Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease

Chen, Yao; Zhu, Jie; Mo, Jun; Yang, Hongyu; Jiang, Xueyang; Lin, Hongzhi; Gu, Kai; Pei, Yuqiong; Wu, Liang; Tan, Renxiang; Hou, Jing Gang; Chen, Jingyi; Lv, Yang; Bian, Yaoyao; Sun, Haopeng

doi:10.1080/14756366.2017.1412314

Cited by 33 publications

(22 citation statements)

References 48 publications

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“…Thirdly, cinnamic acid is readily available and much cheaper compared to available AD therapeutics. Importantly, cinnamic acid derivatives have been demonstrated to function as cholinesterase inhibitors and might have therapeutic beneficial in AD ( Chen et al, 2018 ; Lan et al, 2017 ). In-vitro study by Zhang et al has shown that one of the derivatives, compound 5I, inhibits choloinesterase activity, prevents aggregation of Aβ42 and is neuroprotective against amyloid-stimulated cell toxicity ( Lan et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Cinnamic acid activates PPARα to stimulate Lysosomal biogenesis and lower Amyloid plaque pathology in an Alzheimer's disease mouse model

Chandra

Roy

Jana

et al. 2019

Neurobiology of Disease

110

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The response of the lysosomes, the waste clearance machinery of the cell, to different environmental stimuli is coordinated by a gene network with a master regulator Transcription factor EB (TFEB) at the core. Disruption of multiple facets of the lysosomal and autophagic network has been linked to various neurodegenerative and lysosomal storage disorders, making TFEB an attractive therapeutic target to rescue or augment lysosomal function under pathological scenario. In this study, we demonstrate that cinnamic acid, a naturally occurring plant-based product, induces lysosomal biogenesis in mouse primary brain cells via upregulation of TFEB. We delineate that cinnamic acid activates the nuclear hormone receptor PPARα to transcriptionally upregulate TFEB and stimulate lysosomal biogenesis. Moreover, using in-silico and biochemical approaches we established that cinnamic acid serves as a potent ligand for peroxisome proliferator-activated receptor α (PPARα). Finally, cinnamic acid treatment in male and female 5× Familial Alzheimer’s disease (5XFAD) mice remarkably reduced cerebral amyloid-beta plaque burden and improved memory via PPARα. Therefore, stimulation of lysosomal biogenesis by cinnamic acid may have therapeutic implications for treatment of Alzheimer’s disease and other lysosomal disorders originating from accumulation of toxic protein aggregates.

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Section: Discussionmentioning

confidence: 99%

Cinnamic acid activates PPARα to stimulate Lysosomal biogenesis and lower Amyloid plaque pathology in an Alzheimer's disease mouse model

Chandra

Roy

Jana

et al. 2019

Neurobiology of Disease

110

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“…Behavioural studies revealed that all the three compounds, 83-85 showed enhanced cognitive function in the Institute of Cancer Research (ICR) mice in vivo. Administration of the three compounds caused no remarkable morphological liver changes making them safe and promising compounds for the treatment of Alzheimer's disease [59].…”

Section: Cinnamic Acid Derivatives With Neurological Activitymentioning

confidence: 96%

“…Binding patterns of compounds 83 and 84 with cholinesterases showed π-π stacking interactions, hydrogen bonds and van der Waals forces. At 25 µM, the three compounds inhibited Aβ 1–42 aggregation with an inhibitory rate between 31.82% and 34.57% when compared to resveratrol (30.36%), a reference compound [ 59 ].…”

Section: Cinnamic Acid Derivatives With Neurological Activitymentioning

confidence: 99%

Cinnamic Acid Derivatives and Their Biological Efficacy

Ruwizhi

Aderibigbe

2020

IJMS

248

134

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The role played by cinnamic acid derivatives in treating cancer, bacterial infections, diabetes and neurological disorders, among many, has been reported. Cinnamic acid is obtained from cinnamon bark. Its structure is composed of a benzene ring, an alkene double bond and an acrylic acid functional group making it possible to modify the aforementioned functionalities with a variety of compounds resulting in bioactive agents with enhanced efficacy. The nature of the substituents incorporated into cinnamic acid has been found to play a huge role in either enhancing or decreasing the biological efficacy of the synthesized cinnamic acid derivatives. Some of the derivatives have been reported to be more effective when compared to the standard drugs used to treat chronic or infectious diseases in vitro, thus making them very promising therapeutic agents. Compound 20 displayed potent anti-TB activity, compound 27 exhibited significant antibacterial activity on S. aureus strain of bacteria and compounds with potent antimalarial activity are 35a, 35g, 35i, 36i, and 36b. Furthermore, compounds 43d, 44o, 55g–55p, 59e, 59g displayed potent anticancer activity and compounds 86f–h were active against both hAChE and hBuChE. This review will expound on the recent advances on cinnamic acid derivatives and their biological efficacy.

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“…These include lipocrine, which combines a derivative of tacrine with lipoic acid to produce a conjugate with extremely potent anti-AChE activity (IC 50 = 0.253 nM), reduced AChE-induced Aβ aggregation (IC 50 = 45 μM) and protection of human neuronal cells from ROS formation evoked by oxidative stress [ 63 ]. Other examples comprise hybrids of tacrine with ferulic acid [ 64 ], melatonin [ 65 ], trolox [ 66 ], vanillin [ 67 ] and many other conjugating moieties [ 42 , 68 , 69 ].…”

Section: Introductionmentioning

confidence: 99%

New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer’s Disease Treatment

et al. 2020

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New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 ± 0.16 µM, IC50(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7. Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates 8 appear promising as candidates for AD therapeutics.

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Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease

Cited by 33 publications

References 48 publications

Cinnamic acid activates PPARα to stimulate Lysosomal biogenesis and lower Amyloid plaque pathology in an Alzheimer's disease mouse model

Cinnamic acid activates PPARα to stimulate Lysosomal biogenesis and lower Amyloid plaque pathology in an Alzheimer's disease mouse model

Cinnamic Acid Derivatives and Their Biological Efficacy

New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer’s Disease Treatment

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