Generation of Broad-Spectrum Antifungal Drug Candidates from the Natural Product Compound Aureobasidin A.
Basic Information
ID: ALA3588806
Journal: ACS Med Chem Lett
Title: Generation of Broad-Spectrum Antifungal Drug Candidates from the Natural Product Compound Aureobasidin A.
Authors: Wuts PG, Simons LJ, Metzger BP, Sterling RC, Slightom JL, Elhammer AP.
Abstract: The natural product aureobasidin A (AbA) is a potent, well-tolerated antifungal agent with robust efficacy in animals. Although native AbA is active against a number of fungi, it has little activity against Aspergillus fumigatus, an important human pathogen, and attempts to improve the activity against this organism by structural modifications have to date involved chemistries too complex for continued development. This report describes novel chemistry for the modification of AbA. The key step involves functionalization of the phenylalanine residues in the compound by iridium-catalyzed borylation. This is followed by displacement of the pinacol boron moiety to form the corresponding bromide or iodide and substitution by Suzuki biaryl coupling. The approach allows for synthesis of a truly wide range of derivatives and has produced compounds with A. fumigatus minimal inhibitory concentrations (MIC) of <0.5 μg/mL. The approach is readily adaptable to large-scale synthesis and industrial production.
CiteXplore: 26101567
DOI: 10.1021/acsmedchemlett.5b00029
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