title: Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and structure-activity relationships.
abstract: The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to the ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.
authors.affiliation: Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139, USA. paul_charifson@vrtx.com
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Grillot
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Parsons
authors.forename: Michael
authors.initials: M
authors.lastname: Badia
authors.forename: Steve
authors.initials: S
authors.lastname: Bellon
authors.forename: David D
authors.initials: DD
authors.lastname: Deininger
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Drumm
authors.forename: Christian H
authors.initials: CH
authors.lastname: Gross
authors.forename: Arnaud
authors.initials: A
authors.lastname: LeTiran
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Liao
authors.forename: Nagraj
authors.initials: N
authors.lastname: Mani
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.forename: Steven
authors.initials: S
authors.lastname: Ronkin
authors.forename: Dean
authors.initials: D
authors.lastname: Shannon
authors.forename: Lora L
authors.initials: LL
authors.lastname: Swenson
authors.forename: Qing
authors.initials: Q
authors.lastname: Tang
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Tessier
authors.forename: Ski-Kai
authors.initials: SK
authors.lastname: Tian
authors.forename: Martin
authors.initials: M
authors.lastname: Trudeau
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.forename: Yunyi
authors.initials: Y
authors.lastname: Wei
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Dean
authors.initials: D
authors.lastname: Stamos
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors*; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D012377:Rodentia; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001562:Benzimidazoles; D059005:Topoisomerase II Inhibitors; D014508:Urea; C031000:benzimidazole; D027101:DNA Topoisomerase IV