Synthesis, Characterization, and Antimicrobial Activity Screening of Some Novel 3-(2-(3-(Substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline Derivatives as Potential Antimycobacterial Agents.

Microbial infections remain a grave threat to global health security due to increasing antibiotic resistance. The coronavirus pandemic has increased the risk of microbial infection. To combat these infections, the search for new therapeutic agents is in high demand. A series of new 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline (-) derivatives have been synthesized. The structure of synthesized compounds was analyzed by spectroscopic methods. The newly synthesized oxetanyl-quinoline derivatives were evaluated for antibacterial activity against (NCIM 2574), (NCIM 2388), (NCIM 2063), (NCIM 2178), and antifungal activity against (ATCC 504) and (NCIM 3100). Six oxetanyl-quinoline derivatives , , , , , and have shown good antibacterial activity against with MIC 31.25-62.5 μM, 3-(((3-(2-fluoro-6-((8-fluoro-2-methylquinolin-3-yl)oxy)phenyl)oxetan-3-yl)oxy)methyl)benzonitrile () reporting comparable activity against with respect to the standard drug streptomycin. Compound also showed good activity against with MIC 31.25 μM. The eight compounds , , , , , , , and have shown good antifungal activity against . The synthesized compounds were also screened for antimycobacterial activity against H37Rv by MTT assay. Among the nine derivatives, compounds , , , , , , and showed excellent antimycobacterial activity with MIC 3.41-12.23 μM, and two derivatives showed good activity with MIC 27.29-57.73 μM. All the derivatives were further evaluated for cytotoxicity against the Vero cell line and were found to be nontoxic. The study of compounds - was performed against ATP synthase (PDB ID: 4V1F) and most of the compounds showed the stable and significant binding to ATP synthase, confirming their plausible mode of action as ATP synthase inhibitors. Thus, the significant antimycobacterial activity of 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline derivatives has suggested that the oxatenyl-quinoline compounds could assist in the development of lead compounds to treat mycobacterial infections.