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European journal of medicinal chemistry 163건

  1. [해외논문]   Synthesis and antimycobacterial activity of triterpenic A-ring azepanes   SCI SCIE

    Medvedeva, Natalya I. (Ufa Institute of Chemistry of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054, Ufa, Russian Federation ) , Kazakova, Oxana B. (Ufa Institute of Chemistry of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054, Ufa, Russian Federation ) , Lopatina, Tatyana V. (Ufa Institute of Chemistry of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054, Ufa, Russian Federation ) , Smirnova, Irina E. (Ufa Institute of Chemistry of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054, Ufa, Russian Federation ) , Giniyatullina, Gul'nara V. (Ufa Institute of Chemistry of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054, Ufa, Russian Federation ) , Baikova, Irina P. (Ufa Institute of Chemistry of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054, Ufa, Russian Federation ) , Kataev, Vladimir E. (Arbuzov Institute of Organic and Physical Chemistry, Kazan Center of the Russian Academy of Sciences, Arbuzova st., 8, 420088, Kazan, Russian Federation)
    European journal of medicinal chemistry v.143 ,pp. 464 - 472 , 2018 , 0223-5234 ,

    초록

    Abstract A series of A-ring azepanones and azepanes derived from betulonic, oleanonic and ursonic acids was synthesized and evaluated for their in vitro antimycobacterial activities against M. tuberculosis (MTB) H37Rv and SDR-TB in the National Institute of Allergy and Infectious Diseases. Triterpenic A-azepano-28-hydroxy-derivatives were synthesized by the reduction with LiAlH 4 of triterpenic azepanones available from the Beckmann rearrangement of the corresponding C3-oximes. Modification of azepanes at NH-group and atoms С12, C20, C28 and C29 of triterpenic core led to the derivatives with oxo, epoxy, aminopropyl, oximino and acyl substituents. The primary assay of tested triterpenoids against MTB H37Rv demonstrated their MIC values ranged from 3.125 to >200 μM. Ursane type A-azepano-28-cinnamoates were the most active being 2 and 4 times more efficient than the initial 28-hydroxy-derivative. The follow-up testing revealed A-azepano-28-cinnamoyloxybetulin as a leader compound with MIC 2 and MBC 4 μM against MTB H37Rv and MICs 4, 1 and 1 μM against INH, RIF and OFX resistant strains, respectively. Five oleanane and ursane azepanes pronounced better activity than isoniazid against INH-R1 and rifampicin against INH-R2 strains. This work opens a new direction in the design and synthesis of new antitubercular agents basing on azepanotriterpenoids. Highlights A series of lupane, oleanane and ursane A-azepanotriterpenoids were synthesized. The primary in vitro assay of tested triterpenoids against MTB H37Rv demonstrated MICs from 3.125 to ˃200 μM. A-azepano-C28-cinnamoyloxybetulin is the most active compound with MICs 2 μM (MTB H37Rv) and from 1 to 4 μM (SDR strains). Oleanane and ursane azepanes showed better activity than isoniazid against INH-R1 and rifampicin against INH-R2 strains. Graphical abstract [DISPLAY OMISSION]

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  2. [해외논문]   A fluorine scan of a tubulin polymerization inhibitor isocombretastatin A-4: Design, synthesis, molecular modelling, and biological evaluation   SCI SCIE

    Naret, Timothé (BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS, University Paris-Saclay, F-92290, Châtenay Malabry, France ) , e (Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, F-91198, Gif sur Yvette, France ) , Bignon, Jé (BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS, University Paris-Saclay, F-92290, Châtenay Malabry, France ) , rô (BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS, University Paris-Saclay, F-92290, Châtenay Malabry, France ) , me (Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, F-91198, Gif sur Yvette, France ) , Bernadat, Guillaume (Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, F-91198, Gif sur Yvette, France ) , Benchekroun, Mohamed (Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, F-91198, Gif sur Yvette, France ) , Levaique, Helene (Service de Pharmacologie et d'Immunoanalyse (SPI), CEA, INRA, University Paris-Saclay, F-91191, Gif sur Yvette, France ) , Lenoir, Christine (INSERM, UMR-S1176, University Paris-Saclay, F-94276,) , Dubois, Joelle , Pruvost, Alain , Saller, Franç , ois , Borgel, Delphine , Manoury, Boris , Leblais, Veronique , Darrigrand, Romain , Apcher, Sé , bastien , Brion, Jean-Daniel , Schmitt, Etienne , Leroux, Fré , dé , ric R. , Alami, Mouad , Hamze, Abdallah
    European journal of medicinal chemistry v.143 ,pp. 473 - 490 , 2018 , 0223-5234 ,

    초록

    Abstract A novel series of tubulin polymerization inhibitors, based on fluorinated derivatives of iso combretastatin A-4 was synthesized with the goal of evaluating the effect of these compounds on the proliferative activity. The introduction of fluorine atom was performed on the phenyl ring or at the linker between the two aromatic rings. The modification of iso CA-4 by introduction of difluoromethoxy group at the para-position ( 3i ) and substitution of the two protons of the linker by two fluorine atoms ( 3m ), produced the most active compounds in the series, with IC 50 values of 0.15–2.2 nM ( 3i ) and 0.1–2 nM ( 3m ) respectively, against a panel of six cancer cell lines. Compounds 3i and 3m had greater antiproliferative activity in comparison with references CA-4 or iso CA-4, the presence of fluorine group leads to a significant enhancement of the antiproliferative activity. Molecular docking studies indicated that compounds 3i and 3m occupy the colchicine binding site of tubulin. Evaluation of cytotoxicity in Human noncancer cells indicated that the compounds 3i and 3m were practically ineffective in quiescent peripheral blood lymphocytes, and may have a selective antiproliferative activity against cancer cells. Analyses of cell cycle distribution, and morphological microtubules organization showed that compound 3m induced G 2 /M phase arrest and, dramatically disrupted the microtubule network. Highlights New fluorinated analogs of iso CA-4 were synthesized. Compounds 3i and 3m exhibit cytotoxic activities on nM to sub nM range over six cancer cell lines. Strong tubulin polymerization inhibition were observed for the compound 3i (IC 50 = 0.4 μM). Compounds 3i and 3m have very poor activities over peripheral blood lymphocytes with IC 50 > 10 mM. Docking studies indicate that 3i and 3m interact with the colchicine binding site. Graphical abstract [DISPLAY OMISSION]

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  3. [해외논문]   Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors   SCI SCIE

    Yuan, Haoliang (Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China ) , Liu, Qiufeng (CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China ) , Zhang, Li (Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China ) , Hu, Shihe (Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China ) , Chen, Tiantian (CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China ) , Li, Huifang (Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia V6H 3Z6, Canada ) , Chen, Yadong (Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical Universit) , Xu, Yechun , Lu, Tao
    European journal of medicinal chemistry v.143 ,pp. 491 - 502 , 2018 , 0223-5234 ,

    초록

    Abstract The c-Met kinase has emerged as an attractive target for developing antitumor agents because of its close relationship with the development of many human cancers, poor clinical outcomes and even drug resistance. A series of novel c-Met kinase inhibitors have been identified with multiple workflow in this work, including virtual screening, X-ray crystallography, biological evaluation and structural optimization. The experimentally determined crystal structure of the best hit compound HL-11 in c-Met kinase domain was highly consistent with the computational prediction. Comparison of the hit compounds with different c-Met kinase inhibitory activity by molecular dynamics simulations suggested the key protein-ligand interactions for structural optimization. Based on these, structural optimization produced compound 11e with better c-Met kinase inhibitory activity and improved anti-proliferative activity. These experimental findings proved the reliability and efficiency of our in silico methods. This strategy will facilitate further lead discovery and optimization for novel c-Met kinase inhibitors. Highlights Compound HL-11 identified with the reliable virtual screening workflow exhibited potent c-Met kinase inhibitory activity. Molecular dynamics simulations suggested the key protein-ligand interactions for structural optimization of compound HL-11 . The experimentally resolved crystal binding mode of compound HL-11 was highly consistent with the computational prediction. The novel compound 11e exhibited better c-Met kinase inhibitory activity and improved anti-proliferative activity. Graphical abstract [DISPLAY OMISSION]

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  4. [해외논문]   Novel ruthenium methylcyclopentadienyl complex bearing a bipyridine perfluorinated ligand shows strong activity towards colorectal cancer cells   SCI SCIE

    Teixeira, Ricardo G. (Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal ) , Brá (Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal ) , s, Ana Rita (Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal ) , Cô (Department of Chemistry, Nanoscience Center, University of Jyväskylä, P. O. Box 35, FI-40014 Jyväskylä, Finland ) , rte-Real, Leonor (Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal ) , Tatikonda, Rajendhraprasad (Área Departamental de Engenharia Química, ISEL-Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, Rua Conselheiro Emídio Navarro, 1, 1959-007 Lisboa, Portugal ) , Sanches, Anabela (Grupo Xenomar, Centro de Investigacións Científicas Avanzadas (CICA), Departamento de Química,) , Robalo, M. Paula , Avecilla, Fernando , Moreira, Tiago , Garcia, M. Helena , Haukka, Matti , Preto, Ana , Valente, Andreia
    European journal of medicinal chemistry v.143 ,pp. 503 - 514 , 2018 , 0223-5234 ,

    초록

    Abstract Three new compounds have been synthesized and completely characterized by analytical and spectroscopic techniques. The new bipyridine-perfluorinated ligand L1 and the new organometallic complex [Ru(η 5 -MeCp)(PPh 3 ) 2 Cl] ( Ru1 ) crystalize in the centrosymmetric triclinic space group P 1 ¯ . Analysis of the phenotypic effects induced by both organometallic complexes Ru1 and [Ru(η 5 -MeCp)(PPh 3 )( L1 )][CF 3 SO 3 ] ( Ru2 ), on human colorectal cancer cells (SW480 and RKO) survival, showed that Ru2 has a potent anti-proliferative activity, 4–6 times higher than cisplatin, and induce apoptosis in these cells. Data obtained in a noncancerous cell line derived from normal colon epithelial cells (NCM460) revealed an intrinsic selectivity of Ru2 for malignant cells at low concentrations, showing the high potential of this compound as a selective anticancer agent. Highlights Novel ruthenium methylcyclopentadienyl complexes. [Ru(η 5 -MeCp)(PPh 3 )(bipyridine-perfluorinated)] + is highly active on human colorectal cancer cells. Apoptosis is the mechanism of cell death. Intrinsic selectivity for malignant cells. Graphical abstract [DISPLAY OMISSION]

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  5. [해외논문]   Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives   SCI SCIE

    Shagufta (Corresponding author. ) , Ahmad, Irshad (Corresponding author.)
    European journal of medicinal chemistry v.143 ,pp. 515 - 531 , 2018 , 0223-5234 ,

    초록

    Abstract Tamoxifen (ICI 46 474), trans -1-(4-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, is the most commonly used drug for the treatment of estrogen receptor positive breast cancer and has been saving lives worldwide for the past four decades. Tamoxifen is considered a pioneering drug due to its ubiquitous use in both treatment and chemoprevention of breast cancer and also for research addressing novel selective estrogen receptor modulators (SERMs). Tamoxifen is cost effective, lifesaving, and devoid of major side effects in the majority of patients. The discovery of tamoxifen metabolites such as 4-hydroxy tamoxifen, N- desmethyl tamoxifen, and endoxifen has facilitated understanding of tamoxifen's and its metabolites' mechanisms of action in breast cancer therapy. Continuous efforts are being made by both industry and academia to synthesize novel tamoxifen derivatives in order to better understand the mechanism of this drug's action and to generate new agents with reduced side effects for many therapeutic targets. This review article comprises the tamoxifen derivatives reported in the literature in the last few years and we anticipate that it will assist medicinal chemists in the synthesis of novel and pharmacologically potent agents for various therapeutic targets. Highlights Tamoxifen is a pioneering drug for the treatment of ER-positive breast cancer cells. Tamoxifen derivatives exhibited promising activity for cancer in addition to demonstrating other therapeutic activities. Recent literature concerning synthesized tamoxifen derivatives and their pharmacological activities is reviewed. The tamoxifen scaffold is an attractive target for the drug development. The review will be useful for researchers who are developing novel tamoxifen derivatives aimed at several targets. Graphical abstract [DISPLAY OMISSION]

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  6. [해외논문]   Cytotoxicity, molecular modeling, cell cycle arrest, and apoptotic induction induced by novel tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline chalcones   SCI SCIE

    Mohamed, Magda F. (Department of Chemistry (Biochemistry Branch), Faculty of Science, Cairo University, Giza, Egypt ) , Hassaneen, Hamdi M. (Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt ) , Abdelhamid, Ismail A. (Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt)
    European journal of medicinal chemistry v.143 ,pp. 532 - 541 , 2018 , 0223-5234 ,

    초록

    Abstract Novel tetrahydro-[1,2,4]triazolo[3,4- a ]isoquinolin-3-yl)-3-arylprop-2-en-1-one derivatives were synthesized and their structures were confirmed by different spectral tools. Cytotoxicity test revealed that some compounds exhibited strong to moderate effect, while others showed weak action against different cancer cell lines (MCF7, A549, HCT116, and Hepg2). Breast carcinoma revealed higher sensitivity toward all derivatives especially compounds 5 and 8 which offered the lowest IC 50 values (50.05, and 27.15 μg/ml) respectively, relative to the positive control 5-fluorouracil (5-FU) (IC 50 = 178 μg/ml). In addition, the two compounds exhibited less toxic effect toward normal melanocytes (HFB4). Several theoretical and experimental studies were done to reveal the molecular mechanisms that control breast carcinoma metastasis using the two promising novels 5 and 8 . Docking simulation studies against the two proteins EGFR and DHFR demonstrate that compound 8 showed higher binding affinity toward the two proteins more than compound 5 , suggesting that trimethoxy groups may be responsible for this higher activity through the formation of five hydrogen bonding with the active domain (4r3r) and other four interactions with the active domain (1dls). Real time PCR assay illustrates that the two compounds up regulated BAX, p53, caspase-3 genes and down regulated BCL2, MMP1, CDK4 ones. In addition, it was noted that compound 8 was more effective in gene regulation and apoptotic induction than compound 5. Also, flow cytometer analysis demonstrates that both compounds 5 and 8 induced cell growth arrest at G1 phase and thus, inhibit G1/S transition and cell cycle progression. In addition, both compounds stimulate apoptotic death of breast cells significantly to reach 8.72%, and 17.28% respectively, compared to their control (0.55%). Apoptotic induction of breast cells was enhanced effectively through activation of caspase-3 by compound 8 using Elisa assay. Highlights Tetrahydro-[1,2,4]triazolo[3,4- a ]isoquinoline. Chalcones. Breast cancer. Modeling docking study. Apoptosis. Graphical abstract [DISPLAY OMISSION]

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  7. [해외논문]   Quinoxaline: An insight into the recent pharmacological advances   SCI SCIE

    Tariq, Sana (Corresponding author.) , Somakala, K. , Amir, Mohd.
    European journal of medicinal chemistry v.143 ,pp. 542 - 557 , 2018 , 0223-5234 ,

    초록

    Abstract Quinoxaline, a fused heterocycle of benzene and pyrazine rings has gained considerable attention in the field of contemporary medicinal chemistry. The moiety is of substantial importance because of its wide array of pharmacological activities viz. anti-cancer, antimalarial, anti-inflammatory, antimicrobial, anti-HIV etc. Diversely substituted quinoxalines are important therapeutic agents in the pharmaceutical industry. This review focusses on the quinoxaline derivatives developed during the last decennial period and their biomedical applications. A compilation of patents on quinoxaline is also included herein. Highlights Quinoxaline is a ring complex made up of a benzene ring and a pyrazine ring. A wide range of biological activities: antimicrobial, anticancer, antimalarial, anti-inflammatory etc. are discussed. Derivatives developed during the last decennial period are described. This review will be helpful for medicinal chemists in the development of useful therapeutics. Graphical abstract [DISPLAY OMISSION]

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  8. [해외논문]   Synthesis and bio-inspired optimization of drimenal: Discovery of chiral drimane fused oxazinones as promising antifungal and antibacterial candidates   SCI SCIE

    Li, Dangdang (Department of Pesticide Science, College of Plant Protection, Nanjing Agricultural University, Weigang 1, Xuanwu District, Nanjing 210095, People's Republic of China ) , Zhang, Shasha (Department of Pesticide Science, College of Plant Protection, Nanjing Agricultural University, Weigang 1, Xuanwu District, Nanjing 210095, People's Republic of China ) , Song, Zehua (Department of Pesticide Science, College of Plant Protection, Nanjing Agricultural University, Weigang 1, Xuanwu District, Nanjing 210095, People's Republic of China ) , Li, Wei (Department of Pesticide Science, College of Plant Protection, Nanjing Agricultural University, Weigang 1, Xuanwu District, Nanjing 210095, People's Republic of China ) , Zhu, Feng (College of Chemistry and Pharmacy, Northwest A&F University, No. 3 Taicheng Road, Yangling, Shaanxi 712100, People's Republic of China ) , Zhang, Jiwen (College of Chemistry and Pharmacy, Northwest A&F University, No. 3 Taicheng Road, Yangling, Shaanxi 712100, People's Republic of China ) , Li, Shengkun (Department of Pesticide Science, College of Plant Prot)
    European journal of medicinal chemistry v.143 ,pp. 558 - 567 , 2018 , 0223-5234 ,

    초록

    Abstract The synthesis of antifungal natural product drimenal was accomplished. Bio-inspired optimization protruded chiral 8-( R )-drimane fused oxazinone D as a lead, considering favorable physicochemical profiles for novel pesticides. The improved scalable synthesis of scaffold D was implemented by Hofmann rearrangment under mild conditions. Detailed structural optimization was discussed for both antifungal and antibacterial exploration. Substituted groups (SGs) with C 3 ∼C 5 hydrocarbon chain are recommended for exploration of antifungal agents, while substituents with C 4 ∼C 6 carbon length are preferred for antibacterial ingredients. The chiral drimane fused oxazinone D8 was selected as a promising antifungal candidate against Botrytis cirerea , with an EC 50 value of 1.18 mg/L, with the enhancement of up to >25 folds and >80 folds than the mother compound D , and acyclic counterpart AB5 , respectively. The in vivo bioassay confirmed much better preservative effect of D8 than that of Carbendazim. The chiral oxazinone variant D10 possessed prominent antibacterial activity, with MIC values of 8 mg/L against both Bacillus subtilis and Ralstonia solanacearum , showing advantages over the positive control streptomycin sulfate. Highlights Synthesis and bioassay of natural products drimenal and drimenol was accomplished from sclareol. Bio-inspired optimization protruded 8-( R )-drimane fused oxazinone D as a lead for novel agrochemicals. Practical synthesis and divergent optimization of scaffold D were implemented. Both antifungal and antibacterial candidates with prominent activities were achieved. Graphical abstract [DISPLAY OMISSION]

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  9. [해외논문]   Structure–activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity   SCI SCIE

    Saleeb, Michael (Department of Chemistry, Umeå) , Sundin, Charlotta (University, 90187, Umeå, Sweden ) , Aglar, Ö (Department of Chemistry, Umeå) , znur (University, 90187, Umeå, Sweden ) , Pinto, Ana Filipa (Department of Chemistry, Umeå) , Ebrahimi, Mahsa (University, 90187, Umeå, Sweden ) , Forsberg, Å (Department of Medicinal Biochemistry and Biophysics, Karolinska Institute, 17177, Stockholm, Sweden ) , ke (Department of Medicinal Biochemistry and Biophysics, Karolinska Institute, 17177, Stockholm, Sweden ) , Schü (Department of Molecular Biology, Umeå) , ler, Herwig (University, 90187, Umeå, Sweden ) , Elofsson, Mikael (Department of Medicinal Biochemistry and Biophysics, Karolinska Institute, 17177, Stockholm, Sweden )
    European journal of medicinal chemistry v.143 ,pp. 568 - 576 , 2018 , 0223-5234 ,

    초록

    Abstract During infection, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa employs its type III secretion system to translocate the toxin exoenzyme S (ExoS) into the eukaryotic host cell cytoplasm. ExoS is an essential in vivo virulence factor that enables P. aeruginosa to avoid phagocytosis and eventually kill the host cell. ExoS elicits its pathogenicity mainly via ADP-ribosyltransferase (ADPRT) activity. We recently identified a new class of ExoS ADPRT inhibitors with in vitro IC 50 of around 20 μM in an enzymatic assay using a recombinant ExoS ADPRT domain. Herein, we report structure–activity relationships of this compound class by comparing a total of 51 compounds based on a thieno [2,3- d ]pyrimidin-4(3 H )-one and 4-oxo-3,4-dihydroquinazoline scaffolds. Improved inhibitors with in vitro IC 50 values of 6 μM were identified. Importantly, we demonstrated that the most potent inhibitors block ADPRT activity of native full-length ExoS secreted by viable P. aeruginosa with an IC 50 value of 1.3 μM in an enzymatic assay. This compound class holds promise as starting point for development of novel antibacterial agents. Highlights Inhibitors of ADP-ribosyltransferase (ADPRT) activity of P. aeruginosa toxin ExoS. 64-E1 inhibits ExoS ADPRT with IC 50 ≤ 7 μM. Development of enzymatic assay based on native ExoS secreted from P. aeruginosa. The thienopyrimidinone inhibitors blocked the native ExoS ADPRT activity. Graphical abstract [DISPLAY OMISSION]

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  10. [해외논문]   Xanthine oxidase inhibitory activity of natural and hemisynthetic flavonoids from Gardenia oudiepe (Rubiaceae) in vitro and molecular docking studies   SCI SCIE

    Santi, M.D. (Farmacognosia, Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Haya de La Torre y Medina Allende, Edificio Ciencias II, X5000HUA Córdoba, Argentina ) , Paulino Zunini, M. (Center of Bioinformatics, Faculty of Chemistry - UdelaR, 11800 Montevideo, Uruguay ) , Vera, B. (Center of Bioinformatics, Faculty of Chemistry - UdelaR, 11800 Montevideo, Uruguay ) , Bouzidi, C. (Laboratoire de Pharmacognosie, UMR/CNRS 8638, Faculté) , Dumontet, V. (des Sciences Pharmaceutiques et Biologiques, Université) , Abin-Carriquiry, A. (Paris Descartes, Sorbonne Paris Cité, 4, Avenue de L'Observatoire, 75006 Paris, France ) , Grougnet, R. (Laboratoire des Plantes Médicinales de Nouméa, CNRS-Centre IRD, BP 643, 98845 Nouméa Cedex, Nouvelle-Calédonie, France ) , Ortega, M.G. (Department of Neurochemistry, Instituto de Investigaciones Biológicas Clemente Estable, 11600 Montevideo, Uruguay )
    European journal of medicinal chemistry v.143 ,pp. 577 - 582 , 2018 , 0223-5234 ,

    초록

    Abstract Xanthine oxidase (XO), an enzyme widely distributed among mammalian tissues, is associated with the oxidation of xanthine and hypoxanthine to form uric acid. Reactive oxygen species are also released during this process, leading to oxidative damages and to the pathology called gout. Available treatments mainly based on allopurinol cause serious side effects. Natural products such as flavonoids may represent an alternative. Thus, a series of polymethoxyflavones isolated and hemisynthesized from the bud exudates of Gardenia oudiepe has been evaluated for in vitro XO inhibitory activity. Compounds 1 , 2 and 3 were more active than the reference inhibitor, Allopurinol (IC 50 = 0.25 ± 0.004 μM) with IC 50 values of (0.004 ± 0.001) μM, (0.05 ± 0.01) μM and (0.09 ± 0.003) μM, respectively. Structure-activity relationships were established. Additionally, a molecular docking study using MOE™ tool was carried out to establish the binding mode of the most active flavones with the enzyme, showing important interactions with its catalytic residues. These promising results, suggest the use of these compounds as potential leads for the design and development of novel XO inhibitors. Highlights Xanthine oxidase inhibitory activity of polymethoxyflavones from Gardenia oudiepe was determinate. Some compounds were more actives than Allopurinol, with IC 50 in the nanomolar range. SAR and docking studies were determinate for those compounds for the first time. Graphical abstract [DISPLAY OMISSION]

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