title: Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors.
abstract: Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent promising candidates for the development of antibiotics possessing a so far unexploited mechanism of action. In a chiral pool synthesis, starting from the D-mannose derived mannonolactone 4, conformationally constrained C-glycosidic as well as open chained hydroxamic acids with a defined stereochemistry were prepared. Diversity was introduced by performing C–C coupling reactions like the Sonogashira and Suzuki cross-coupling reactions. The biological evaluation of the synthesized compounds revealed that in the case of the C-glycosides a long, linear and rigid hydrophobic side chain is required for antibiotic activity against E. coli. The open chain derivatives show higher biological activity than the conformationally constrained C-glycosides. The morpholinomethyl substituted open chain derivative 43, being the most potent compound presented in this paper, inhibits LpxC with a Ki value of 0.35 μM and represents a promising lead structure.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Löppenberg
authors.forename: Hannes
authors.initials: H
authors.lastname: Müller
authors.forename: Carla
authors.initials: C
authors.lastname: Pulina
authors.forename: Alberto
authors.initials: A
authors.lastname: Oddo
authors.forename: Mark
authors.initials: M
authors.lastname: Teese
authors.forename: Joachim
authors.initials: J
authors.lastname: Jose
authors.forename: Ralph
authors.initials: R
authors.lastname: Holl
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006027:Glycosides; D006877:Hydroxamic Acids; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase