Pleuromutilin derivatives having a purine ring. Part 3: Synthesis and antibacterial activity of novel compounds possessing a piperazine ring spacer

In the course of our research aimed at the discovery of metabolically stable pleuromutilin analogues with potent in vitro antibacterial activity against Gram-positive pathogens, the synthesis and antibacterial activity of novel compounds bearing a piperazine ring spacer are described. SAR studies on the water-soluble thioether pleuromutilin analogue 6, which has excellent in vitro and in vivo antibacterial activities, led to discovery of the novel pleuromutilin derivatives having a piperazine ring spacer. These derivatives displayed potent and well-balanced in vitro antibacterial activity against various drug-susceptible and -resistant Gram-positive bacteria. In particular, the promising pleuromutilin analogues 37 and 40 were found to exhibit strong in vivo efficacy against Staphylococcus aureus Smith.