A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking.

Novel series of pleuromutilin analogs containing substituted 1,2,3-triazole moieties were designed, synthesised and assessed for their antibacterial activity against Methicillin-resistant (MRSA). Initially, the antibacterial activities of these derivatives against 4 strains of (MRSA ATCC 43300, ATCC 29213, AD3, and 144) were tested by the broth dilution method. Most of the synthesised pleuromutilin analogs displayed potent activities. Among them, compounds , , and (MIC = 0.5∼1 µg/mL) showed the most effective antibacterial activity and their anti-MRSA activity were further studied by the time-killing kinetics approach. Binding mode investigations by surface plasmon resonance (SPR) with ribosome revealed that the selected compounds all showed obvious affinity for ribosome (K = 2.32 × 10∼5.10 × 10 M). Subsequently, the binding of compounds and to the ribosome was further investigated by molecular modelling. Compound had a superior docking mode with ribosome, and the binding free energy of compound was calculated to be -12.0 kcal/mol.