title: Synthesis and biological evaluation of enantiomerically pure glyceric acid derivatives as LpxC inhibitors.
abstract: Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent a promising class of novel antibiotics, selectively combating Gram-negative bacteria. In order to elucidate the impact of the hydroxymethyl groups of diol (S,S)-4 on the inhibitory activity against LpxC, glyceric acid ethers (R)-7a, (S)-7a, (R)-7b, and (S)-7b, lacking the hydroxymethyl group in benzylic position, were synthesized. The compounds were obtained in enantiomerically pure form by a chiral pool synthesis and a lipase-catalyzed enantioselective desymmetrization, respectively. The enantiomeric hydroxamic acids (R)-7b (Ki=230nM) and (S)-7b (Ki=390nM) show promising enzyme inhibition. However, their inhibitory activities do not substantially differ from each other leading to a low eudismic ratio. Generally, the synthesized glyceric acid derivatives 7 show antibacterial activities against two Escherichia coli strains exceeding the ones of their respective regioisomes 6.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstr. 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Germany.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tangherlini
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstr. 48, D-48149 Münster, Germany.
authors.forename: Tullio
authors.initials: T
authors.lastname: Torregrossa
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstr. 48, D-48149 Münster, Germany; NRW Graduate School of Chemistry, University of Münster, Germany.
authors.forename: Oriana
authors.initials: O
authors.lastname: Agoglitta
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstr. 48, D-48149 Münster, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Köhler
authors.affiliation: Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck Str. 4, 06120 Halle (Saale), Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Melesina
authors.affiliation: Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck Str. 4, 06120 Halle (Saale), Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstr. 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Germany. Electronic address: hollr@uni-muenster.de.
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*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005988:Glyceric Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005988:Glyceric Acids; C042971:glyceric acid; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase
keywords: Chiral pool synthesis; Enantioselective desymmetrization; Glyceric acid derivatives; LpxC inhibitors; Molecular docking studies; Structure–activity relationships