Design, synthesis, in vitro and in vivo evaluation against MRSA and molecular docking studies of novel pleuromutilin derivatives bearing 1, 3, 4-oxadiazole linker

• Published in: Bioorganic chemistry 2021-07, Vol.112, p.104956, Article 104956
• Main Authors: Liu, Jie, Zhang, Guang-Yu, Zhang, Zhe, Li, Bo, Chai, Fei, Wang, Qi, Zhou, Zi-Dan, Xu, Ling-Ling, Wang, Shou-Kai, Jin, Zhen, Tang, You-Zhi
• Format: Article
• Language: English
• Subjects: 1, 3, 4-Oxadiazole; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Diterpenes - chemical synthesis; Diterpenes - chemistry; Diterpenes - pharmacology; Dose-Response Relationship, Drug; Drug Design; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Molecular docking; Molecular Docking Simulation; Molecular Structure; MRSA; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Pleuromutilin; Pleuromutilins; Polycyclic Compounds - chemical synthesis; Polycyclic Compounds - chemistry; Polycyclic Compounds - pharmacology; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104956

[Display omitted] •Synthesis of novel pleuromutilin derivatives containing 1, 3, 4-oxadiazole.•Compound 133 exhibited superior in vivo efficacy against MRSA (-1.82 log10 CFU/mL).•Compound 133 possessed middle affinity with the 50S ribosome. A class of pleuromutilin derivatives containing 1, 3, 4-oxadiazole were designed and synthesized as potential antibacterial agents against Methicillin-resistant staphylococcus aureus (MRSA). The ultrasound-assisted reaction was proposed as a green chemistry method to synthesize 1, 3, 4-oxadiazole derivatives (intermediates 85–110). Among these pleuromutilin derivatives, compound 133 was found to be the strongest antibacterial derivative against MRSA (MIC = 0.125 μg/mL). Furthermore, the result of the time-kill curves displayed that compound 133 could inhibit the growth of MRSA in vitro quickly (- 4.36 log10 CFU/mL reduction). Then, compound 133 (- 1.82 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (- 0.82 log10 CFU/mL) in reducing MRSA load in mice thigh model. Besides, compound 133 exhibited low cytotoxicity to RAW 264.7 cells. Molecular docking studies revealed that compound 133 was successfully localized in the binding pocket of 50S ribosomal subunit (ΔGb = -10.50 kcal/mol). The results indicated that these pleuromutilin derivatives containing 1, 3, 4-oxadiazole might be further developed into novel antibiotics against MRSA.