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

Liu, Jie; Zhang, Guangyu; Zhang, Zhe; Li, Bo; Chai, Fei; Wang, Qi; Zhou, Zi‐Dan; Xu, Lingling; Wang, Shou-Kai; Jin, Zhen; Tang, You‐Zhi

doi:10.1016/j.bioorg.2021.104956

Cited by 18 publications

(22 citation statements)

References 28 publications

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“…These results were consistent with the binding affinity in SPR and the MIC results of the in vitro experiment. In summary, compound 9 has strong binding activity with the 50S ribosome supported by binding mode characterization [19].…”

Section: Docking Studiesmentioning

confidence: 79%

“…Since pleuromutilin was first isolated from two basidiomycete species in 1951, thousands of pleuromutilin derivatives have been synthesized [18]. Most studies have shown that modification of the C-14 position of pleuromutilin could led to compounds with improved antimicrobial activity [19]. All marketed drugs of pleuromutilin use thioether substitutions at the C-22 position [13].…”

Section: Effect On Liver Microsomal Cyp3a4 Enzyme Activitymentioning

confidence: 99%

“…Thus, we focused our attention on the semisynthetic pleuromutilin de rivatives without the azole group. In our previous work, several series of pleuromutilin derivatives through an amine at the C-22 position showed good antibacterial activity [18,19]. Ultimately, 23 pleuromu tilin derivatives, where the thioether was replaced by an amine group at the C22 position were designed, synthesized and evaluated for their antibacterial activities against fou strains, including MRSA, in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

et al. 2022

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A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound 9 was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound 9 had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound 9 (KD = 1.77 × 10−8 M) showed stronger affinity to the 50S ribosome than tiamulin (KD = 2.50 × 10−8 M). The antibacterial activity of compound 9 was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log10 CFU/mL), and compound 9 performed a treatment effect (~1.3 log10 CFU/mL). In addition, compound 9 was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC50 = 2.92 μg/mL).

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Section: Docking Studiesmentioning

confidence: 79%

Section: Effect On Liver Microsomal Cyp3a4 Enzyme Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

et al. 2022

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“…Compound 13 , tiamulin and retapamulin at 2 × MIC induced killing of MRSA (-1.2 log 10 CFU/mL, −0.96 log 10 CFU/mL and −1.08 log 10 CFU/mL reduction) after 3 h of incubation. 99.9% of MRSA was killed by 4 × MIC of compounds 10 and 18 at 24 h. After exposure for 24 h, compound 13 killed 99.9% of MRSA at 2 × MIC concentration 23 . The results indicated that compounds 10 , 13 and 18 against MRSA were time-dependent agents.…”

Section: Resultsmentioning

confidence: 96%

“…The results indicated that compounds 10 , 13 and 18 against MRSA were time-dependent agents. For time-dependent antibacterial agents, multiple or continuous intravenous administration may achieve better therapeutic effects 23 , 24 .…”

Section: Resultsmentioning

confidence: 99%

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

Wang

Liu

Zhou

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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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).

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Design, synthesis, and biological evaluation of pleuromutilin derivatives containing 1,2,4‐triazole linker

Zhou

Wang

et al. 2023

Drug Development Research

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A series of thioether pleuromutilin derivatives containing 1,2,4‐triazole on the side chain of C14 were designed and synthesized. The in vitro antibacterial activities experiments of the synthesized derivatives showed that compounds 72 and 73 displayed superior in vitro antibacterial effect against MRSA minimal inhibitory concentration (MIC = 0.0625 μg/mL) than tiamulin (MIC = 0.5 μg/mL). The results of time‐kill study and postantibiotic effect study indicated that compound 72 could inhibit the growth of MRSA quickly (−2.16 log10 CFU/mL) and showed certain postantibiotic effect (PAE) time (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 1.30 and 1.35 h) against MRSA. Furthermore, the binding mode between compound 72 and 50S ribosome of MRSA was explored by molecular docking and five hydrogen bonds were formed between compound 72 and 50S ribosome.

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

Cited by 18 publications

References 28 publications

Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

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

Design, synthesis, and biological evaluation of pleuromutilin derivatives containing 1,2,4‐triazole linker

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