- 1,2,3-Triazole pharmacophore-based benzofused nitrogen/sulfur heterocycles with potential anti-Moraxella catarrhalis activity
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Versatile 1,2,3-triazole pharmacophore-based benzofused heterocycles containing halogen-substituted aromatic (9-17 and 25-28), 7-substituted coumarin (18-23 and 29-30) or penciclovir-like subunit (31a,b-38a) were designed and synthesized to evaluate their
- Mara?i?, Silvija,Kraljevi?, Tatjana Gazivoda,Paljetak, Hana ?ip?i?,Peri?, Mihaela,Matija?i?, Mario,Verbanac, Donatella,Cetina, Mario,Rai?-Mali?, Silvana
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- Highly Selective Sensing of Li+ in H2O/CH3CN via Fluorescence ‘Turn-on’ Response of a Coumarin-Indole Linked Dyad: an Experimental and Theoretical Study
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A coumarin-indole dyad, N-((7-hydroxy-2-oxo-2H-chromen-4-yl)methyl)-1H-indole-2-carboxamide has been synthesized and characterized by 1H-NMR and 13C-NMR. Effect of various metal ions on fluorescent behavior was also studied. The synthesized compound showed remarkable specificity towards Li+ in organo-aqueous medium over other metal ions. Coordination of the compound with Li+ induces a turn-on fluorescence response. The sensor exhibited good binding constant and low detection limit towards Li+. Experimental results have been verified with Density Functional Theory and Time Dependent Density Functional Theory calculations.
- Kumari, Santosh,Joshi, Sunita,Sarmah, Amrit,Pant, Debi,Sakhuja, Rajeev
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- Synthesis and biological evaluation of morpholines linked coumarin–triazole hybrids as anticancer agents
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A series of novel morpholines linked coumarin–triazole hybrids (6a–6v) has been synthesized and evaluated for their anti-proliferative potential on a panel of five human cancer cell lines, namely bone (MG-63), lung (A549), breast (MDA-MB-231), colon (HCT-15) and liver (HepG2), using MTT assay. Among all, the compound 6n {7-((1-(2,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl) methoxy)-4-((2,6-dimethylmorpholino) methyl)-2H-chromen-2-one} showed significant growth inhibition against MG-63 cells with an IC50 value of 0.80 ± 0.22 μM. Further, induction of apoptosis by 6n of MG-63 cells confirmed as a result of morphological changes, the sub-G1 phase arrest, increased percentage of apoptotic cells, and decrease in mitochondrial membrane potential and increase in reactive oxygen species levels. The in vitro Gal-1 expression in cell culture supernatant of MG-63 cells treated with compound 6n showed dose-dependent reduction. The binding constant (Ka) of 6n with Gal-1 was calculated from the intercept value which was observed as 3.0 × 105 M?1 by fluorescence spectroscopy. Surface plasmon resonance showed that 6n binds to Gal-1 with binding constant (Ka) of 1.29E+04 1/Ms and equilibrium constant KD value of 7.54E?07 M, respectively. Molecular docking studies revealed the binding interactions of 6n with Gal-1.
- Goud, Nerella Sridhar,Pooladanda, Venkatesh,Mahammad, Ghouse S.,Jakkula, Pranay,Gatreddi, Santhosh,Qureshi, Insaf A.,Alvala, Ravi,Godugu, Chandraiah,Alvala, Mallika
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- Design, synthesis, and characterization of 7-methoxy-4- (aminomethyl)coumarin as a novel and selective cytochrome P450 2D6 substrate suitable for high-throughput screening
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In this study, a selective substrate for cytochrome P450 2D6 was designed using a small molecule model developed by M. J. De Groot et al. [(1997) Chem. Res. Toxicol. 10, 41-48]. The substrate, 7-methoxy-4- (aminomethyl)coumarin (MAMC), and its putative O-demethylated metabolite 7- hydroxy-4-(aminomethyl)coumarin (HAMC) were synthesized, and their respective fluorescence properties were characterized. The selectivity of MAMC for P450 2D6 was characterized using microsomes containing single human P450 isoenzymes and human liver microsomes. Formation of the metabolic product HAMC was easily assessed in real time with fluorescence spectroscopy, since MAMC and HAMC excitation and emission wavelengths differed significantly. HPLC analysis confirmed that HAMC was the single metabolic product of MAMC and that HAMC formation accounts for the total increase in fluorescence. It was found that, in microsomes from yeast or lymphoblastoid cells selectively expressing P450 isoenzymes, MAMC was selective for P450 2D6 at a concentration of 25 μM with only P450 1A2 contributing significantly to the formation of HAMC. P450s 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4, and 3A5 were shown not to metabolize MAMC at a concentration of 25 μM. K(m) and ν(max) values of MAMC for P450 2D6 were found to be 26.2 ± 2.8 μM and 2.9 ± 0.07 min-1, respectively. For P450 1A2, MAMC was found to have a K(m) value of 29.7 ± 6.2 μM and a ν(max) of 0.57 ± 0.07 min-1. Formation of HAMC in human liver microsomes could be completely inhibited by quinidine, at a concentration of 0.5 μM selective for P450 2D6, and furafylline, at a concentration of 30 μM selective for P450 1A2. In conclusion, O- demethylation of 7-methoxy-4-(aminomethyl)coumarin is a rapid and easily determined parameter for P450 2D6 activity and, due to the fluorescent properties of the metabolite formed, may be a valuable new tool for high- throughput screening purposes.
- Onderwater, Rob C. A.,Venhorst, Jennifer,Commandeur, Jan N. M.,Vermeulen, Nico P. E.
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- Novel chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids as potential antibacterial repressors against methicillin-resistant Staphylococcus aureus
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The increasing resistance of methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics has led to a growing effort to design and synthesize novel structural candidates of chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids with
- Hu, Yuanyuan,Hu, Chunfang,Pan, Guangxing,Yu, Congwei,Ansari, Mohammad Fawad,Yadav Bheemanaboina, Rammohan R.,Cheng, Yu,Zhou, Chenghe,Zhang, Jiaheng
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- Synthesis and biological evaluation of novel 4,7-disubstituted coumarins as selective tumor-associated carbonic anhydrase IX and XII inhibitors
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With an aim to develop novel potential anti-cancer agents we have designed a series of novel 4,7-disubstituted coumarin hybrids synthesis and evaluated for their inhibitory activity against the human carbonic anhydrase isoforms namely CA I, CA II, CA IX and CA XII. The results of CA inhibition clearly showed that the novel 4, 7-disubstituted coumarin hybrids (7a–i & 8a–j) exhibited selective inhibition towards tumor associated isoforms, CA IX and CA XII without inhibiting CA I and CA II isoforms. Among all the compound 8b showed a significant inhibition against hCA IX with a Ki of 0.58 μM whereas, the compound 7c showed a significant inhibition against hCA XII with a Ki of 0.36 μM respectively. All other compounds have shown a good inhibition against hCA IX and hCA XII over hCA I and hCA II within the range of 0.46 to 9.35 μM. Therefore, compound 8b and 7c would be the potential leads for developing selective cytotoxic agents targeting hCA IX and XII.
- Chandra, K. Muni,Goud, Nerella Sridhar,Arifuddin, Mohammed,Alvala, Mallika,Alvala, Ravi,Angeli, Andrea,Supuran, Claudiu T.
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- Synthesis, 18F-radiolabeling and apoptosis inducing studies of novel 4, 7-disubstituted coumarins
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In present study, a new series of 4, 7-disubstituted coumarin derivatives (7a-y) have been synthesized as galectin-1 targeting apoptosis inducing agents and evaluated for their in vitro cytotoxic potentials against a panel of selected human cancer cell lines namely, Brest (MCF7), Ovarian (SKOV3), Prostate (PC-3 & DU145) and normal embryonic kidney (HEK293T) cells, using MTT assay. Most of the compounds exhibited potent growth inhibitory action against the treated cancer cell lines with an IC50 range of 10–30 μM. Compound 7q exhibited a significant growth inhibition against prostate cancer (PC-3 & DU145) cell lines with an IC50 value of 7.45 ± 0.03 μM, 8.95 ± 0.17 μM respectively. Further, the target compound 7q was radiolabeled with fluorine-18 [18F] to be used as a novel PET radiotracer for imaging of tumors via targeting galectin-1, using appropriate reaction conditions in the GE Tracer-lab FX2N synthesis module. The purification of the [18F] radiolabeled compound [18F]-7q was successfully achieved with 60% ethanol. The radiochemical purity was>85% and residual solvent limits of DMF was 65 ± 3 ppm as analysed by HPLC, TLC & GC analytical methods. The apoptosis studies confirm the inhibition of cell proliferation with morphological changes like cell shrinkage, blebbing and cell wall deformation, increasing the ROS levels, and loss of mitochondrial membrane potential by Acridine orange/Ethidium bromide staining, Hoechst-33342 staining, H2DCFDA staining, annexin V-FITC/PI, and JC-1 staining methods. In flow cytometric analysis, 7q selectively arrested the sub-G1 phase of the cell cycle in a dose-dependent manner. In Gal-1 ELISA studies, compound 7q efficiently reduced the levels of Gal-1 protein in dose-dependent manner with an IC50 value of 100 μM. The binding constant (Ka) of 7q with Gal-1 was observed as 1.3 × 104 M?1 by fluorescence spectroscopy. The molecular docking studies clearly showed possible interactions and the pharmacokinetic (ADMET) properties of compound 7q with Gal-1. Hence, the novel 4, 7-disubstituted coumarins could be a potential cytotoxic and PET imaging agents via Gal-1.
- Alvala, Mallika,Alvala, Ravi,Bharath, Rose Dawn,Goud, Nerella Sridhar,Kanth Makani, Venkata Krishna,Kumar, Pardeep,Nagaraj, Chandana,Pal-Bhadra, Manika,Pranay, Jakkula,Qureshi, Insaf A.,Yerramsetty, Suresh
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- β-Cyclodextrin included coumarin derivatives as selective fluorescent sensors for Cu2+ ions in HeLa cells
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A highly sensitive and selective fluorescent sensor for Cu2+ ions in water medium is reported using 4-((benzo[d]thiazol-2-ylthio)methyl)-5,7-dihydroxy-2H-chromen-2-one (1) included β-cyclodextrin, as a probe. The fluorogenic supramolecule has displayed good selectivity and affinity towards Cu2+ ions over other cations after examining in biological systems with intracellular Cu2+ ions, especially in cultured HeLa cells using fluorescence microscopic imaging. The lowest detection limit of Cu2+ ions observed using this probe is as low as 2.52 × 10-10 M. The observed on-off fluorescence with the periodic addition of Cu2+ ion is explained via an Intramolecular Charge Transfer mechanism (ICT) and the inclusion of 1 in β-cyclodextrin is characterised by 1H-NMR molecular modeling studies. The results show that the present β-CD:1 system, studied in HeLa cells, can be potentially used in monitoring the biological functions of Cu2+ ions.
- Khan, Raihana Imran,Pitchumani, Kasi
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- B(C6F5)3-catalyzed synthesis of coumarins via Pechmann condensation under solvent-free conditions
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Tris(pentafluorophenyl)borane [B(C6F5)3] catalyzed simple, efficient and environmentally benign protocol has been developed for the Pechmann condensation using variety of phenols and β-ketoesters under solvent-free conditions to afford coumarin derivatives. The present protocol displayed significant advantages such as low catalyst loading, short reaction time, mild reaction conditions, low toxicity, easy work-up, high yields, and compatibility with other functional groups. In addition, it is a convenient, clean, and fast alternative approach for synthesizing variety of coumarin derivatives. Moreover, the applicability of this method towards large-scale synthesis demonstrated its suitability for the industrial application. Graphic abstract: [Figure not available: see fulltext.]
- Prajapti, Santosh Kumar,Rao, S. Prakash
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p. 469 - 473
(2021/03/26)
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- Synthesis of C4-substituted coumarins via Pechmann condensation catalyzed by sulfamic acid. Insights into the reaction mechanism by HRMS analysis
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A series of functionalized C4-substituted coumarins were synthesized by exploring the reaction of activated and non-activated phenols and β-ketoesters under solvent-free conditions in the presence of sulfamic acid as a Br?nsted acid catalyst. Fifteen exam
- Moraes, Maiara C.,Lenard?o, Eder J.,Barcellos, Thiago
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p. 151 - 163
(2022/01/28)
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- Design, synthesis and biological evaluation of potential anti-AD hybrids with monoamine oxidase B inhibitory and iron-chelating effects
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A series of active hybrids combining 3-hydroxypyridin-4(1H)-one and coumarin pharmacophores were designed and synthesized as potential agents for the treatment of Alzheimer's disease (AD). All the compounds exhibited excellent iron-chelating activities (p
- Guo, Jianan,Mi, Zhisheng,Jiang, Xiaoying,Zhang, Changjun,Guo, Zili,Li, Linzi,Gu, Jinping,Zhou, Tao,Bai, Renren,Xie, Yuanyuan
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- Design and synthesis of pyrimidine-5-carbonitrile hybrids as COX-2 inhibitors: Anti-inflammatory activity, ulcerogenic liability, histopathological and docking studies
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Two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold have been synthesized and evaluated for their COX-1/COX-2 inhibitory activity. Compounds 10c, 10e, 10h-j, 14e-f, 14i and 16 were found to be the most potent and selective inhibitors of COX-2 (IC50 0.041–0.081 μM, SI 139.74–321.95). Eight compounds were further investigated for their in vivo anti-inflammatory activity. The most active derivatives 10c, 10j and 14e displayed superior in vivo anti-inflammatory activity (% edema inhibition 39.3–48.3, 1 h; 58.4–60.5, 2 h; 70.8–83.2, 3 h; 78.9–89.5, 4 h) to the reference drug celecoxib (% edema inhibition 38.0, 1 h; 48.8, 2 h; 58.4, 3 h; 65.4, 4 h). These derivatives were also tested for their ulcerogenic liability, compound 10j showed better safety profile with reference to celecoxib while 10c and 14e exhibited mild lesions. Molecular docking studies of 10c, 10j, and 14e in the COX-2 active site revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to access the selectivity side pocket.
- Alfayomy, Abdallah M.,Abdel-Aziz, Salah A.,Marzouk, Adel A.,Shaykoon, Montaser Sh. A.,Narumi, Atsushi,Konno, Hiroyuki,Abou-Seri, Sahar M.,Ragab, Fatma A.F.
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- Compound with glucose-reducing and lipid-regulating effects as well as preparation and application thereof
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The invention discloses a compound with glucose-reducing and lipid-regulating effects as well as a preparation and application thereof. The compound with glucose-reducing and lipid-regulating effectsis a compound with structures as shown in a formula I and a formula II and a pharmaceutically acceptable salt, wherein the structures as shown in the formula I and the formula II are specifically shown in the specification. The preparation is a tablet, a capsule, powder, a pill or an injection prepared by adding pharmaceutically acceptable auxiliary materials into the compound with the glucose-reducing and lipid-regulating effects. The application is the application of the compound with the glucose-reducing and lipid-regulating effects in preparing an FFA1/PPARdelta dual agonist. The application is the application of the compound with the glucose-reducing and lipid-regulating effects in preparation of drugs for preventing and/or treating glucose metabolic disorder and/or lipid metabolic disorder diseases. The compound and the medicinal salt thereof can be potentially used for treating or preventing diabetes, hyperlipidemia, fatty liver and other related metabolic syndromes, and have wide development prospects.
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Paragraph 0017
(2021/03/13)
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- Amino Acids Bearing Aromatic or Heteroaromatic Substituents as a New Class of Ligands for the Lysosomal Sialic Acid Transporter Sialin
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Sialin, encoded by the SLC17A5 gene, is a lysosomal sialic acid transporter defective in Salla disease, a rare inherited leukodystrophy. It also enables metabolic incorporation of exogenous sialic acids, leading to autoantibodies against N-glycolylneuraminic acid in humans. Here, we identified a novel class of human sialin ligands by virtual screening and structure-activity relationship studies. The ligand scaffold is characterized by an amino acid backbone with a free carboxylate, an N-linked aromatic or heteroaromatic substituent, and a hydrophobic side chain. The most potent compound, 45 (LSP12-3129), inhibited N-acetylneuraminic acid 1 (Neu5Ac) transport in a non-competitive manner with IC50 ≈ 2.5 μM, a value 400-fold lower than the KM for Neu5Ac. In vitro and molecular docking studies attributed the non-competitive character to selective inhibitor binding to the Neu5Ac site in a cytosol-facing conformation. Moreover, compound 45 rescued the trafficking defect of the pathogenic mutant (R39C) causing Salla disease. This new class of cell-permeant inhibitors provides tools to investigate the physiological roles of sialin and help develop pharmacological chaperones for Salla disease.
- Dubois, Lilian,Pietrancosta, Nicolas,Cabaye, Alexandre,Fanget, Isabelle,Debacker, Cécile,Gilormini, Pierre-André,Dansette, Patrick M.,Dairou, Julien,Biot, Christophe,Froissart, Roseline,Goupil-Lamy, Anne,Bertrand, Hugues-Olivier,Acher, Francine C.,Mccort-Tranchepain, Isabelle,Gasnier, Bruno,Anne, Christine
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supporting information
p. 8231 - 8249
(2020/09/21)
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- Synthesis and biological evaluation of some coumarin hybrids as selective carbonic anhydrase IX and XII inhibitors
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Two series, coumarin-linked to thiazolidinone via a pyrazole linker (6a-m, Series 1) and coumarin-linked 1,2,3-triazoles (5a-j, Series 2) were synthesized and the synthesized compounds were subjected for evaluation against the four physiologically and pha
- Alvala, Mallika,Angeli, Andrea,Argulwar, Omkar S.,Arifuddin, Mohammed,Soman, Jyothsna,Sridhar Goud, Nerella,Supuran, Claudiu T.,Thacker, Pavitra S.
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- Preparation method and application of N-(pyrimidine-2-yl) coumarin-7-amine derivative as protein kinase inhibitor
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The invention discloses a cyclin-dependent kinase inhibitor. The cyclin-dependent kinase inhibitor comprises an N-(pyrimidine-2-yl) coumarin-7-amine derivative shown as a general formula (I). In-vitropharmacodynamic tests prove that the compound has a high-selectivity inhibition effect on CDK9 kinase, and can be applied to reducing or inhibiting the activity of CDK9 kinase in cells. The inventionalso discloses a preparation method of the inhibitor and application of the inhibitor in drugs for CDK family kinase mediated diseases, especially hyperproliferative diseases, virus-induced infectious diseases and cardiovascular diseases.
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Paragraph 0244; 0247-0249
(2020/12/14)
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- The biothiol-triggered organotrisulfide-based self-immolative fluorogenic donors of hydrogen sulfide enable lysosomal trafficking
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Biothiol-reactive organotrisulfide-based self-immolative fluorogenic donors of H2S are rationally designed for the efficient monitoring of intracellular and lysosomal trafficking of H2S with a concomitant turn-on fluorescence. The non-toxic nature of the donors with a sustained release of H2S will certainly be helpful for their biomedical applications in the future.
- Mahato, Sulendar K.,Bhattacherjee, Debojit,Bhabak, Krishna P.
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supporting information
p. 7769 - 7772
(2020/07/27)
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- Ethylenic conjugated coumarin thiazolidinediones as new efficient antimicrobial modulators against clinical methicillin-resistant Staphylococcus aureus
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In an effort for the development of novel antimicrobial agents, ethylenic conjugated coumarin thiazolidinediones as potential multi-targeting new antimicrobial compounds were synthesized through convenient procedures from commercially available resorcinol and were evaluated for their antimicrobial potency. Bioactive evaluation revealed that some of the prepared compounds showed strong antimicrobial activities towards the tested microorganisms including clinically drug-resistant strains. Especially, propargyl derivative 12b exhibited effective anti-MRSA potency with MIC value of 0.006 μmol/mL, which was highly advantageous over clinical antibacterial drug norfloxacin. Compound 12b showed rapid killing effect, low toxicity against hepatocyte LO2 cell line, and no obvious drug resistance development against MRSA. Preliminary exploration of action mechanism manifested that molecule 12b acted upon MRSA through forming stable supramolecular complex with bacterial DNA which might impede DNA replication. Molecular docking showed that compound 12b could bind with DNA-gyrase through hydrogen bonds.
- Hu, Chun-Fang,Zhang, Peng-Li,Sui, Yan-Fei,Lv, Jing-Song,Ansari, Mohammad Fawad,Battini, Narsaiah,Li, Shuo,Zhou, Cheng-He,Geng, Rong-Xia
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- Coumarin-Caged Compounds of 1-Naphthaleneacetic Acid as Light-Responsive Controlled-Release Plant Root Stimulators
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Six coumarin-caged compounds of 1-naphthaleneacetic acid (NAA) comprising different substituents on the coumarin moiety were synthesized and evaluated for their photophysical and chemical properties as light-responsive controlled-release plant root stimulators. The 1H NMR and HPLC techniques were used to verify the release of NAA from the caged compounds. After irradiation at 365 nm, the caged compounds exhibited the fastest release rate at t1/2 of 6.7 days and the slowest release rate at t1/2 of 73.7 days. Caged compounds at high concentrations (10-5 and 10-6 M) significantly stimulate secondary root germination while free NAA at the same level is toxic and leads to inhibition of secondary root germination. The cytotoxicity of the caged compounds against fibroblasts and vero cells were evaluated, and the results suggested that, at 10-5-10-6 M, caged compounds exhibited no significant cytotoxicity to the cells. Thus, the caged compounds of NAA in this study could be of great benefit as efficient agrochemicals.
- Han, Bao-Hang,Jarussophon, Suwatchai,Kaewchangwat, Narongpol,Niamnont, Nakorn,Prateepchinda, Sagaw,Suttisintong, Khomson,Thanayupong, Eknarin,Unger, Onuma,Yata, Teerapong
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p. 6268 - 6279
(2020/07/31)
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- GPR40 receptor stimulant, and preparation method, pharmaceutical composition and application thereof
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The invention discloses a GPR40 receptor stimulant, and a preparation method, a pharmaceutical composition and application thereof. The invention particularly discloses a GPR40 receptor stimulant shown in general formula (I) and pharmacologically acceptable salt thereof, a preparation process of the compound, a pharmaceutical composition containing the compound of general formula (I), and application of the compound and the pharmaceutical composition in anti-diabetes.
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Paragraph 0163; 0199-0202
(2019/10/15)
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- Theoretical and experimental investigation of NMR, IR and UV-visible spectra of hydroxyl-substituted-4-chloromethylcoumarin derivatives
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UV-Visible, FTIR and NMR experimental and theoretical spectral results have been compared for five substituted-4-chloromethylcoumarin derivatives (6-OH, 7-OH, 6,7-di-OH, 7,8-di-OH and 5,7-di-OH-substituted-4-chloromethylcoumarins). The theoretical investigation was conducted using density functional theory (DFT), namely the M06-2X functional form with 6-311+G(2df,2p) basis set. The 13C-NMR and 1H-NMR chemical shifts, vibrational spectra and molecular orbitals of the excited states were calculated based on their optimized geometries. The calculated values were found to have close agreement with the experimental values. The theoretical data are useful and could be important in the proper selection of compounds as intermediates for different chemical applications and modifications.
- Loarueng, Chutipapha,Boekfa, Bundet,Jarussophon, Suwatchai,Pongwan, Pawinee,Kaewchangwat, Narongpol,Suttisintong, Khomson,Jarussophon, Nongpanga
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p. 116 - 127
(2019/11/11)
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- The Fragment-Based Development of a Benzofuran Hit as a New Class of Escherichia coli DsbA Inhibitors
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A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli (EcDsbA). This enzyme is critical for the correct folding of virulence factors in many pathogenic Gram-negative bacteria, and small molecule inhibitors can potentially be developed as anti-virulence compounds. Biophysical screening of a library of fragments identified several classes of fragments with affinity to EcDsbA. One hit with high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid (6), was chemically elaborated at several positions around the scaffold. X-ray crystal structures of the elaborated analogues showed binding in the hydrophobic binding groove adjacent to the catalytic disulfide bond of EcDsbA. Binding affinity was calculated based on NMR studies and compounds 25 and 28 were identified as the highest affinity binders with dissociation constants (KD) of 326 ± 25 and 341 ± 57 μM respectively. This work suggests the potential to develop benzofuran fragments into a novel class of EcDsbA inhibitors.
- Duncan, Luke F.,Wang, Geqing,Ilyichova, Olga V.,Scanlon, Martin J.,Heras, Bego?a,Abbott, Belinda M.
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- Design, synthesis and application of multichannel fluorescent probe for differentiating and detecting Cys/Hcy, GSH and H2S simultaneously
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The invention relates to a preparation method of a multichannel fluorescent probe for differentiating and detecting Cys/Hcy, GSH and H2S simultaneously and an application of the fluorescent probe in detecting Cys/Hcy, GSH and H2S in vitro and in living ce
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Paragraph 0026-0032
(2019/04/27)
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- Design, synthesis, and mechanism of dihydroartemisinin-coumarin hybrids as potential anti-neuroinflammatory agents
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Cancer patients frequently suffer from cancer-related fatigue (CRF), which is a complex syndrome associated with weakness and depressed mood. Neuroinflammation is one of the major inducers of CRF. The aim of this study is to find a potential agent not only on the treatment of cancer, but also for reducing CRF level of cancer patients. In this study, total-thirty new Dihydroartemisinin-Coumarin hybrids (DCH) were designed and synthesized. The in vitro cytotoxicity against cancer cell lines (HT-29, MDA-MB-231, HCT-116, and A549) was evaluated. Simultaneously, we also tested the anti-neuroinflammatory activity of DCH. DCH could inhibit the activated microglia N9 release of NO, TNF-α, and IL-6. The docking analysis was shown that MD-2, the coreceptor of TLR4, might be one of the targets of DCH.
- Yu, Haonan,Hou, Zhuang,Yang, Xiaoguang,Mou, Yanhua,Guo, Chun
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- Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones
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A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC50 against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes.
- Rullo, Mariagrazia,Catto, Marco,Carrieri, Antonio,de Candia, Modesto,Altomare, Cosimo Damiano,Pisani, Leonardo
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- A sequential enzyme-activated and light-triggered pro-prodrug nanosystem for cancer detection and therapy
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DT-diaphorase is a cytosolic flavoenzyme whose level is strongly elevated in a number of tumor types. Incorporating a DT-diaphorase's substrate in the structure of anticancer drugs may facilitate cancer detection and therapy. Herein, we developed a novel pro-prodrug nanosystem for cancer detection and therapy, which features enzyme-activated fluorescence emission and subsequent light-triggered drug release. The pro-prodrug molecule comprises an anticancer drug methotrexate (MTX), an enzyme (DT-diaphorase) responsive quinone propionic acid moiety and a light-activatable coumarinyl. In the absence of DT-diaphorase, the quinone propionic acid moiety quenches the fluorescence of coumarin via photoinduced electron transfer (PET) and blocks the photocleavage pathway. DT-diaphorase can annihilate the effect of PET and restore the fluorescence of coumarin. This fluorescence serves as the reporting signal for assessing the enzyme biomarker level and discriminates tumor cells from normal cells, and subsequently photocontrollable release of the active drug, MTX, can be activated via one- or two-photon irradiation. This pro-prodrug nanosystem shows strong cytotoxicity toward cancer cells and a negligible effect on normal cells. This strategy provides a new platform for constructing nanosystems for cancer detection and subsequent on-demand selective killing of cancer cells via both internal- and external-stimuli activation.
- Chen, Zelin,Li, Bowen,Xie, Xin,Zeng, Fang,Wu, Shuizhu
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p. 2547 - 2556
(2018/05/22)
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- A highly selective and sensitive fluorescent probe for simultaneously distinguishing and sequentially detecting H2S and various thiol species in solution and in live cells
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A novel dual-channel fluorescent probe (NCR) based on differences in reactivity among H2S, Cys/Hcy, and GSH was rationally designed for simultaneously distinguishing and sequentially sensing H2S, Cys/Hcy, and GSH using two emission channels, which also demonstrated that NCR can be used for targeting mitochondria in mammalian cells.
- Qiao, Dan,Shen, Tangliang,Zhu, Mengyuan,Liang, Xiao,Zhang, Lu,Yin, Zheng,Wang, Binghe,Shang, Luqing
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supporting information
p. 13252 - 13255
(2018/12/11)
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- Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings
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A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different β-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC50 = 1.2 μM, cLogP = 1.3; TAK-875: EC50 = 5.1 μM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.
- Sun, Zhaozhu,Zhou, Tian,Pan, Xuan,Yang, Ying,Huan, Yi,Xiao, Zhiyan,Shen, Zhufang,Liu, Zhanzhu
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supporting information
p. 3050 - 3056
(2018/08/11)
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- Practical and Scalable Synthesis of 7-Azetidin-1-yl-4-(hydroxymethyl)coumarin: An Improved Photoremovable Group
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7-Substituted 4-methylcoumarin derivatives are widely employed as photoprotecting groups in chemistry and biology. We have recently shown that the 7-azetidinylated version of this photocage releases carboxylic acids in aqueous solution more efficiently than the traditionally used 7-diethylamino variant. Here we present a robust and scalable route to prepare the 7-azetidinylated alcohol, a useful precursor for the photoprotection of a variety of leaving groups, and its use in the preparation of model phosphate, sulfonate, and carbamate derivatives.
- Bassolino, Giovanni,Halabi, Elias A.,Rivera-Fuentes, Pablo
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supporting information
p. 846 - 852
(2017/12/28)
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- Biphenyl heterocyclic derivatives, their preparation and their use as medicaments (by machine translation)
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The present invention relates to a novel biphenyl heterocyclic derivative represented by a general formula (I) and a preparation method thereof and use of a pharmaceutical composition containing the derivative for preparation of a drug for treating diabetes. The biphenyl heterocyclic derivative has extremely excellent hypoglycemic activity in vivo, and excellent in vivo safety and low liver toxicity risk of the compound having such a structure are unexpectedly found, and the novel biphenyl heterocyclic derivative may be used for preventing or treating diabetes.
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Paragraph 0077-0080
(2018/06/21)
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- Preparation of a novel, efficient, and recyclable magnetic catalyst, γ-Fe2O3@HAp-Ag nanoparticles, and a solvent- and halogen-free protocol for the synthesis of coumarin derivatives
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In this protocol, Ag supported on the hydroxyapatite-core–shell magnetic γ-Fe2O3nanoparticles (γ-Fe2O3@HAp-Ag NPs) as a novel, efficient, and magnetically recyclable catalyst is synthesized, and characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and vibrating sample magnetometry (VSM). The use of the catalyst is described in the synthesis of coumarin derivatives by the Pechmann condensation of various phenols with β-ketoesters under solvent- and halogen-free conditions at 80?°C. This novel and inexpensive method offers advantages, such as recyclability simple experimental protocol, short reaction time, minimal work-up procedure, and excellent yields of products, together with desirable, eco-friendly, green aspects by avoiding toxic elements and solvents, and ease of recovery from the reaction mixture using an external magnet.
- Abbasi, Zahra,Rezayati, Sobhan,Bagheri, Maryam,Hajinasiri, Rahimeh
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- Nanosilica molybdic acid: synthesis, characterization and application as a green and reusable catalyst for the Pechmann condensation
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Abstract: Nanosilica molybdic acid (SMA NPs) was founded as an efficient and recyclable nanocatalyst for the synthesis of coumarin derivatives in excellent yields with good purity. Nano-SMA as a new solid acid was characterized by X-ray fluorescence, X-ray diffraction, energy-dispersive X-ray analyzer, transmission electron microscopy and Fourier transform infrared spectroscopy. Coumarin derivatives were obtained via the Pechmann condensation reaction of phenols and β-ketoesters at 80?°C under solvent-free conditions. The main advantages of the present procedure are high yields, shorter reaction time and green chemistry procedure, simple work-up and inexpensive and reusability of the catalyst. Graphical Abstract: [Figure not available: see fulltext.]
- Kiani, Mahtab,Karami, Bahador
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p. 655 - 663
(2017/01/17)
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- Coumarin esterified derivative with effect of inhibiting transcriptional activity of RXRalpha (Retinoid X Receptor) as well as preparation method and application of coumarin esterified derivative
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The invention discloses a coumarin esterified derivative with an effect of inhibiting transcriptional activity of RXRalpha (Retinoid X Receptor) as well as a preparation method and application of the coumarin esterified derivative. The coumarin esterified derivative is a 4-chloromethyl-7-hydroxy coumarin esterified derivative shown by the following general formula. The invention also discloses a preparation method of the 4-chloromethyl-7-hydroxy coumarin esterified derivatives. The preparation method comprises the following steps: preparing 4-chloromethyl-7-hydroxy coumarin under solvent-free conditions by taking anhydrous bismuth chloride as a catalyst; preparing corresponding acyl chloride through different side chain acids; and reacting with the 4-chloromethyl-7-hydroxy coumarin, thereby obtaining the corresponding compound. The coumarin esterified derivative disclosed by the invention has a certain effect of inhibiting the transcriptional activity of RXRalpha and provides a thought for developing medicines taking the RXRalpha as a target. The structural formula is as shown in the specification.
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Paragraph 0019; 0031; 0032; 0033; 0034
(2017/09/26)
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- Psoralen amine derivatives and use
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The invention relates to psoralen amine derivatives and use. The psoralen amine derivatives 4 (4a-4t) are finally obtained through the steps: firstly, subjecting resorcinol, which serves as a starting raw material, to condensation with ethyl chloroacetoacetate in the presence of sulfuric acid, so as to obtain 4-chloromethyl-7-hydroxy coumarin (an intermediate 1); then, subjecting the intermediate 1 to a reaction with five different kinds of secondary amines, so as to obtain 4-substituted amido methyl-7-hydroxy coumarin 2 (intermediates 2a-2e); then, introducing four different kinds of side chains to 7-bit of intermediates 2, so as to obtain intermediates 3 (3a-3t); and finally, subjecting the intermediates 3 to ring closing in an ethanol solution of potassium hydroxide to form psoralen. Proven by action tests on mouse B16 cell melanogenesis and tyrosinase activity are carried out by using 20 obtained psoralen amine derivatives, compounds 4c-4h, 4j-4p and 4s-4t, i.e., 15 psoralen amine derivatives in all are applied to the clinical preparation of drugs for treating vitiligo.
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Paragraph 0087; 0088
(2017/11/16)
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- Synthesis of 4-aryl-1,2,3-triazolyl appended natural coumarin-related compounds with antiproliferative and radical scavenging activities and intracellular ROS production modification
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Novel natural coumarin-based umbelliferone, herniarin and esculetin series linked to hydroxy- and methoxy-substituted and non-substituted phenyl rings through a 1,2,3-triazole spacer were provided by environmentally friendly click chemistry under microwave irradiation. The antioxidative activity of the compounds was evaluated by DPPH-scavenging activity and cyclic voltammetry assays. While adjacent 6- and 7-hydroxyl groups in coumarins made a major contribution to antioxidative power and a decrease of ROS production relative to esculetin, a p-methoxy-substituted phenyl moiety had an impact on pronounced and selective antiproliferative activity against chronic leukemia cells in blast crisis (K562) with no significant change in the ROS generation. 6,7-Dihydroxycoumarin can be considered as a promising scaffold with a major contribution to antioxidant potential and, thereby, further structural modification of 6,7-dihydroxycoumarin linked to aryl-1,2,3-triazole may provide a hybrid molecule that may be of interest for potential application to prevent diseases related to the oxidative-stress imbalance.
- Bistrovi?,Stipani?ev,Opa?ak-Bernardi,Juki?,Martinez,Glava?-Obrovac, Lj,Rai?-Mali?
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p. 7531 - 7543
(2017/08/02)
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- BIO-INSPIRED AND ANTIMICROBIAL POLYMERS CONTAINING AMINO ACID-LIKE MONOMER BUILDING BLOCKS
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Methods for killing a microbial are provided that include introducing a functionalized amide polymer to a microbe, where the functionalized amide polymer includes a polymer backbone selected from polyesters and polyurethanes; an amide group with a pendant functional group, where the nitrogen atom of the amide group is part of the polymer backbone; and a net positive charge.
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Paragraph 0080
(2017/07/14)
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- Magnetic nanoparticles functionalized ethane sulfonic acid (MNESA): as an efficient catalyst in the synthesis of coumarin derivatives using Pechmann condensation under mild condition
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This paper reports an efficient heterogeneous catalyst based on sulfonic acid functionalization of magnetic nanoparticles. This new catalyst was prepared using the reaction between magnetic nanoparticles and sodium 2-bromoethane-1-sulfonate. Magnetic nanoparticles functionalized ethane sulfonic acid (MNESA) was found as efficient catalyst for the synthesis of coumarin derivatives using Pechmann condensation under mild condition. This reaction was catalyzed by MNESA under solvent-free condition at 90?°C, to give the corresponding products in excellent yields. The catalyst is easily separated from the reaction condition and can be reused for several times with consistence in the activity.
- Samadizadeh, Marjaneh,Nouri, Saeed,Kiani Moghadam, Faeze
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p. 6089 - 6103
(2016/06/01)
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- Ion-mediated single-molecular optical switching and sensing based on the fluorophore-tethered calix[4]pyrrole
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The design and synthesis of the first asymmetrically "two-walled" meso-substituted calix[4]pyrrole tethered by a fluorophore and its subsequent implication as an archetype sequential 'on-off-on-off' fluorescent single-molecular switch are reported. The cu
- Sareen, Divya,Lee, Ji Hye,Hwang, Hyonseok,Yoo, Soeun,Lee, Chang-Hee
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supporting information
p. 5852 - 5855
(2016/05/19)
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- Galactose-decorated light-responsive hydrogelator precursors for selectively killing cancer cells
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A multi-functional gelator precursor with high photosensitivity is rationally designed, which can not only selectively target hepatocellular carcinoma (HCC) cells, but also form intracellular self-assembly triggered by light and subsequently inducing cell
- Ji, Wei,Liu, Guofeng,Wang, Fang,Zhu, Zhu,Feng, Chuanliang
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supporting information
p. 12574 - 12577
(2016/10/31)
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- Aromatic polycyclic carboxylic acid derivatives
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The invention belongs to the field of medicine technology, and specifically relates to an aromatic polycyclic carboxylic acid derivative GPR40 receptor agonist with a general formula (I), a pharmaceutically acceptable salt thereof, and an ester or stereoi
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Paragraph 0289; 0290; 0291
(2016/10/17)
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- Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors: synthesis, molecular docking and anticonvulsant studies
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Among many others, coumarin derivatives are known to show human carbonic anhydrase (hCA) inhibitory activity. Since hCA inhibition is one of the underlying mechanisms that account for the activities of some antiepileptic drugs (AEDs), hCA inhibitors are expected to have anti-seizure properties. There are also several studies reporting compounds with an imidazole and/or benzimidazole moiety which exert these pharmacological properties. In this study, we prepared fifteen novel coumarin-bearing imidazolium and benzimidazolium chloride, nine novel benzoxazinone-bearing imidazolium and benzimidazolium chloride derivatives and evaluated their hCA inhibitory activities and along with fourteen previously synthesized derivatives we scanned their anticonvulsant effects. As all compounds inhibited purified hCA isoforms I and II, some of them also proved protective against Maximal electroshock seizure (MES) and ScMet induced seizures in mice. Molecular docking studies with selected coumarin derivatives have revealed that these compounds bind to the active pocket of the enzyme in a similar fashion to that previously described for coumarin derivatives.
- Karata?, Mert Olgun,Uslu, Harun,Sar?, Suat,Alag?z, Mehmet Abdullah,Karakurt, Arzu,Al?c?, Bülent,Bilen, Cigdem,Yavuz, Emre,Gencer, Nahit,Arslan, Oktay
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p. 760 - 772
(2016/07/07)
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- Novel oxime ether derivative and preparation method thereof and application of derivative by serving as drug
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The invention relates to a novel oxime ether derivative shown as a general formula (I) (please see the formula in the description) and a preparation method thereof and application of a pharmaceutical composition containing the derivative in preparation of a drug for treating diabetes and a metabolic syndrome. The oxime ether derivative has the excellent in-vivo hypoglycemic activity and can be used for preventing or treating the diabetes.
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Paragraph 0092; 0094; 0095
(2016/10/08)
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- Gastroprotective activity of synthetic coumarins: Role of endogenous prostaglandins, nitric oxide, non-protein sulfhydryls and vanilloid receptors
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Natural or synthetic coumarins showed gastroprotective and antiulcer activity in animal models. In this study, we have synthetized twenty coumarins using classic methods to evaluate their gastroprotective effects on the ethanol/HCl-induced gastric lesion model in mice at 20?mg/kg. Among the coumarins synthetized, compounds 6 and 10 showed the greatest gastroprotective activity being as active as lansoprazole at 20?mg/kg and reducing gastric lesions by 75 and 76%, respectively. Then, in a second experiment, compounds 6 and 10 were re-evaluated in order to understand the possible mode of gastroprotective activity. Regarding coumarin 6, the protective effect was reduced by pre-treatment of the mice with N-ethylmaleimide and l-NAME suggesting that sulfhydryl compounds and endogenous nitric oxide are involved in its gastroprotective activity. While for coumarin 10 the effect was reduced by pre-treatment with indomethacin suggesting that prostaglandins are positively involved in its gastroprotective activity.
- Sepulveda, Beatriz,Quispe, Cristina,Simirgiotis, Mario,Torres-Benítez, Alfredo,Reyes-Ortíz, Johanna,Areche, Carlos,García-Beltrán, Olimpo
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supporting information
p. 5732 - 5735
(2016/11/25)
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- Novel nitrogen-containing heterocyclic derivative and preparation method thereof and application of derivative by serving as drug
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The invention relates to a novel nitrogen-containing heterocyclic derivative shown as a general formula (I) (please see the formula in the description) and a preparation method thereof and application of a pharmaceutical composition containing the derivative in preparation of a drug for treating diabetes and a metabolic syndrome. The nitrogen-containing heterocyclic derivative has the excellent in-vivo hypoglycemic activity and can be used for preventing or treating the diabetes.
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Paragraph 0081-0085
(2017/02/24)
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- Benzouracil-coumarin-arene conjugates as inhibiting agents for chikungunya virus
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Chikungunya virus (CHIKV) is an arbovirus that was first recognized in an epidemic form in East Africa in 1952-1953. The virus is primarily transmitted through mosquitoes and the resulting disease, chikungunya fever, is found in nearly 40 countries. Neith
- Hwu, Jih Ru,Kapoor, Mohit,Tsay, Shwu-Chen,Lin, Chun-Cheng,Hwang, Kuo Chu,Horng, Jia-Cherng,Chen, I-Chia,Shieh, Fa-Kuen,Leyssen, Pieter,Neyts, Johan
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p. 103 - 109
(2015/04/22)
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- PROCESS AND INTERMEDIATES FOR PREPARING GPR40 AGONISTS
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The present invention relates to compounds of formula I wherein RS denotes F or CF3, Ra denotes H or C1-4-alkyl and Z denotes a leaving group or an optionally substituted or protected hydroxyl group, suitable as
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Paragraph 0239
(2015/03/31)
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- PROCESS AND INTERMEDIATES FOR PREPARING INDANYLOXYDIHYDROBENZOFURANYL ACETIC ACID DERIVATIVES AS GPR40 AGONISTS
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The present invention relates to compounds of formula (I) werein Rs denotes F or CF3, Ra denotes H or C1-4-alkyl and Z denotes a leaving group or an optionally substituted or protected hydroxyl group, suitable a
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Page/Page column 63
(2015/04/15)
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- Synthesis of the coumarins via pechmann method in the presence of environmentally friendly Y(NO3)3×6H2O
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Several substituted coumarins can be prepared in high yield and purity by direct reaction of β-keto esters and phenol derivatives in the presence of a catalytic amount Y(NO3)3×6H2O as Lewis acid and at ambient temperature under solvent-free conditions. Several substituted coumarins can be prepared in high yield and purity by direct reaction of β-keto esters and phenol derivatives in the presence of a catalytic amount Y(NO3)3×6H2O as Lewis acid and at ambient temperature under solvent-free conditions. This method that is based on Pechmann condensation is very easy and rapid reaction for the synthesis of coumarin derivatives. Copyright
- Karami, Bahador,Kiani, Mahtab
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p. 213 - 216
(2014/05/06)
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- BENZOPYRONE DERIVATIVE AND USE THEREOF
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The present invention relates to the field of pharmaceutical chemistry, and in particular, to a benzopyrone derivative and a use thereof. The benzopyrone derivative is compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof. It has been found by experiments that, this type of compounds is useful in prevention or treatment of neuropsychical diseases.
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Paragraph 0025; 0067
(2014/03/22)
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- BENZOPYRONE DERIVATIVE AND USE THEREOF
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The present invention relates to the field of pharmaceutical chemistry, and in particular, to a benzopyrone derivative and a use thereof. The benzopyrone derivative is compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof. It has been found by experiments that, this type of compounds is useful in prevention or treatment of neuropsychical diseases.
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Paragraph 0066; 0204
(2014/05/07)
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- Synthesis and biological evaluation of coumarin-1,2,3-triazole- dithiocarbamate hybrids as potent LSD1 inhibitors
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Two series of coumarin-1,2,3-triazole-dithiocarbamate hybrids were designed, synthesized and evaluated for their inhibitory activity towards lysine specific demethylase 1 (LSD1). Compounds 8a, 8d-8f, 8i-8l presented potent activity against lysine specific demethylase 1. Among them, compound 8k showed potent and reversible inhibition against lysine specific demethylase 1 with an IC50 value of 0.39 μM, which was 74-fold more potent than that of tranylcypromine (2-PCPA). Besides, compound 8k displayed excellent selectivity against lysine specific demethylase 1 without inhibition against monoamine oxidases (MAOs) A and B. Further investigation revealed that compound 8k was active at both recombinant and cell levels by upregulating the expression of H3K4me1, H3K4me2 and H3K9me2. This journal is the Partner Organisations 2014.
- Ye, Xian-Wei,Zheng, Yi-Chao,Duan, Ying-Chao,Wang, Meng-Meng,Yu, Bin,Ren, Jing-Li,Ma, Jin-Lian,Zhang, En,Liu, Hong-Min
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supporting information
p. 650 - 654
(2014/05/06)
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