1. Academic Validation
  2. Design, synthesis and biological evaluation of novel pleuromutilin derivatives containing piperazine and 1,2,3-triazole linker

Design, synthesis and biological evaluation of novel pleuromutilin derivatives containing piperazine and 1,2,3-triazole linker

  • Bioorg Chem. 2020 Dec;105:104398. doi: 10.1016/j.bioorg.2020.104398.
Guang-Yu Zhang 1 Zhe Zhang 1 Kang Li 1 Jie Liu 1 Bo Li 1 Zhen Jin 2 Ya-Hong Liu 2 You-Zhi Tang 3
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
  • 2 Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China.
  • 3 Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China. Electronic address: youzhitang@scau.edu.cn.
Abstract

A series of novel pleuromutilin derivatives containing piperazine ring, 1, 2, 3-triazoles and secondary amines on the side chain of C14 were synthesized under mild conditions via click reaction. The in vitro Antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213 ,144 and AD3) and one strain of Escherichia coli (ATCC 25922) were evaluated by the broth dilution method. Among these derivatives, 22-[2-(4-((4-nitrophenyl piperazine)methyl)-1,2,3-triazol-1-yl)-1-(piperazine-1-yl) ethyl-1-one] deoxy pleuromutilin (compound 59) showed the most prominent in vitro Antibacterial effect against MRSA (MIC = 1 μg/mL). Furthermore, compound 59 displayed more rapid bactericidal kinetic than tiamulin time-kill studies and possessed a longer PAE than tiamulin against MRSA in vitro. In addition, in vivo Antibacterial activities of compound 59 against MRSA were further evaluated employing thigh Infection model. And compound 59 (-8.89 log10 CFU/mL) displayed superior activities than tiamulin. Compound 59 was further evaluated in CYP450 inhibition assay and the results showed that it exhibited low to moderate inhibitory effects on CYP1A2, CYP2E1, CYP2D6 and CYP3A4 Enzymes. The PK properties of compound 59 were then measured. The half-life (t1/2), clearance rate (Cl) and the area under the plasma concentration time curve (AUC0→∞) of compound 59 were 0.74 h, 0.29 L/h/kg and 46.28 μg·h/mL, respectively.

Keywords

1,2,3-Triazole; Antibacterial activity; Click chemistry; MRSA; Pleuromutilin.

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