کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1361891 981473 2007 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli
چکیده انگلیسی

The type II fatty acid pathway (FAS-II) is a validated target for antimicrobial drug discovery. An activity-guided isolation procedure based on Plasmodium falciparum enoyl-ACP reductase (PfFabI) enzyme inhibition assay on the n  -hexane-, the CHCl3-CHCl3- and the aq MeOH extracts of the Turkish marine sponge Agelas oroides yielded six pure metabolites [24-ethyl-cholest-5α-7-en-3-β-ol (1), 4,5-dibromopyrrole-2-carboxylic acid methyl ester (2), 4,5-dibromopyrrole-2-carboxylic acid (3), (E)-oroidin (4), 3-amino-1-(2-aminoimidazoyl)-prop-1-ene (5), taurine (6)] and some minor, complex fatty acid mixtures (FAMA–FAMG). FAMA, consisting of a 1:2 mixture of (5Z,9Z)-5,9-tricosadienoic (7) and (5Z,9Z)-5,9-tetracosadienoic (8) acids, and FAMB composed of 8, (5Z,9Z)-5,9-pentacosadienoic (9) and (5Z,9Z)-5,9-hexacosadienoic (10) acids in ≈3:3:2 ratio were the most active PfFabI inhibitory principles of the hexane extract (IC50 values 0.35 μg/ml). (E)-Oroidin isolated as free base (4a) was identified as the active component of the CHCl3 extract. Compound 4a was a more potent PfFabI inhibitor (IC50 0.30 μg/ml = 0.77 μM) than the (E)-oroidin TFA salt (4b), the active and major component of the aq MeOH extract (IC50 5.0 μg/ml). Enzyme kinetic studies showed 4a to be an uncompetitive PfFabI inhibitor (Ki: 0.4 ± 0.2 and 0.8 ± 0.2 μM with respect to substrate and cofactor). In addition, FAMA and FAMD (mainly consisting of methyl-branched fatty acids) inhibited FabI of Mycobacterium tuberculosis (MtFabI, IC50s 9.4 and 8.2 μg/ml, respectively) and Escherichia coli (EcFabI, IC50s 0.5 and 0.07 μg/ml, respectively). The majority of the compounds exhibited in vitro antiplasmodial, as well as trypanocidal and leishmanicidal activities without cytotoxicity towards mammalian cells. This study represents the first marine metabolites that inhibit FabI, a clinically relevant enzyme target from the FAS-II pathway of several pathogenic microorganisms.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 15, Issue 21, 1 November 2007, Pages 6834–6845
نویسندگان
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