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Issue 6, 2015
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Synthesis and antibacterial activity evaluation of C-5 side chain modified analogues of FYL-66, a potential agent against methicillin-resistant Staphylococcus aureus

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Abstract

FYL-66 and its hydrochloride FYL-67 have been identified as new chemical entities (NCE) with pronounced in vitro and in vivo activities against MRSA and MSSA. Aiming to explore the structure–activity relationship at the C-5 side chain of FYL-66 and find novel potential antibacterial agents, a series of analogues were designed and synthesized by the introduction of various substituents at the C-5 position of the oxazolidinone ring. Their in vitro antibacterial activities were also evaluated by the microdilution method. Novel compounds 31, 33, 37, 39 and 40 demonstrated potent antibacterial activities with MIC values in the range of 2–4 μg mL−1. Difluoro-substituted analogue 40 was found to possess a good balance between antibacterial efficacy, physicochemical properties and safety profile. In a murine systemic infection model, analogue 40 showed comparable protection rates with FYL-66. The absolute bioavailability of 40 was 89.6% with half-lives of 8.87 ± 3.25 h (p.o.) and 5.40 ± 1.40 h (i.v.), respectively. Meanwhile, our findings show the importance of the C-5 side chain of FYL-66 and imply compounds with small C-5 substituents mimicking the acetamide group display better activities. It is also quite intriguing that different antibacterial effects are presented by analogues of FYL-66, Linezolid and other oxazolidinones with the same fluoro-substitution patterns of the acetyl group at the C-5 position.

Graphical abstract: Synthesis and antibacterial activity evaluation of C-5 side chain modified analogues of FYL-66, a potential agent against methicillin-resistant Staphylococcus aureus

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Publication details

The article was received on 10 Mar 2015, accepted on 20 Apr 2015 and first published on 21 May 2015


Article type: Concise Article
DOI: 10.1039/C5MD00101C
Citation: Med. Chem. Commun., 2015,6, 1156-1172

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    Synthesis and antibacterial activity evaluation of C-5 side chain modified analogues of FYL-66, a potential agent against methicillin-resistant Staphylococcus aureus

    X. Yang, Z. Li, Z. Wang, Z. Sang, H. Long, J. Tang, T. Yang, Y. Liu and Y. Luo, Med. Chem. Commun., 2015, 6, 1156
    DOI: 10.1039/C5MD00101C

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