title: Design and synthesis of potent Gram-negative specific LpxC inhibitors.
abstract: Antibiotic resistant hospital acquired infections are on the rise, creating an urgent need for novel bactericidal drugs. Enzymes involved in lipopolysaccharide (LPS) biosynthesis are attractive antibacterial targets since LPS is the major structural component of the outer membrane of Gram-negative bacteria. Lipid A is an essential hydrophobic anchor of LPS and the first committed step in lipid A biosynthesis is catalyzed by a unique zinc dependent metalloamidase, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). LpxC is an attractive Gram-negative only target that has been chemically validated by potent bactericidal hydroxamate inhibitors that work by coordination of the enzyme's catalytic zinc ion. An exploratory chemistry effort focused on expanding the SAR around hydroxamic acid zinc-binding 'warheads' lead to the identification of novel compounds with enzyme potency and antibacterial activity similar to CHIR-090.
authors.affiliation: Department of Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA. umar.faruk.mansoor@merck.com
authors.forename: U Faruk
authors.initials: UF
authors.lastname: Mansoor
authors.forename: Dilrukshi
authors.initials: D
authors.lastname: Vitharana
authors.forename: Panduranga Adulla
authors.initials: PA
authors.lastname: Reddy
authors.forename: Dayna L
authors.initials: DL
authors.lastname: Daubaras
authors.forename: Paul
authors.initials: P
authors.lastname: McNicholas
authors.forename: Peter
authors.initials: P
authors.lastname: Orth
authors.forename: Todd
authors.initials: T
authors.lastname: Black
authors.forename: M Arshad
authors.initials: MA
authors.lastname: Siddiqui
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001570:Benzodiazepinones / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006877:Hydroxamic Acids / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001570:Benzodiazepinones; D006877:Hydroxamic Acids; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase; D015032:Zinc