Synthesis of novel thiazole/thiadiazole conjugates of fluoroquinolones as potent antibacterial and antimycobacterial agents

Abstract

Twenty azole-fluoroquinolone hybrids were designed and synthesized by conjugating thiazole and thiadiazole structures to ciprofloxacin and norfloxacin via a 2-oxoethyl bridge. The structures and purities of the synthesized compounds were proven by spectral techniques. The antimycobacterial effects of target compounds 21–40 were tested against Mycobacterium tuberculosis H37Rv strain. Among the 20 synthesized compounds, 12 exhibited minimal inhibition concentration (MIC) values in the range of 1.56–25 μg/mL. Among the molecules screened for antimycobacterial effects, the most effective was compound 35, a thiadiazole-ciprofloxacin hybrid. The cytotoxic effect of this molecule was found to be lower than the reference drugs, and it was also determined to be a more effective inhibitor than ciprofloxacin and norfloxacin in the DNA-gyrase supercoiling test. The antimicrobial effects of compounds 21–40 were screened by agar-well diffusion and microdilution tests against Gram-positive/negative bacteria, a fast-growing mycobacterium, and two yeast strains. While most of the compounds tested showed antibacterial effects, the most effective fluoroquinolone derivative appeared to be compound 31 with an MIC value of < 0.63 μg/mL against all Gram-negative bacteria tested. Azole-fluoroquinolone hybrids 21–40 did not show any activity against non-pathogenic Lactobacillus species and yeast-like fungi, indicating that they have selective antibacterial and antimycobacterial activity, particularly against Gram-negative bacteria. In silico molecular docking studies were conducted to uncover the interactions between lead compound 35 and the DNA gyrase proteins of M. tuberculosis and S. aureus. Additionally, a 100 ns molecular dynamics simulation was carried out to assess the stability of the complexes formed between compound 35 and both proteins.