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

Drug Dev Res. 2023 Jun;84(4):703-717. doi: 10.1002/ddr.22050. Epub 2023 Mar 10.

Abstract

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.

Keywords: 1,2,4-triazole; MRSA; antibacterial activity; pleuromutilin.

MeSH terms

  • Anti-Bacterial Agents* / chemistry
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Pleuromutilins
  • Polycyclic Compounds* / chemistry
  • Polycyclic Compounds* / pharmacology
  • Structure-Activity Relationship

Substances

  • 1,2,4-triazole
  • Anti-Bacterial Agents
  • Polycyclic Compounds