Design, Synthesis and Antibacterial Studies of 1,3,4-Oxadiazole-Fluoroquinolone Hybrids and Their Molecular Docking Studies

A series of novel hybrids built on fluoroquinolone skeleton were synthesized by introducing 1,3,4-oxadiazole derivatives to the C-7 site of ciprofloxacin or norfloxacin. In vitro antibacterial evaluation showed that hybrids 4 b-d (5-(hydroxyphenyl)-1,3,4-oxadiazol-2-yl substituted ciprofloxacin) were an increased activity against Staphylococcus aureus, with a minimum inhibitory concentration (MIC) of <= 0.125 mu g/mL, four times superior to the parent drug. Hybrids 4 b-e (4 e, 5-(4-(trifluoromethyl) phenyl)-1,3,4-oxadiazol-2-yl substituted ciprofloxacin) also exhibited significant activity against methicillin-resistant S. aureus (MRSA), resistant to the parent drug. All the hybrids demonstrated a bactericidal effect on standard bacteria with the MBC value not exceeding four times of their corresponding MIC values. In time-killing assays, 4 c demonstrated a superior bactericidal action in eradicating S. aureus and E. coli within 2 h, respectively, equipotent to ciprofloxacin. In the molecular docking study, hybrids 4 c exhibited a high binding affinity for type IV topoisomerase with a minimum binding energy of -10.2 kcal/mol.

Automated summary

A series of novel hybrids based on fluoroquinolone skeleton were synthesized by introducing 1,3,4-oxadiazole derivatives to ciprofloxacin or norfloxacin at the C-7 site. In vitro antibacterial evaluation showed that some of the hybrids exhibited increased activity against Staphylococcus aureus and methicillin-resistant S. aureus, with some demonstrating bactericidal effects on standard bacteria. Molecular docking study revealed high binding affinity of certain hybrids to type IV topoisomerase.