New acylated bis-catecholates and 1,3-benzoxazine-2,4-dione derivatives based on secondary diamino acids (N-(aminoalkyl)glycines, N-aminopropyl-alanine, and N-aminopropyl-4-aminovaleric acid), on N-(aminoalkyl)aminomethyl benzoic acids, on N-(aminoalkyl)aminomethyl phenoxyacetic acids, or on 3,5-diaminobenzoic acid were synthesized as artificial siderophores. The corresponding diamino acids were obtained from the diamines and oxocarboxylic acids by catalytic hydrogenation. The acylated bis-catecholates and 1,3-benzoxazine-2,4-diones were coupled with ampicillin or amoxicillin to new siderophore aminoacylpenicillin conjugates. These conjugates exhibited very strong antibacterial activity in vitro against Gram-negative bacterial pathogens including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Escherichia coli, Klebsiella pneumoniae, and Serratia marcescens. The ampicillin derivative 7b (HKI 9924154) and the corresponding amoxicillin derivative 8 (HKI 9924155) represent the most active compounds. The conjugates can use bacterial iron siderophore uptake routes to penetrate the Gram-negative outer membrane permeability barrier. This was demonstrated by assays with mutants deficient in components of the iron transport systems. New siderophore penicillin V conjugates with the siderophore component attached to the phenyl ring of penicillin V are inactive against these Gram-negative bacteria.
Different mono-, bis- or triscatecholates and mixed mono- or biscatecholate hydroxamates were synthesized as potential siderophores for mycobacteria. SiderOphore activity was tested by growth promotion assays using wild type strains and iron transport mutants of mycobacteria as well as Gram-negative bacteria. Some triscatecholates and biscatecholate hydroxamates were active in mutants of Mycobacterium smegmatis deficient in mycobactin and exochelin biosynthesis or exochelin permease, respectively, indicating an uptake route independent of the exochelin/mycobactin pathway. Structure activity relationships were studied. Ampicillin conjugates of some of these compounds were inactive against mycobacteria but active against Gram-negative bacteria.
Summary
8-Acyloxy-1,3-benzoxazine-2,4-diones as masked catechol derivatives represent a novel type of siderophore components, whose growth promoting activity is low or not existing if tested alone. But after conjugation with ?-lactam antibiotics the resulting conjugates show a signifi- cantly increased antibacterial activity against Gram-negative bacteria compared with their parent antibiotics. Investigations using a set of penetration and iron transport mutants demon- strated that the conjugates use iron transport systems to penetrate the bacterial outer mem- brane. Title compounds were synthesized from (2,3-dimethoxycarbonyloxy)-benzoic acid and different amino compounds. Conjugates with penicillins and cephalosporins were prepared.
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.
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