Issue 5, 2021

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

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.

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

Supplementary files

Article information

Article type
Paper
Submitted
09 Dec. 2020
Accepted
08 Janv. 2021
First published
08 Janv. 2021

Org. Biomol. Chem., 2021,19, 1022-1036

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

M. T. Morshed, H. T. Nguyen, D. Vuong, A. Crombie, E. Lacey, A. D. Ogunniyi, S. W. Page, D. J. Trott and A. M. Piggott, Org. Biomol. Chem., 2021, 19, 1022 DOI: 10.1039/D0OB02460K

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