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.
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.
Heinisch
Lothar
L
Hans Knöll-Institute for Natural Product Research, Jena, Germany. Heinisch@pmail.hki-jena.de
Wittmann
Steffen
S
Stoiber
Thomas
T
Scherlitz-Hofmann
Ina
I
Ankel-Fuchs
Dorothe
D
Möllmann
Ute
U
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
D000577:Amides; D000900:Anti-Bacterial Agents; D001565:Benzoates; D002396:Catechols; D007202:Indicators and Reagents; D017262:Siderophores; D000667:Ampicillin