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Natural product inhibitors of fatty acid biosynthesis: synthesis of the marine microbial metabolites pseudopyronines A and B and evaluation of their anti-infective activities |
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| Authors: | Anna C Giddens Helena I Boshoff Remo Perozzo Feng Wang Brent R Copp |
| Institution: | a Department of Chemistry, The University of Auckland, Private Bag 92019, Auckland, New Zealand b Tuberculosis Research Section, LCID, NIAID, NIH, Bethesda, MD 20892, USA c Centre for Pharmacognosy and Phytotherapy, University of London, London WC1N 1AX, United Kingdom d School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva 4, Switzerland e Swiss Tropical Institute, 4002 Basel, Switzerland f Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA |
| Abstract: | Total syntheses of the title natural products, pseudopyronines A (1) and B (2), have been achieved using methyl β-oxo carboxylic ester starting materials. The natural products and a small set of structurally related compounds were evaluated for growth inhibitory activity against a range of pathogenic microorganisms and were found to exhibit good potency (IC50≥0.46 μg/mL) and selectivity towards Leishmania donovani. Several of the compounds inhibited recombinant fatty acid biosynthesis enzymes from both Plasmodium falciparum and Mycobacterium tuberculosis, validating these targets in the search for new anti-infective agents. |
| Keywords: | Fatty acid biosynthesis Marine natural product Leishmania Mycobacterium |
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