- Design and synthesis of novel coumarin derivatives as potential acetylcholinesterase inhibitors for Alzheimer's disease
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Twenty novel 7-benzyloxycoumarin based compounds were synthesized with a variety of bioactive chemical fragments. The synthesized compounds showed remarkable acetylcholinesterase (AChE) inhibitory activity. In vitro assay revealed that compounds 7-benzyloxy-4-{[(4-phenylthiazol-2(3H)-ylidene)hydrazono]methyl}-2H-chromen-2-one (5b, IC50= 0.451μM), 7-benzyloxy-4-({[4-(4-methoxyphenyl)thiazol-2(3H)-ylidene]hydrazono}methyl)-2H-chromen-2-one (5d, IC50= 0.625μM), 5-amino-1-[2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)acetyl]-1H-pyrazole-4-carbonitrile (13c, IC50= 0.466μM), 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-(2-methylimino-4-phenylthiazol-3(2H)-yl)acetamide (16a, IC50= 0.500μM) and 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-[4-(4-methoxyphenyl)-2-methyliminothiazol-3(2H)-yl]acetamide (16b, IC50= 0.590μM) exhibited promising AChE inhibitory activity even better than donepezil (IC50= 0.711μM). Kinetic study for compound 5b implied mixed type inhibitor which could bind peripheral anionic site (PAS) and catalytic active site (CAS) of AChE enzyme. In addition, in vivo evaluation of compounds 5b, 13c and 16a confirmed significant memory improvement in scopolamine-induced impairment model in tested mice. Furthermore, in silico studies were performed on the synthesized compounds which included molecular docking study at the active site of recombinant human acetylcholinesterase enzyme (rhAChE) as well as prediction of ADMET and other physicochemical parameters. A correlation between the docking results and IC50 of tested compounds was routinely observed and shared similar binding pattern to the co-crystallized ligand donepezil.
- Amin, Kamilia M.,Abdel Rahman, Doaa E.,Abdelrasheed Allam, Heba,El-Zoheiry, Haidy H.
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- BENZOPYRANE AND IMIDAZOLE DERIVATIVES USEFUL FOR THE STABILIZATION OF AMYLOIDOGENIC IMMUNOGLOBULIN LIGHT CHAINS
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In immunoglobulin light chain amyloidosis (AL), the unique antibody light chain (LC) protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. For treating AL patients, such as those with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, provided herein are small molecule compounds of Formula Ia, Formula Ib, and Formula II that are kinetic stabilizers of the native dimeric structure of full-length LCs, which compounds can slow or stop the amyloidogenicity cascade at its origin.
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Paragraph 00103; 00107
(2020/10/19)
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- Synthesis and evaluation of 7-substituted coumarin derivatives as multimodal monoamine oxidase-B and cholinesterase inhibitors for the treatment of Alzheimer's disease
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A series of 7-substituted coumarin derivatives were designed and synthesised to display ChE and MAO-B inhibitory activity. The compounds consisted out of a coumarin structure (MAO-B inhibitor) and benzyl-, piperidine-, N-benzylpiperidine- or p-bromo-N-benzylpiperizine moiety, resembling the N-benzylpiperidine function of donepezil (ChE inhibitor), connected via an alkyl ether linkage at the 7 position. The biological assay results indicated that all the compounds (1–25) displayed selective inhibition to hMAO-B over hMAO-A, with the benzyloxy series (1–8, 10–13) showing nano-molar hMAO-B inhibition (IC50: 0.5–73?nM). Limited ChE inhibitory activity was however observed for the benzyloxy series with the exception of 2 and especially 3 showing selective BuChE inhibition. From this series 3 showed the best multifunctional activity (eqBuChE IC50?=?0.96?μM, hMAO-A IC50?=?2.13?μM, hMAO-B IC50?=?0.0021?μM). Within the N-benzylpiperidine (16–19) and p-bromo-N-benzylpiperizine (21–24) series the compounds in general showed moderate ChE and MAO-B inhibitory activity. Of these compounds 19 was the most potent multifunctional agent showing good eeAChE and eqBuChE inhibition (IC50?=?9.10?μM and 5.90?μM, respectively), and relatively potent and selective hMAO-B inhibition (IC50?=?0.30?μM, SI?= >33). Molecular modeling revealed that 19 was able to bind simultaneously to the CAS, mid-gorge and PAS sites of AChE and BuChE suggesting that it will be able to inhibit AChE induced Aβ aggregation. From this study, compounds that 3 and 19 can be considered as promising multifunctional lead compounds.
- Joubert, Jacques,Foka, Germaine B.,Repsold, Benjamin P.,Oliver, Douglas W.,Kapp, Erika,Malan, Sarel F.
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p. 853 - 864
(2016/10/26)
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- New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties
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A number of derivatives of 7-hydroxycoumarins containing aromatic or monoterpene substituents at hydroxy-group were synthesized based on a hit compound from a virtual screen. The ability of these compounds to inhibit tyrosyl-DNA phosphodiesterase I (Tdp 1), important target for anti-cancer therapy, was studied for the first time. It was found that the 7-hydroxycoumarin derivatives with monoterpene pinene moiety are effective inhibitors of Tdp 1 with the most active derivative (+)-25c with IC50value of 0.675?μM. This compound has low cytotoxicity (CC50?>100?μM) when tested against human cancer cells which is crucial for presupposed application in combination with clinically established anticancer drugs. The ability of the new compounds to enhance the cytotoxicity of camptothecin, an established topoisomerase 1 poison, was demonstrated.
- Khomenko, Tatyana,Zakharenko, Alexandra,Odarchenko, Tatyana,Arabshahi, Homayon John,Sannikova, Victoriya,Zakharova, Olga,Korchagina, Dina,Reynisson, Jóhannes,Volcho, Konstantin,Salakhutdinov, Nariman,Lavrik, Olga
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p. 5573 - 5581
(2016/10/24)
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- 4-Methylcoumarins with cytotoxic activity against T24 and RT4 human bladder cancer cell lines
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Bladder cancer is one of the most prevalent malignancies of the genitourinary tract, and approximately 25% of patients develop superficial cancers with invasive and metastatic pathology. Coumarins and their derivatives have antiproliferative activity and
- Vianna,Ruschel,Dietrich,Figueiró,Morrone,Canto,Corvello,Velho,Crestani,Teixeira,Von Poser,Battastini,Eifler-Lima
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p. 905 - 911
(2015/05/27)
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- Bioorthogonal Enzymatic Activation of Caged Compounds
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Engineered cytochrome P450 monooxygenase variants are reported as highly active and selective catalysts for the bioorthogonal uncaging of propargylic and benzylic ether protected substrates, including uncaging in living E. coli. observed selectivity is supported by induced-fit docking and molecular dynamics simulations. This proof-of-principle study points towards the utility of bioorthogonal enzyme/protecting group pairs for applications in the life sciences.
- Ritter, Cornelia,Nett, Nathalie,Acevedo-Rocha, Carlos G.,Lonsdale, Richard,Kr?ling, Katja,Dempwolff, Felix,Hoebenreich, Sabrina,Graumann, Peter L.,Reetz, Manfred T.,Meggers, Eric
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supporting information
p. 13440 - 13443
(2015/11/09)
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- INHIBITORS OF PLASMODIUM FALCIPARUM EQUILIBRATIVE NUCLEOSIDE TRANSPORTER TYPE 1 AS ANTI-PARASITIC COMPOUNDS
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Inhibitors of Plasmodium falciparum equilibrative nucleoside transporter type 1 are identified and methods of use as anti-parasitic compounds are provided.
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Page/Page column 63; 65
(2015/01/16)
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- Synthesis and antioxidant activities of novel 4-Schiff base-7-benzyloxy- coumarin derivatives
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4-Schiff base-7-benzyloxy-coumarins 5a1-5h2 and its derivative 6 were designed and synthesized based on the 7-benzyloxy-coumarin structure as novel antioxidants. The in vitro antioxidant activities screening revealed that 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities of compounds 5b1, 5d1, 5f1, 5f2, 5g1 and 5g2, and 2,2′-azinobis-(3- ethylbenzthiazoline-6-sulfonate) cation (ABTS+) radical scavenging activities of compounds 5a1, 5b1, 5c1, 5c 2, 5d1, 5e1, 5e2, 5f2, 5g1, 5g2 and 5h1 were better than that of the commercial antioxidant butylated hydroxytoluene (BHT), while the superoxide anion radical scavenging activities of 5a2 and 5g2 were stronger than that of the commercial antioxidant butylated hydroxyanisole (BHA), and the hydroxyl radical scavenging activity of 5e1 was much better than that of the common antioxidant ascorbic acid.
- Zhang, Ye,Zou, Biqun,Chen, Zhenfeng,Pan, Yingming,Wang, Hengshan,Liang, Hong,Yi, Xianghui
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experimental part
p. 6811 - 6815
(2011/12/22)
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- Inhibition of monoamine oxidases by functionalized coumarin derivatives: Biological activities, QSARs, and 3D-QSARs
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A large series of coumarin derivatives (71 compounds) were tested for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory activity. Most of the compounds acted preferentially on MAO-B with IC50 values in the micromolar to low-nanomolar range; high inhibitory activities toward MAO-A were also measured for sulfonic acid esters. The most active compound was 7-[(3,4-difluorobenzyl)oxy]-3,4-dimethylcoumarin, with an IC50 value toward MAO-B of 1.14 nM. A QSAR study of 7-X-benzyloxy meta-substituted 3,4-dimethylcoumarin derivatives acting on MAO-B yielded good statistical results (q2 = 0.72, r2 = 0.86), revealing the importance of lipophilic interactions in modulating the inhibition and excluding any dependence on electronic properties. CoMFA was performed on two data sets of MAO-A and MAO-B inhibitors. The GOLPE procedure, with variable selection criteria, was applied to improve the predictivity of the models and to facilitate the graphical interpretation of results.
- Gnerre,Catto,Leonetti,Weber,Carrupt,Altomare,Carotti,Testa
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p. 4747 - 4758
(2007/10/03)
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- Aromatic Benzylation: Part VII - Synthesis of Nuclear Benzylated 2,3-Dimethylchromones and 4-Methylcoumarins
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Reaction of 5,7-dihydroxy-2,3-dimethylchromone (1) with benzyl alcohol in the presence of BF3-Et2O and dioxan gives a mixture of 6-C-benzyl-(4a; ca. 32 percent yield), 8-C-benzyl-(3a; ca. 20 percent) and 6,8-di-C-benzyl-(2a; ca.9 percent) derivatives.A similar reaction of 7-hydroxy-4-methylcoumarin gives a mixture of 6-C-benzyl-(9a; ca. 26.4percent), 7-O-benzyl-(6; ca. 17.6percent), 6,8-di-C-benzyl-(7a; ca. 6.5percent) and 3,8-di-C-benzyl-(8a; ca. 2.4percent) derivatives.
- Jain, A. C.,Kumar, Ajay,Mishra, S. K.
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p. 862 - 865
(2007/10/02)
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