinoline derivatives containing a morpholine group were designed and synthesized, and their anti-cholinesterase activities and ABTS radical-scavenging activities were tested. Among them, compounds 11a, 11g, 11h, 11j, 11l, and 12a had comparable inhibition activities to reference galantamine in AChE. Especially, compound 11g revealed the most potent inhibition on AChE and BChE with IC50 values of 1.94 ± 0.13 μM and 28.37 ± 1.85 μM, respectively. The kinetic analysis demonstrated that both the compounds 11a and 11g acted as mixed-type AChE inhibitors. A further docking comparison between the 11a- and 12a-AChE complexes agreed with the different inhibitory potency observed in experiments. Besides, compounds 11f and 11l showed excellent ABTS radical-scavenging activities, with IC50 values of 9.07 ± 1.34 μM and 6.05 ± 1.17 μM, respectively, which were superior to the control, Trolox (IC50 = 11.03 ± 0.76 μM). It is worth noting that 3-aminoquinoline derivatives 12a–12d exhibited better drug-like properties.

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Design, synthesis, and biological evaluation of novel xanthone-alkylbenzylamine hybrids as multifunctional agents for the treatment of Alzheimer’s disease

Cited by 18 publications

References 38 publications

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

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

Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease

Novel Morpholine-Bearing Quinoline Derivatives as Potential Cholinesterase Inhibitors: The Influence of Amine, Carbon Linkers and Phenylamino Groups

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