title: N-O chemistry for antibiotics: discovery of N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds as selective antibacterial agents using nitroso Diels-Alder and ene chemistry.
abstract: The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ∼100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring-opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium  Micrococcus luteus  ATCC 10240 (MIC(90) = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of  Staphylococcus aureus  (MRSA) and  Enterococcus faecalis  (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Wencewicz
authors.forename: Baiyuan
authors.initials: B
authors.lastname: Yang
authors.forename: James R
authors.initials: JR
authors.lastname: Rudloff
authors.forename: Allen G
authors.initials: AG
authors.lastname: Oliver
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Miller
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015169:Colony Count, Microbial; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006898:Hydroxylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009603:Nitroso Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D000900:Anti-Bacterial Agents; D006898:Hydroxylamines; D009603:Nitroso Compounds; D011725:Pyridines