Alkynyl-containing phenylthiazoles: Systemically active antibacterial agents effective against methicillin-resistant Staphylococcus aureus (MRSA).

摘要: Abstract The promising activity of phenylthiazoles against multidrug-resistant bacterial pathogens, in particular MRSA, has been hampered by their limited systemic applicability, due to rapid metabolism hepatic microsomal enzymes, resulting short half-lives. Here, we investigated a series with alkynyl side-chains that were synthesized the objective improving stability metabolism, extending utility from topical applications treatment more invasive, MRSA infections. most compounds inhibited growth clinically-relevant isolates in vitro at concentrations as low 0.5 μg/mL, and exerted antibacterial effect interfering cell wall synthesis via inhibition undecaprenyl diphosphate synthase phosphatase. We also identified two successfully eradicated inside infected macrophages. In vivo PK analysis compound 9 revealed biological half-life ∼4.5 h. In mice, demonstrated comparable potency vancomycin, lower dose (20 mg/kg versus 50 mg/kg), reducing burden systemic, deep-tissue infection, using neutropenic mouse thigh-infection model. Compound thus represents new phenylthiazole lead for infections warrants further development.