title: Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE), Part II: development of inhibitors with broad spectrum, Gram-negative antibacterial activity.
abstract: The structurally related bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as prime candidates for the development of broad spectrum antibacterial agents. However, GyrB/ParE targeting antibacterials with spectrum that encompasses robust Gram-negative pathogens have not yet been reported. Using structure-based inhibitor design, we optimized a novel pyrrolopyrimidine inhibitor series with potent, dual targeting activity against GyrB and ParE. Compounds were discovered with broad antibacterial spectrum, including activity against Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli. Herein we describe the SAR of the pyrrolopyrimidine series as it relates to key structural and electronic features necessary for Gram-negative antibacterial activity.
authors.affiliation: Trius Therapeutics, 6310 Nancy Ridge Dr., San Diego, CA 92121, USA.
authors.forename: Micheal
authors.initials: M
authors.lastname: Trzoss
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bensen
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Chen
authors.forename: Thanh
authors.initials: T
authors.lastname: Lam
authors.forename: Junhu
authors.initials: J
authors.lastname: Zhang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: Bryan
authors.initials: B
authors.lastname: Kwan
authors.forename: Mark
authors.initials: M
authors.lastname: Stidham
authors.forename: Kirk
authors.initials: K
authors.lastname: Nelson
authors.forename: Vickie
authors.initials: V
authors.lastname: Brown-Driver
authors.forename: Amanda
authors.initials: A
authors.lastname: Castellano
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Shaw
authors.forename: Felice C
authors.initials: FC
authors.lastname: Lightstone
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Wong
authors.forename: Toan B
authors.initials: TB
authors.lastname: Nguyen
authors.forename: John
authors.initials: J
authors.lastname: Finn
authors.forename: Leslie W
authors.initials: LW
authors.lastname: Tari
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D011743:Pyrimidines; D011758:Pyrroles; D059005:Topoisomerase II Inhibitors; C527741:pyrrolopyrimidine; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase