title: Synthesis and biological activity of tris- and tetrakiscatecholate siderophores based on poly-aza alkanoic acids or alkylbenzoic acids and their conjugates with beta-lactam antibiotics.
abstract: New linear and tripodal tri-aza- and tetra-aza alkanoic acids or alkylbenzoic acids were prepared as basic structures for siderophore mimetics from polyamines and oxocarbonic acids or formylbenzoic acids by catalytic hydrogenation. From these acids acetylated tris- and tetrakiscatecholates or 8-acyloxy-2,4-dioxo-benzoxazine derivatives as well as compounds with spacer groups were synthesized. These derivatives were coupled with ampicillin, amoxicillin, bacampicillin or cefaclor to new siderophore antibiotic conjugates. Most of the catecholate derivatives showed high siderophore activities in strains of Pseudomonas aeruginosa and Escherichia coli in a growth promotion assay under iron limitation conditions. The beta-lactam conjugates were highly active in vitro against Gram-negative bacteria correlating to the siderophore activity of the catecholate moiety and depending on the beta-lactam part. One ampicillin conjugate based on 5-(aminoethyl)-2,5,8-triazaalkylbenzoic acid was highly active against Gram-negative and Gram-positive bacteria. It was shown that conjugates with enhanced activity against Gram-negative bacteria use active iron uptake routes to penetrate the bacterial outer membrane barrier. Correlations between structure and biological activity were studied.
authors.affiliation: Hans Knöll-Institute for Natural Product Research, Jena, Germany. Heinisch@pmail.hki-jena.de
authors.forename: Lothar
authors.initials: L
authors.lastname: Heinisch
authors.forename: Steffen
authors.initials: S
authors.lastname: Wittmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Stoiber
authors.forename: Ina
authors.initials: I
authors.lastname: Scherlitz-Hofmann
authors.forename: Dorothe
authors.initials: D
authors.lastname: Ankel-Fuchs
authors.forename: Ute
authors.initials: U
authors.lastname: Möllmann
mesh_terms: D000215:Acylation; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000667:Ampicillin / Q000138:chemical synthesis / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology; D002396:Catechols / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D008826:Microbial Sensitivity Tests; D017262:Siderophores / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D001565:Benzoates; D002396:Catechols; D007202:Indicators and Reagents; D017262:Siderophores; D000667:Ampicillin