Isothiazolones are
widely used as biocides in industrial processing
systems and personal care products, but their use to treat infections
in humans has been hampered by their inherent cytotoxicity. Herein,
we report a strategy to alleviate isothiazolone toxicity and improve
antibacterial and antibiofilm potency by functionalization with a
nitroxide moiety. Isothiazolone–nitroxide hybrids 6 and 22 were prepared over three steps in moderate yields
(58 and 36%, respectively) from (Z)-3-(benzylsulfanyl)-propenoic
acid. Hybrid 22 displayed better activity (minimum inhibitory
concentration (MIC) = 35 μM) than the widely used methylisothiazolinone
(MIT 1, MIC = 280 μM) against methicillin-susceptible Staphylococcus aureus (MSSA). Hybrid 22 was even more active against drug-resistant strains, such as vancomycin-resistant Staphylococcus aureus (VRSA, MIC = 8.75 μM)
over MIT 1 (MIC = 280 μM). The enhanced antibacterial
activity of hybrid 22 over MIT 1 was retained
against established MSSA and VRSA biofilms, with minimum biofilm eradication
concentration (MBEC) values of 35 and 70 μM, respectively, for 22 (the MBEC value for MIT 1 against both strains
was ≥280 μM). No toxicity was observed in human epithelial
T24 cells treated with hybrid 22 in concentrations up
to 560 μM using a lactate dehydrogenase assay.