Potent trifluoromethoxy, trifluoromethylsulfonyl, trifluoromethylthio and pentafluorosulfanyl containing (1,3,4-oxadiazol-2-yl)benzamides against drug-resistant Gram-positive bacteria.

According to the Centers for Disease Control and Prevention (CDC), methicillin-resistant Staphylococcus aureus (MRSA) affects about 80000 patients in the US annually and directly causes about 11000 deaths. Therefore, despite the fact that there are several drugs available for the treatment of MRSA, there is a need for new chemical entities. We previously reported that 1,3,4-oxadiazolyl sulfonamide F6 was bacteriostatic and inhibited MRSA strains with a minimum inhibitory concentration (MIC) of 2 mu g mL(-1). Here, we report the discovery of trifluoromethoxy (OCF3), trifluoromethylsulfonyl (SO2CF3), trifluoromethylthio (SCF3) and pentafluorosulfanyl (SF5) containing (1,3,4-oxadiazol-2-yl)benzamides exhibiting potent antibacterial activities against MRSA [MIC values as low as 0.06 mu g mL(-1) against linezolid-resistant S. aureus (NRS 119)]. Interestingly, whereas the OCF3 and SO2CF3 containing oxadiazoles were bacteriostatic, the SCF3 and SF5 containing oxadiazoles were bactericidal. They exhibited a wide spectrum of activities against an extensive panel of Gram-positive bacterial strains, including MRSA, vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant enterococcus (VRE) and methicillin-resistant or cephalosporin-resistant Streptococcus pneumoniae. Furthermore, compounds 6 and 12 outperformed vancomycin in clearing intracellular MRSA in infected macrophages. Moreover, the tested compounds behaved synergistically or additively with antibiotics used for the treatment of MRSA infections.