Design, synthesis and antibacterial evaluation of pleuromutilin derivatives

We report herein the design, synthesis, and structure-activity relationship studies of pleuromutilin derivatives containing urea/thiourea functionalities. The antibacterial activities of these new pleuromutilin derivatives were evaluated in vitro against Gram-positive pathogens (GPPs) (Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium) and Mycoplasma pneumoniae by the broth dilution method. Most of the targeted compounds exhibit good potency in inhibiting the growth of pathogens including Methicillin-susceptible S. aureus (MSSA, ATCC29213, MIC: 0.0625-16 μg/mL), Methicillin-resistant S. aureus (MRSA, ATCC43300, MIC: 0.125-16 μg/mL) and M. pneumoniae (ATCC15531 MIC: 0.125-1 μg/mL, ATCC29342 MIC: 0.0625-0.25 μg/mL and drug resistant strain MIC: 0.5-2 μg/mL). In particular, the compounds 6m and 6n containing phenyl-urea group showed excellent activity with the MIC value less than 0.0625 μg/mL against S. aureus ATCC29213. The compound 6h exhibited better activity than tiamulin against Methicillin-resistant S. aureus ATCC43300.