title: Antibacterial optimization of 4-aminothiazolyl analogues of the natural product GE2270 A: identification of the cycloalkylcarboxylic acids.
abstract: 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.
authors: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, United States. matthew.lamarche@novartis.com
authors: Matthew J
authors: MJ
authors: LaMarche
authors: Jennifer A
authors: JA
authors: Leeds
authors: Kerri
authors: K
authors: Amaral
authors: Jason T
authors: JT
authors: Brewer
authors: Simon M
authors: SM
authors: Bushell
authors: Janetta M
authors: JM
authors: Dewhurst
authors: JoAnne
authors: J
authors: Dzink-Fox
authors: Eric
authors: E
authors: Gangl
authors: Julie
authors: J
authors: Goldovitz
authors: Akash
authors: A
authors: Jain
authors: Steve
authors: S
authors: Mullin
authors: Georg
authors: G
authors: Neckermann
authors: Colin
authors: C
authors: Osborne
authors: Deborah
authors: D
authors: Palestrant
authors: Michael A
authors: MA
authors: Patane
authors: Elin M
authors: EM
authors: Rann
authors: Meena
authors: M
authors: Sachdeva
authors: Jian
authors: J
authors: Shao
authors: Stacey
authors: S
authors: Tiamfook
authors: Lewis
authors: L
authors: Whitehead
authors: Donghui
authors: D
authors: Yu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019540:Area Under Curve; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D005260:Female; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000235:genetics; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D010456:Peptides, Cyclic; D013844:Thiazoles; C068122:GE 2270 A