Semisynthesis and biological evaluation of a focused library of unguinol derivatives as next-generation antibiotics

Mahmud T. Morshed, Hang T. Nguyen, Daniel Vuong, Andrew Crombie, Ernest Lacey, Abiodun D. Ogunniyi, Stephen W. Page, Darren J. Trott, Andrew M. Piggott*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    2 Citations (Scopus)

    Abstract

    In this study, we report the semisynthesis and in vitro biological evaluation of thirty-four derivatives of the fungal depsidone antibiotic, unguinol. Initially, the semisynthetic modifications were focused on the two free hydroxy groups (3-OH and 8-OH), the three free aromatic positions (C-2, C-4 and C-7), the butenyl side chain and the depsidone ester linkage. Fifteen first-generation unguinol analogues were synthesised and screened against a panel of bacteria, fungi and mammalian cells to formulate a basic structure activity relationship (SAR) for the unguinol pharmacophore. Based on the SAR studies, we synthesised a further nineteen second-generation analogues, specifically aimed at improving the antibacterial potency of the pharmacophore. In vitro antibacterial activity testing of these compounds revealed that 3-O-(2-fluorobenzyl)unguinol and 3-O-(2,4-difluorobenzyl)unguinol showed potent activity against both methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MIC 0.25-1 μg mL−1) and are promising candidates for further development in vivo.

    Original languageEnglish
    Pages (from-to)1022-1036
    Number of pages15
    JournalOrganic and Biomolecular Chemistry
    Volume19
    Issue number5
    DOIs
    Publication statusPublished - 7 Feb 2021

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