ABSTRACT
The structure-activity relationship (SAR) for a novel series of catechol conjugated siderophore cephalosporins is described with their in vitro activities against multi-drug resistant Gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia and Enterobacteriaceae. Cefiderocol (3) was one of the best molecules which displayed well-balanced and potent activities against multi-drug resistant Gram-negative pathogens including carbapenem resistant bacteria among the prepared compounds with the modified C-7 side chain and the modified C-3 side chain. Cefiderocol (3) is a highly promising parenteral cephalosporin for the treatment of multi-drug resistant Gram-negative infection.
Subject(s)
Anti-Bacterial Agents/pharmacology , Cephalosporins/pharmacology , Gram-Negative Bacteria/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cephalosporins/chemical synthesis , Cephalosporins/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , CefiderocolABSTRACT
A novel series of 7beta-[2-(2-amino-5-chloro-thiazol-4-yl)-2(Z)-((S)-1-carboxyethoxyimino)acetamido]cephalosporins bearing various pyridinium groups at the C-3' position were synthesized and their in vitro antibacterial activities against gram-negative pathogens including Pseudomonas aeruginosa and several gram-positive pathogens were evaluated. Among the cephalosporins prepared, we found that a cephalosporin bearing the 2-amino-1-(3-methylamino-propyl)-1H-imidazo[4,5-b]pyridinium group at the C-3' position (8a) showed potent and well-balanced antibacterial activities against P. aeruginosa and other gram-negative pathogens including the strains which produce class C beta-lactamase and extended spectrum beta-lactamase (ESBL). Compound 8a also showed efficacious in vivo activity and high stability against AmpC beta-lactamase. These findings indicate that 2-aminoimidazopyridinium having an aminoalkyl group at the 1-position as a C-3' side chain is suitable for cephalosporins bearing an aminochlorothiazolyl moiety and a carboxyethoxyimino moiety on the C-7 side chain.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Cephalosporins/chemistry , Pseudomonas aeruginosa/drug effects , Cephalosporins/chemical synthesis , Gram-Negative Bacteria/drug effects , Pyridines , Structure-Activity Relationship , beta-LactamasesABSTRACT
A series of 7beta-[2-(2-aminothiazol-4-yl)-2-(Z)-(carboxymethoxyimino)acetamido]cephalosporins bearing a 1-(substituted)-1H-pyrrolo[3,2-b]pyridinium group at C-3' position was synthesized and their in vitro antibacterial activities against Pseudomonas aeruginosa and other Gram-negative pathogens were evaluated. Among the cephalosporins prepared, 7beta-[2-(2-amino-5-chlorothiazol-4yl)-2(Z)-((S)-1-carboxyethoxyimino)acetamido]cephalosporins (42d) showed potent antibacterial activities against P. aeruginosa and other Gram-negative pathogens including the strains which produce class C beta-lactamase and extended spectrum beta-lactamase (ESBL). These results imply that both the Cl atom on the C-7 aminothiazole moiety and the alpha-substituent at the iminoether moiety are essential for the stability against beta-lactamase and the potent activity against Gram-negative bacteria including P. aeruginosa.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cephalosporins/chemistry , Cephalosporins/pharmacology , Gram-Negative Bacteria/drug effects , Pseudomonas aeruginosa/drug effects , Anti-Bacterial Agents/chemical synthesis , Cephalosporins/chemical synthesis , Drug Administration Routes , Humans , Structure-Activity RelationshipABSTRACT
Among the prepared novel cephalosporin derivatives related to S-3578, a series of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-[1-(aminoalkyl)-1H-pyrazolo[4,3-b]pyridinium-4-yl]methyl-3-cephem-4-carboxylate showed potent activity against both MRSA and Pseudomonas aeruginosa, and displayed good water solubility.
Subject(s)
Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cephalosporins/chemistry , Methicillin Resistance , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
Among the prepared C-3' substituted-pyridinium cephalosporins, a series of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido] cephalosporins bearing 4-[3-(aminoalkyl)-ureido]-1-pyridinium at C-3' showed highly potent antibacterial activity against MRSA and Pseudomonas aeruginosa.
Subject(s)
Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Methicillin Resistance , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cephalosporins/chemistry , Microbial Sensitivity Tests , Molecular Structure , Pyridinium Compounds/chemical synthesis , Pyridinium Compounds/chemistry , Pyridinium Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
A series of N-alkylated and aminomethylated derivatives of chloroorienticin B, a vancomycin-related glycopeptide antibiotic, were synthesized. Doubly-modified derivatives having both hydrophobic and hydrophilic substituents exhibited potent antibacterial activity against MRSA and VRE along with considerable water-solubility.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enterococcus/drug effects , Methicillin Resistance , Staphylococcus aureus/drug effects , Vancomycin Resistance , Vancomycin/chemical synthesis , Vancomycin/pharmacology , Anti-Bacterial Agents/chemistry , Microbial Sensitivity Tests , Solubility , Vancomycin/analogs & derivatives , Vancomycin/chemistryABSTRACT
An efficient and practical method was established for solid-phase parallel synthesis of the peptide-bearing carboxamide derivatives of chloroorienticin B, and over 80 compounds were synthesized simultaneously. Among the derivatives prepared, compounds having both tryptophan and tyrosine residues (1-3) were found to possess potent antibacterial activity against VRE.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Methicillin Resistance , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Vancomycin Resistance , Vancomycin/chemical synthesis , Vancomycin/pharmacology , Amides/chemistry , Amino Acids/chemistry , Anti-Bacterial Agents/chemistry , Combinatorial Chemistry Techniques , Enterococcus/drug effects , Microbial Sensitivity Tests , Oligopeptides/chemistry , Staphylococcus aureus/drug effects , Vancomycin/analogs & derivatives , Vancomycin/chemistryABSTRACT
A series of 7-aminothiadiazolylcephalosporins having a 1-(substituted)-1H-imidazo[4,5-b]pyridinium group at the C-3' position of the cephem nucleus were synthesized and evaluated for in vitro antibacterial activities. Among the cephalosporins prepared in this study, 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetamido]-3-[1-(3-methylaminopropyl)-1H-imidazo[4,5-b]pyridinium-4-yl]methyl-3-cephem-4-carboxylate sulfate (S-3578) showed extremely potent broad spectrum activity against both gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative bacteria including Pseudomonas aeruginosa, and good water solubility.
