- Claulansine F-donepezil hybrids as anti-alzheimer’s disease agents with cholinergic, free-radical scavenging, and neuroprotective activities
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The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F-donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC50) 1.63-4.62 μM). Moreover, (E)-3-(8-(tert-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol- 5-yl)-N-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (6bd) exhibited better neuroprotective effects against OGD/R (oxygen-glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, 6bd could cross the blood-brain barrier in vitro. More importantly, compared to edaravone, 6bd had stronger free-radical scavenging activity. Molecular docking studies revealed that 6bd could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate 6bd as a leading structure worthy of further investigation.
- Chen, Xinyi,Li, Chuangjun,Liu, Ke,Ma, Jie,Wang, Weiping,Wang, Xiaoliang,Yang, Jingzhi,Zang, Yingda,Zhang, Dongming
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- Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation
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We previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure-activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1-UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit. The optimized compounds inhibit the DCN1-UBE2M protein-protein interaction in our TR-FRET binding assay and inhibit cullin neddylation in our pulse-chase NEDD8 transfer assay. The optimized compounds bind to DCN1 and selectively reduce steady-state levels of neddylated CUL1 and CUL3 in a squamous cell carcinoma cell line. Ultimately, we anticipate that these studies will identify early lead compounds for clinical development for the treatment of lung squamous cell carcinomas and other cancers.
- Hammill, Jared T.,Scott, Daniel C.,Min, Jaeki,Connelly, Michele C.,Holbrook, Gloria,Zhu, Fangyi,Matheny, Amy,Yang, Lei,Singh, Bhuvanesh,Schulman, Brenda A.,Guy, R. Kiplin
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supporting information
p. 2680 - 2693
(2018/04/23)
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- Rational Design and Multibiological Profiling of Novel Donepezil-Trolox Hybrids against Alzheimer's Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties
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A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC50 = 0.54 μM) and hMAO-B (IC50 = 4.3 μM), significant antioxidant activity (41.33 μM IC50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aβ1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H2O2, rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug.
- Cai, Pei,Fang, Si-Qiang,Yang, Xue-Lian,Wu, Jia-Jia,Liu, Qiao-Hong,Hong, Hao,Wang, Xiao-Bing,Kong, Ling-Yi
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p. 2496 - 2511
(2017/11/21)
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- NOVEL LIPOIC ACID-4-AMINO PIPERIDINE CONJUGATED COMPOUNDS AND USES OF THE SAME
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The present invention relates to a novel lipoic acid/4-amino benzyl piperidine conjugated compound in which a lipoic acid as an antioxidant is conjugated with a 4-amino benzyl piperidine derivative, and to a pharmaceutical composition and functional health food composition containing the same for preventing or treating Alzheimer′s disease and degenerative diseases. The lipoic acid/4-amino benzyl piperidine conjugated compound according to the present invention exhibits activity to inhibit cholinesterase (ChE) of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and thus is an effective material in the prevention or treatment of Alzheimer′s disease and degenerative diseases. The pharmaceutical composition of the present invention contains, as an active ingredient, the lipoic acid/4-amino benzyl piperidine conjugated compound that inhibits activity of cholinesterase (ChE), and thus can be used to prevent and treat Alzheimer′s disease and degenerative diseases and can be utilized as a functional health food for alleviating Alzheimer′s disease and degenerative diseases or improving learning ability and memory power.
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Paragraph 0069-0072
(2020/03/03)
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- Development of cholinesterase inhibitors using 1-benzyl piperidin-4-yl (α)-lipoic amide molecules
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A series of hybrid molecules between (α)-lipoic acid (ALA) and 4-amino-1-benzyl piperidines were synthesized and their in vitro cholinesterase (acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)) inhibitory activities were evaluated. Even thoug
- Lee, Seung-Hwan,Kim, Beom-Cheol,Kim, Jae-Kwan,Lee, Hye Sook,Shon, Min Young,Park, Jeong Ho
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p. 1681 - 1686
(2014/07/07)
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