title: Base substituted 5'-O-(N-isoleucyl)sulfamoyl nucleoside analogues as potential antibacterial agents.
abstract: Aminoacyl-sulfamoyl adenosines are well-known nanomolar inhibitors of the corresponding prokaryotic and eukaryotic tRNA synthetases in vitro. Inspired by the aryl-tetrazole containing compounds of Cubist Pharmaceuticals and the modified base as found in the natural antibiotic albomycin, the selectivity issue of the sulfamoylated adenosines prompted us to investigate the pharmacophoric importance of the adenine base. We therefore synthesized and evaluated several isoleucyl-sulfamoyl nucleoside analogues with either uracil, cytosine, hypoxanthine, guanine, 1,3-dideaza-adenine (benzimidazole) or 4-nitro-benzimidazole as the heterocyclic base. Based on the structure and antibacterial activity of microcin C, we also prepared their hexapeptidyl conjugates in an effort to improve their uptake potential. We further compared their antibacterial activity with the parent isoleucyl-sulfamoyl adenosine (Ile-SA), both in in vitro and in cellular assays. Surprisingly, the strongest in vitro inhibition was found for the uracil containing analogue 16f. Unfortunately, only very weak growth inhibitory properties were found as of low uptake. The results are discussed in the light of previous literature findings.
authors.affiliation: KU Leuven, Medicinal Chemistry, Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Bharat
authors.initials: B
authors.lastname: Gadakh
authors.affiliation: KU Leuven, Medicinal Chemistry, Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Gaston
authors.initials: G
authors.lastname: Vondenhoff
authors.affiliation: KU Leuven, Medicinal Chemistry, Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Eveline
authors.initials: E
authors.lastname: Lescrinier
authors.affiliation: KU Leuven, Medicinal Chemistry, Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.affiliation: KU Leuven, Medicinal Chemistry, Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Mathy
authors.initials: M
authors.lastname: Froeyen
authors.affiliation: KU Leuven, Medicinal Chemistry, Rega Institute for Medical Research, Leuven, Belgium. Electronic address: Arthur.VanAerschot@REGA.KULeuven.be.
authors.forename: Arthur
authors.initials: A
authors.lastname: Van Aerschot
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000241:Adenosine
keywords: Aminoacyl-tRNA synthetases; Base modifications; Enzyme inhibitors; In vitro affinity; Molecular modeling; Nucleoside antibiotics