title: Lead structures for new antibacterials: stereocontrolled synthesis of a bioactive muraymycin analogue.
abstract: Naturally occurring muraymycin nucleoside antibiotics represent a promising class of novel antibacterial agents. The structural complexity suggests the investigation of simplified analogues as potential lead structures, which can then be further optimized towards highly potent antimicrobials. Herein we report studies on muraymycin-derived potential lead structures lacking an aminoribose motif found in most naturally occurring muraymycins. We have identified a 5'-defunctionalized motif to be ideal in terms of stability and chemical accessibility and have synthesized a full-length muraymycin analogue based on this structure using a novel fully stereocontrolled route. The obtained 5'-deoxy analogue of the natural product muraymycin C4 showed good inhibitory properties towards the bacterial target protein MraY, sufficient pharmacokinetic stability and no cytotoxicity against human cells, thus making it a promising lead for antibacterial drug development.
authors.affiliation: Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123 Saarbrücken (Germany); Department of Chemistry, Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstr. 2, 37077 Göttingen (Germany).
authors.forename: Anatol P
authors.initials: AP
authors.lastname: Spork
authors.forename: Martin
authors.initials: M
authors.lastname: Büschleb
authors.forename: Oliver
authors.initials: O
authors.lastname: Ries
authors.forename: Daniel
authors.initials: D
authors.lastname: Wiegmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Boettcher
authors.forename: Agnes
authors.initials: A
authors.lastname: Mihalyi
authors.forename: Timothy D H
authors.initials: TD
authors.lastname: Bugg
authors.forename: Christian
authors.initials: C
authors.lastname: Ducho
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D008826:Microbial Sensitivity Tests; D009711:Nucleotides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D009711:Nucleotides
keywords: amino acids; antibiotics; medicinal chemistry; natural products; nucleosides