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 and Andrew M. Piggott

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

Publication Date: January 8, 2021



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.

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