Synthesis and Biological Properties of Pyridoxine Derivatives Containing 1,3-Oxazolidine-2-one Fragments
摘要
Objective: One of the most promising approaches to addressing the problem of bacterial resistance is the development of antibacterial drugs with a novel mechanism of action. Oxazolidinones are a class of synthetic antibacterial drugs with high activity against a wide range of Gram-positive bacteria, including resistant strains. A library of 11 pyridoxine derivatives containing 1,3-oxazolidin-2-one fragments at the second, fifth, and sixth positions was synthesized. Methods: The structures of the synthesized compounds were confirmed by 1H, 13C NMR spectroscopy and mass spectrometry. The target oxazolidinone derivatives were obtained using organic synthesis methods. Numerous biological experiments were performed to evaluate the antibacterial activity and toxicity of the synthesized compounds. Results and Discussion: The antimicrobial activity testing on 6 reference strains and 6 clinical isolates of Gram-positive bacteria, as well as in vitro toxicity against a panel of normal human cells (HSF, MSC, and HEK-293), revealed a highly active and low-toxicity lead compound containing a 1,3-oxazolidin-2-one fragment at the fifth position of pyridoxine. Subsequent studies on bacterial biofilms of S. aureus and E. faecium demonstrated comparable and, in some cases, superior efficacy to linezolid. The lead compound, unlike linezolid, did not exhibit a mutagenic effect in the Ames test and also showed high safety upon intragastric administration to mice (LD50 >2000 mg/kg). Conclusions: The results indicate that pyridoxine derivatives containing 1,3-oxazolidin-2-one fragments are of interest for antibacterial drug development.