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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 ?M, 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 ?g/ml.

SUBMITTER: Tambo-ong A

PROVIDER: S-EPMC3178263 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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

Tambo-ong Arlyn A Chopra Sidharth S Glaser Bryan T BT Matsuyama Karen K Tran Tran T Madrid Peter B PB

Bioorganic & medicinal chemistry letters 20110812 19

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 tul ...[more]

PMID: 21871799

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