Mannich reaction derivatives of novobiocin with modulated physiochemical properties and their antibacterial activities

Abstract Synthetic derivatives of the natural product antibiotic novobiocin were synthesized in order to improve their physiochemical properties. A Mannich reaction was used to introduce new side chains at a solvent-exposed position of the molecule, and a diverse panel of functional groups was evaluated at this position. Novobiocin and the new derivatives were tested for their binding to gyrase B and their antibacterial activities against Staphylococcus aureus , Mycobacterium tuberculosis , Francisella tularensis and Escherichia coli . While the new derivatives still bound the gyrase B protein potently (0.07–1.8 μM, IC 50 ), they had significantly less antibacterial activity. Two compounds were identified with increased antibacterial activity against M. tuberculosis , with a minimum inhibitory concentration of 2.5 μg/ml.