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

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. Med. Chem. Commun. This journal is Scheme 1 General synthetic route to compounds 11-23. Reagents and conditions: (a) (S)-glycidol, EtOH, 50°C, 35.1%; (b) diethyl carbonate, tBuOK, DMF, 60°C, 85.6%; (c) TsCl, DMAP, Et 3 N, DCM, r.t., 55.8%; (d) DIPEA, ACN, 80°C, 20-70%. Scheme 2 Synthetic route to compounds 24-25. Reagents and conditions: (a) for 24: acetyl chloride, Et 3 N, DCM, 0°C, then r.t., 58%; for 25: benzoyl chloride, Et 3 N, DCM, 0°C, then r.t., 64%. Scheme 3 Synthetic route to compounds 26-28. Reagents and conditions: (a) for 26: CH 3 ONa, CH 3 OH, r.t., 50%; (b) for 27: imidazole, NaH, DMF, r.t., 40%; for 28: thiophenethiol, NaH, DMF, r.t., 37%.MedChemComm Concise Article Scheme 4 Synthetic route to compounds 31. Reagents and conditions: (a) NaN 3 , DMF, 72°C, 89%; (b) TMSA, Cu/CuSO 4 ·5H 2 O, tBuOH, 65°C, 54%; (c) TBAF, AcOH, THF, r.t., 80%. Scheme 5 Synthetic route to compounds 33-41. Reagents and conditions: (a) PPh 3 , THF, r.t., then H 2 O, 45°C, 56%; (b) for 33: propionyl chloride, Et 3 N, DCM, 0°C, then r.t., 88%; for 34: ethyl formate, reflux, 80°C, 87%; for 35: MsCl, Et 3 N, DCM, 0°C, then r.t., 34.11%; for 36: dimethylsulfamoyl chloride, Et 3 N, DCM, 0°C, then r.t., 86%; for 37: CDI, methanol, MeONa, DCM, r.t., 79%; for 38: ethyl isocyanate, diisopropylethylamine, DCM, 0°C, then r.t., 75%; for 39: methyl fluoroacetate, 2,2,2-trifluoroethanol, 75°C, 82%; for 40: ethyl difluoroacetate, methanol, Et 3 N, 0°C, then r.t., 69%; for 41: 2,2,2-trifluoroacetic anhydride, Et 3 N, DCM, 0°C, then r.t., 69%. Scheme 6 Synthetic route to compounds 43-45. Reagents and conditions: (a) TEMPO, NaOCl, NaClO 2 , s...