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


Tasdemir D., Topaloglu B., Perozzo R., Brun R., O'Neill R., Carballeira N. M., ...More

Bioorganic and Medicinal Chemistry, vol.15, no.21, pp.6834-6845, 2007 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 15 Issue: 21
  • Publication Date: 2007
  • Doi Number: 10.1016/j.bmc.2007.07.032
  • Journal Name: Bioorganic and Medicinal Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.6834-6845
  • Istanbul University Affiliated: Yes

Abstract

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- 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. © 2007 Elsevier Ltd. All rights reserved.