In silico fragment-based discovery of indolin-2-one analogues as potent DNA gyrase inhibitors

We describe here the fragment-based design of potent DNA gyrase inhibitors. Using the tools of virtual screening and NMR spectroscopy we identified the binding of two low-molecular weight fragments (2-aminobenzimidazole and indolin-2-one) to the 24 kDa N-terminal fragment of DNA gyrase B. Further in silico optimization of indolin-2-one led to the discovery of potent DNA gyrase inhibitors.

Graphical abstractWe report here compounds with indolin-2-one scaffold as potent DNA gyrase inhibitors. Using the tools of virtual screening and NMR spectroscopy indolin-2-one analogue HTS05063 (18) that inhibits the DNA gyrase supercoiling activity in the low micromolar range was discovered.Figure optionsDownload full-size imageDownload as PowerPoint slide