Synthesis, Antibacterial Activities, Mode of Action and Acute Toxicity Studies of New Oxazolidinone-Fluoroquinolone Hybrids

Abstract

To combat bacterial resistance, a series of new oxazolidinone-fluoroquinolone hybrids have been synthesized and characterized. All synthetic hybrids were preliminarily evaluated for their in vitro antibacterial activities against 6 standard strains and 3 clinical isolates. The majority of hybrids displayed excellent activities against Gram-positive bacteria, but limited activities against Gram-negative bacteria. Hybrids OBP-4 and OBP-5 were found to be the most promising compounds. Further, in vitro antibacterial activities, mode of action and acute toxicity in mice of hybrids OBP-4 and OBP-5 were investigated. Hybrids OBP-4 and OBP-5 exhibited potent activities against Gram-positive bacteria, including drug-resistant strains. Correspondingly, studies on the mode of action of hybrids OBP-4 and OBP-5 indicated a strong inhibitory activity on protein synthesis by binding the active site of 50S subunit, but a weak inhibitory action on DNA synthesis. In addition, LD50 values of hybrids OBP-4 and OBP-5 in the acute oral toxicity were larger than 2000 mg/kg, suggesting a good safety profile.

Next-generation strategy for treating drug resistant bacteria: Antibiotic hybrids

“…MCB-3681 demonstrated lower MIC to C. difficile strains as compared to cadazolid, linezolid and ciprofloxacin, but did not have any effect on C. difficile toxin production or spore production. The influence of MCB-3681 on human microbiota showed no abnormalities31.…”

“…MCB-3681 demonstrated lower MIC to C. difficile strains as compared to cadazolid, linezolid and ciprofloxacin, but did not have any effect on C. difficile toxin production or spore production. The influence of MCB-3681 on human microbiota showed no abnormalities31. iii CBR-2092, a multivalent antibiotic is a hybrid of rifampicin pharmacophore with 4H-4-oxoquinolizine sub-series of fluoroquinolone antibiotics32. This dual action hybrid has demonstrated many benefits over rifampin and fluoroquinolone combination treatment.…”

Hybridization of antimicrobial oxazolidinones with commercial drugs: A fight against the “superbugs”

“…It was further confirmed by in silico molecular docking analysis of the test hybrids in the active site of 50 S ribosomal subunit (PDB ID 4WFA). The reported hybrid molecules also exhibited a good safety profile with LD50 values higher than 2000 mg/kg at which no animals died or developed toxicity sign during the in vivo oral acute toxicity experiments (Liu et al, 2019).…”

“…Similarly, the role of "F" atom in both fluoroquinolones and oxazolidinones is to achieve an improved antibacterial potency owing to better interactions with the molecular target in the microbe. Liu et al (2019) developed hybrid molecules 6-10 (Figure 4) based on fluoroquinolone-oxazolidinone conjugation via piperidine methanol linker aimed at combating microbial resistance. The essential features of both pharmacophores were retained with an aim to get a combined antibacterial profile which includes inhibition of bacterial protein synthesis and evading drug resistance by targeting gyrases and microbial topoisomerase.…”

Oxazolidinones as versatile scaffolds in medicinal chemistry

“…8). [62][63][64][65][66] However, despite promising initial screening, these compounds still lack several studies to advance drug development stages.…”