Extending the N-linked aminopiperidine class to the mycobacterial gyrase domain: Pharmacophore mapping from known antibacterial leads

• N-linked aminopiperidines were designed and synthesized.
• The compounds were screened for DNA gyrase and antitubercular activities.
• Compound 35 showed IC50 of 78 nM against MTB DNA Gyrase and MIC of 0.62 μM.

Bacterial DNA gyrase is a well-established and clinically validated target to develop novel antibacterial. Our effort was designated to search for synthetically better compounds with possibility of hit to lead development. With this as objective, a series of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one derivatives were designed by molecular hybridization strategy and synthesized following nine step reaction to yield activity in low nanomolar range and commendable antibacterial activities. Compound 1-(4-fluorophenyl)-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (35) emerged as the most promising inhibitor with an IC50 of 78 nM against Mycobacterium tuberculosis DNA gyrase enzyme, with MTB MIC of 0.62 μM, and not cytotoxic at 50 μM in eukaryotic cell line.

Compound 35 emerged as potent inhibitor with an IC50 of 78 nM against Mycobacterium tuberculosis DNA Gyrase enzyme, with a good MTB MIC of 0.62 μM, and was not cytotoxic at 50 μM in eukaryotic cell lines.Figure optionsDownload as PowerPoint slide