title: Synthesis and biological evaluation of 8-aminomethyltetracycline derivatives as novel antibacterial agents.
abstract: The C-8 position of the tetracyclines has been largely underexplored because of limitations in traditional semisynthetic techniques. Employing a total synthetic approach allowed for modifications at the C-7 and C-8 positions, enabling the generation of structure-activity relationships for overcoming the two most common tetracycline bacterial-resistance mechanisms: ribosomal protection (tet(M)) and efflux (tet(A)). Ultimately, several compounds were identified with balanced activity against both Gram-positive and Gram-negative bacteria, including pathogens bearing both types of tetracycline-resistance mechanisms. Compounds were screened in a murine systemic infection model to rapidly identify compounds with oral bioavailability, leading to the discovery of several compounds that exhibited efficacy when administered orally in murine pyelonephritis and pneumonia models.
authors.affiliation: Discovery Chemistry, ‡Microbiology, and §Process Chemistry R&D, Tetraphase Pharmaceuticals, Inc. , 480 Arsenal Street, Watertown, Massachusetts 02472, United States.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Clark
authors.forename: Minsheng
authors.initials: M
authors.lastname: He
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Deng
authors.forename: Cuixiang
authors.initials: C
authors.lastname: Sun
authors.forename: Chi-Li
authors.initials: CL
authors.lastname: Chen
authors.forename: Diana K
authors.initials: DK
authors.lastname: Hunt
authors.forename: William J
authors.initials: WJ
authors.lastname: O'Brien
authors.forename: Corey
authors.initials: C
authors.lastname: Fyfe
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Sutcliffe
authors.forename: Catherine
authors.initials: C
authors.lastname: Achorn
authors.forename: Philip C
authors.initials: PC
authors.lastname: Hogan
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Katz
authors.forename: John
authors.initials: J
authors.lastname: Niu
authors.forename: Wu-Yan
authors.initials: WY
authors.lastname: Zhang
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Zhu
authors.forename: Magnus
authors.initials: M
authors.lastname: Ronn
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001424:Bacterial Infections / Q000150:complications; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D015394:Molecular Structure; D011014:Pneumonia / Q000209:etiology / Q000517:prevention & control; D011704:Pyelonephritis / Q000209:etiology / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013753:Tetracycline Resistance / Q000187:drug effects; D013754:Tetracyclines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D013754:Tetracyclines