title: 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.
authors.affiliation: Center for Infectious Disease and Biodefense Research, Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.
authors.forename: Arlyn
authors.initials: A
authors.lastname: Tambo-ong
authors.forename: Sidharth
authors.initials: S
authors.lastname: Chopra
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Glaser
authors.forename: Karen
authors.initials: K
authors.lastname: Matsuyama
authors.forename: Tran
authors.initials: T
authors.lastname: Tran
authors.forename: Peter B
authors.initials: PB
authors.lastname: Madrid
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D008352:Mannich Bases / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D008352:Mannich Bases; D059005:Topoisomerase II Inhibitors; D009675:Novobiocin