Abstract:
:Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure-activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC50 value =20 nM) and chemical stability in aqueous buffer (t1/2=8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds 2o and 2s contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups.
journal_name
J Enzyme Inhib Med Chemjournal_title
Journal of enzyme inhibition and medicinal chemistryauthors
Vergelli C,Schepetkin IA,Crocetti L,Iacovone A,Giovannoni MP,Guerrini G,Khlebnikov AI,Ciattini S,Ciciani G,Quinn MTdoi
10.1080/14756366.2017.1326915subject
Has Abstractpub_date
2017-12-01 00:00:00pages
821-831issue
1eissn
1475-6366issn
1475-6374journal_volume
32pub_type
杂志文章abstract::In order to understand the binding modes of human DNA polymerase alpha (pol alpha) inhibitors on a molecular level, a 3D homology model of the active site of the enzyme was proposed based on the application of molecular modelling methods and molecular dynamic simulations using available crystal coordinates of pol alph...
journal_title:Journal of enzyme inhibition and medicinal chemistry
pub_type: 杂志文章
doi:10.1080/14756360701433414
更新日期:2008-02-01 00:00:00
abstract::Microbial resistance to the available drugs poses a serious threat in modern medicine. We report the design, synthesis and in vitro antimicrobial evaluation of new functionalized 2,3-dihydrothiazoles and 4-thiazolidinones tagged with sulfisoxazole moiety. Compound 8d was most active against Bacillis subtilis (MIC, 0.0...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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doi:10.3109/14756366.2015.1016514
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abstract:CONTEXT:Bacterial sphingomyelinase (SMase) is thought to play a crucial role in bacterial evasion of the immune response during the early stages of infections. OBJECTIVE:The objective of this study was to predict the chemical structure required for competitive SMase inhibition, then synthesize and test the effect of p...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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doi:10.3109/14756366.2013.777717
更新日期:2014-06-01 00:00:00
abstract::A set of novel quinolone-triazole conjugates (12-31) were synthesized in three steps in good yields starting from 2-phenylquinoline-4-carboxylic acid. All the intermediates, as well as the final 1,2,4-triazolyl quinolines were fully characterized by their detailed spectral analysis utilizing different techniques such ...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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doi:10.1080/14756366.2016.1190714
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abstract::Thirty new aryl-pyridazinone-substituted benzenesulphonylurea derivatives (I-XXX) were synthesized and evaluated for their anti-hyperglycaemic activity in glucose-fed hyperglycaemic normal rats. Twenty-three compounds (III-XI, XIV-XVII, XIX-XXIV, XXVI and XXVIII-XXX) showed more or comparable area under the curve (AUC...
journal_title:Journal of enzyme inhibition and medicinal chemistry
pub_type: 杂志文章
doi:10.3109/14756366.2016.1142986
更新日期:2016-12-01 00:00:00
abstract::In the present study, some thiazole derivatives were synthesized via the ring closure reaction of 1-[2-(2-oxobenzo[d]thiazol-3(2H)-yl)acetyl]thiosemicarbazide with various phenacyl bromides. The chemical structures of the compounds were elucidated by (1)H NMR, (13)C NMR and mass spectral data and elemental analyses. E...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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doi:10.3109/14756366.2011.653355
更新日期:2013-06-01 00:00:00
abstract::Complexes of the type [M(pabh)(H2O)Cl], [M(pcbh)(H2O)Cl] and [M(Hpabh)(H2O)2 (SO4)] where, M = Mn(II), Co(II), Ni(II), Cu(II) and Zn(II); Hpabh = p-amino acetophenone benzoyl hydrazone and Hpcbh = p-chloro acetophenone benzoyl hydrazone have been synthesized and characterized with the help of elemental analyses, elect...
journal_title:Journal of enzyme inhibition and medicinal chemistry
pub_type: 杂志文章
doi:10.1080/14756360802318662
更新日期:2009-04-01 00:00:00
abstract::The activation of the β-class carbonic anhydrases (CAs, EC 4.2.1.1) from the bacteria Brucella suis and Francisella tularensis with amine and amino acids was investigated. BsuCA 1 was sensitive to activation with amino acids and amines, whereas FtuCA was not. The most effective BsuCA 1 activators were L-adrenaline and...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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更新日期:2019-12-01 00:00:00
abstract::Starting from a simple general reaction mechanism of activation of aspartic proteinases zymogens involving a uni- and a bimolecular simultaneous activation route and a reversible inhibition step, the time course equation of the zymogen, inhibitor and activated enzyme concentrations have been derived. Likewise, express...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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更新日期:2007-04-01 00:00:00
abstract::Neurodegenerative disorders are consequences of progressive and irreversible loss of neurons due to unwanted apoptosis which involves caspases, a group of cysteine proteases that cleave other proteins and inactivate them. Among several different groups of caspase enzymes, caspases-3 plays a key role in apoptosis and a...
journal_title:Journal of enzyme inhibition and medicinal chemistry
pub_type: 杂志文章
doi:10.1080/14756360701652476
更新日期:2008-06-01 00:00:00
abstract::This study reports on a preliminary structure-activity relationship exploration of 4-aryliden-2-methyloxazol-5(4H)-one-based compounds as MAGL/FAAH inhibitors. Our results highlight that this scaffold may serve for the development of selective MAGL inhibitors. A 69-fold selectivity against MAGL over FAAH was achieved ...
journal_title:Journal of enzyme inhibition and medicinal chemistry
pub_type: 杂志文章
doi:10.3109/14756366.2015.1010530
更新日期:2016-01-01 00:00:00
abstract::In the present study, 2-[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]acetohydrazide (1) was used as starting compound for the synthesis of 2-{[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]acetyl}-4-thiosemicarbazides (2a-c) and 5-{[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazo...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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doi:10.3109/14756366.2014.1003213
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journal_title:Journal of enzyme inhibition and medicinal chemistry
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doi:10.3109/14756366.2015.1050011
更新日期:2016-08-01 00:00:00
abstract::A new series of 12 N(4)-substituted isatin-3-thiosemicarbazones 2a-l has been synthesized, characterized and screened for in vitro cytotoxic, phytotoxic and urease inhibitory effects. All the compounds proved to be active in the brine shrimp bioassay; 2a, 2b, 2d, 2f and 2h-l exhibited a high degree of cytotoxic activi...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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doi:10.1080/14756360802188420
更新日期:2009-04-01 00:00:00
abstract::Glutathione transferase P1-1 is over expressed in some cancer cells and contributes to detoxification of anticancer drugs, leading to drug-resistant tumors. The inhibition of human recombinant GSTP1-1 by natural plant products was investigated using 10 compounds isolated from plants indigenous to Southern and Central ...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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doi:10.3109/14756366.2010.526769
更新日期:2011-08-01 00:00:00
abstract::Nerve agents such as sarin, cyclosarin and tabun are organophosphorus substances able to inhibit the enzyme acetylcholinesterase (AChE; EC 3.1.1.7). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None of the known AChE reactivators is able to react...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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更新日期:2006-10-01 00:00:00
abstract::We investigated the ability of polyphenol fatty acid esters to inhibit the activity of serine proteases trypsin, thrombin, elastase and urokinase. Potent protease inhibition in micromolar range was displayed by rutin and rutin derivatives esterified with medium and long chain, mono- and polyunsaturated fatty acids (1e...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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doi:10.3109/14756366.2010.616860
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journal_title:Journal of enzyme inhibition and medicinal chemistry
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journal_title:Journal of enzyme inhibition and medicinal chemistry
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更新日期:2016-01-01 00:00:00
abstract::Three series of 5-bromo-thieno[2,3-b]pyridines bearing amide or benzoyl groups at position 2 were prepared as pim-1 inhibitors. All the prepared compounds were tested for their pim-1 enzyme inhibitory activity. Two compounds (3c and 5b) showed moderate pim-1 inhibitory activity with IC50 of 35.7 and 12.71 μM, respecti...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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更新日期:2016-12-01 00:00:00
abstract::Carbonic anhydrases (CAs) are widespread metalloenzymes in higher vertebrates including humans. A series of phenolic compounds, including guaiacol, 4-methylguaiacol, 4-propylguaiacol, eugenol, isoeugenol, vanillin, syringaldehyde, catechol, 3-methyl catechol, 4-methyl catechol and 3-methoxy catechol were investigated ...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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更新日期:2015-01-01 00:00:00
abstract::Synthesis and pharmacological evaluation of various 2-(4-isobutylphenyl)propanoic acid derivatives containing 1,3,4-thiadiazole and thiadiazolo[3,2-a][1,3,5]triazine-5-thione nucleus is reported here. The structures of new compounds are supported by IR, (1)H & (13)C NMR data. These compounds were tested in vivo for th...
journal_title:Journal of enzyme inhibition and medicinal chemistry
pub_type: 杂志文章,收录出版
doi:10.3109/14756366.2011.578743
更新日期:2012-02-01 00:00:00
abstract::Two fractions of rat intestinal alkaline phosphatase (IAP) were detected by Western blot: 168 +/- 6 and 475 +/- 45 kDa. The low molecular weight fraction constitutes 43% of the isolated proteins exhibiting 82% of the enzymatic activity, and a heavier fraction constitutes 57% of the isolated proteins and has 18% of the...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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更新日期:2006-12-01 00:00:00
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journal_title:Journal of enzyme inhibition and medicinal chemistry
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journal_title:Journal of enzyme inhibition and medicinal chemistry
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更新日期:2017-12-01 00:00:00
abstract::Abstract Twenty-three phenolic compounds were isolated from Dioscorea opposita by bioactivity-guided method and their inhibitory effect against pancreatic lipase was evaluated. A total of 15 isolates reduced lipase activity at IC50 values of less than 50 µM and 3,3',5-trihydroxy-2'-methoxybibenzyl showed the highest i...
journal_title:Journal of enzyme inhibition and medicinal chemistry
pub_type: 杂志文章
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更新日期:2014-02-01 00:00:00
abstract::This work has been focused on testing the influence of two selected Pt(II) complexes cisplatin, Pt(NH₃)₂Cl₂, and [Pt(dach)Cl₂] on the activity of porcine pancreatic phospholipase A₂ (PLA₂). It has been assumed that this enzyme plays a role in carcinogenesis and that it could be a target in the tumour therapy. The resu...
journal_title:Journal of enzyme inhibition and medicinal chemistry
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abstract::The synthesis and biological evaluation of some novel thiazolofluorenones, thiazolofluorenes and thiazoloanthraquinones, substituted with amino side-chains are described. These polyheterocyclic compounds have been synthesized via the corresponding imino-1,2,3-dithiazoles. Their cytotoxic activity and their eventual se...
journal_title:Journal of enzyme inhibition and medicinal chemistry
pub_type: 杂志文章
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更新日期:2004-12-01 00:00:00
abstract::Usually, all newborns demonstrate high serum unconjugated bilirubin (UCB) level. UCB may induce adverse effects in the central nervous system. We aimed to evaluate the cytotoxic effects of UCB and the protective effects of docosahexaenoic acid (DHA) on astrocyte cell cultures. The viability of astrocyte cells decrease...
journal_title:Journal of enzyme inhibition and medicinal chemistry
pub_type: 杂志文章
doi:10.3109/14756366.2012.684053
更新日期:2013-08-01 00:00:00
abstract::The aims of this study were to examine the antiproliferation of Humulus lupulus extracts on human hepatoma carcinoma (Hep3B) and human colon carcinoma (HT-29) cell lines along with enzyme inhibitory effects of the crude extracts. Potential cell cytotoxicity of six different H. lupulus extracts were assayed on various ...
journal_title:Journal of enzyme inhibition and medicinal chemistry
pub_type: 杂志文章
doi:10.3109/14756366.2015.1004060
更新日期:2016-01-01 00:00:00