Design, synthesis, biological evaluation and molecular docking studies of novel pleuromutilin derivatives containing nitrogen heterocycle and alkylamine groups

Abstract

A series of pleuromutilin derivatives containing alkylamine and nitrogen heterocycle groups were designed and synthesised under mild conditions. The in vitro antibacterial activity of these semisynthetic derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, S.aureus ATCC 29213, S.aureus AD3, and S.aureus 144) were evaluated by the broth dilution method. Compound 13 was found to have excellent antibacterial activity against MRSA (MIC = 0.0625 μg/mL). Furthermore, compound 13 was further studied by the time-killing kinetics and the post-antibiotic effect approach. In the mouse thigh infection model, compound 13 exhibited superior antibacterial efficacy than that of tiamulin. Meanwhile, compound 13 showed a lower inhibitory effect than that of tiamulin on RAW264.7 and 16HBE cells at the concentration of 10 μg/mL. Molecular docking study revealed that compound 13 can effectively bind to the active site of the 50S ribosome (the binding free energy = −9.66 kcal/mol).

Design, synthesis, biological evaluation and molecular docking study of novel pleuromutilin derivatives containing substituted benzoxazole as antibacterial agents

“…A general synthetic route based on the 22-deoxy-22-tosylpleuromutilin (compound 6 ), and a variety of benzoxazole-2-thiol derivatives were used to prepare target productions ( Scheme 1 ). Synthetic route of target productions was referred from our previous literatures 16 . Compound 6 (1.0 g; 1.87 mmol; 1.0 equiv) was dissolved in acetonitrile (20 ml).…”

“…In our previous research, we successfully designed and synthesised a range of pleuromutilin derivatives that demonstrated potent antimicrobial activity against MRSA 14 – 16 . One promising class of compounds in synthetic chemistry is benzoheterocycles containing mercaptans, which exhibit a wide variety of biological and pharmacological activities 17–19 .…”

Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Pleuromutilin Derivatives Containing Thiazole

“…The synthesis of compound 9 was performed as described in our previous work. 35 It was obtained by stirring the mixture of compound 1 and p-toluenesulfonyl chloride in dichloromethane. After stirring at room temperature for 3 h, compound 9 was then recrystallized from ethanol.…”

“…After incubation for 18−24 h, the visualized colonies were counted. According to the previous report, 35 the PAE was computed (Figure 3). 17 ICR/Swiss mice, aged 6 weeks, have been chosen for the in vivo study.…”

“…After incubation for 18−24 h, the visualized colonies were counted. According to the previous report, 35 the PAE was computed (Figure 3).…”