title: Synthesis of ciprofloxacin dimers for evaluation of bacterial permeability in atypical chemical space.
abstract: We describe the synthesis and evaluation of a library of variably-linked ciprofloxacin dimers. These structures unify and expand on the use of fluoroquinolones as probes throughout the antibiotic literature. A dimeric analog (19) showed enhanced inhibition of its intracellular target (DNA gyrase), and translation to antibacterial activity in whole cells was demonstrated. Overall, cell permeation was governed by physicochemical properties and bacterial type. A principal component analysis demonstrated that the dimers occupy a unique and privileged region of chemical space most similar to the macrolide class of antibiotics.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Audrey G
authors.initials: AG
authors.lastname: Ross
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
authors.forename: Bret M
authors.initials: BM
authors.lastname: Benton
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Donovan
authors.initials: D
authors.lastname: Chin
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: De Pascale
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Fuller
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Leeds
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
authors.forename: Folkert
authors.initials: F
authors.lastname: Reck
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
authors.forename: Daryl L
authors.initials: DL
authors.lastname: Richie
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Vo
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA. Electronic address: matthew.lamarche@novartis.com.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LaMarche
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002939:Ciprofloxacin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004269:DNA, Bacterial / Q000378:metabolism*; D010539:Permeability
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D004269:DNA, Bacterial; D002939:Ciprofloxacin
keywords: Antibacterial; Antibiotic; Bacterial permeability; Chemical space; DNA gyrase; Dimer; Fluoroquinolone; Middle space