title: Fluorocyclines. 1. 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent.
abstract: This and the accompanying report (DOI: 10.1021/jm201467r ) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP-434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference , Boston, MA , September 12-15, 2010 , poster F1 - 2157 ), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).
authors.affiliation: Discovery Chemistry, Tetraphase Pharmaceuticals, 480 Arsenal Street, Watertown, Massachusetts 02472, United States. xyxiao@tphase.com
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Xiao
authors.forename: Diana K
authors.initials: DK
authors.lastname: Hunt
authors.forename: Jingye
authors.initials: J
authors.lastname: Zhou
authors.forename: Roger B
authors.initials: RB
authors.lastname: Clark
authors.forename: Nick
authors.initials: N
authors.lastname: Dunwoody
authors.forename: Corey
authors.initials: C
authors.lastname: Fyfe
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
authors.forename: William J
authors.initials: WJ
authors.lastname: O'Brien
authors.forename: Louis
authors.initials: L
authors.lastname: Plamondon
authors.forename: Magnus
authors.initials: M
authors.lastname: Rönn
authors.forename: Cuixiang
authors.initials: C
authors.lastname: Sun
authors.forename: Wu-Yan
authors.initials: WY
authors.lastname: Zhang
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Sutcliffe
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003520:Cyclophosphamide; D024901:Drug Resistance, Multiple, Bacterial; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000209:etiology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008297:Male; D016106:Methicillin Resistance; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013753:Tetracycline Resistance; D013754:Tetracyclines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D011759:Pyrrolidines; D013754:Tetracyclines; C571179:eravacycline; D003520:Cyclophosphamide