Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli

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• 作者：Deniz Tasdemir ; Bü ; lent Topaloglu ; Remo Perozzo ; Reto Brun ; Rosann O’ ; Neill ; Né ; stor M. Carballeira ; Xujie Zhang ; Peter J. Tonge ; Anthony Linden ; Peter Rü ; edi
• 关键词：Agelas ; Enoyl-ACP reductase ; Plasmodium ; Mycobacterium ; Escherichia
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2007
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 November 2007
• 卷：15
• 期：21
• 页码：6834-6845
• 文件大小：289 K

摘要

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 CHCl_3^- 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 (K_i: 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.