Design, synthesis, antibacterial activity evaluation and molecular docking study of pleuromutilin derivatives bearing amide side chains.

A seize of pleuromutilin derivatives containing amide side chains were designed and synthesized as potential antibiotics against Methicillin-resistant Staphylococcus aureus (MRSA). Among all target compounds (compounds 11-30), compound 25 was found to have the strongest antibacterial activity against MRSA (minimum inhibitory concentration = 0.5 μg/ml). The result of the time-kill curves indicated that compound 25 could repress the growth of MRSA in vitro obviously (-3.72 log 10 CFU/ml reduction). Furthermore, molecular docking studies demonstrated that compound 25 was localized in the binding pocket of 50S ribosomal subunit (ΔGb = -8.99 kcal/mol). Besides, compound 25 displayed low cytotoxicity to RAW 264.7 cells. The results suggested that compound 25 might be further developed into a novel antimicrobial agent against MRSA.