ABSTRACT
A simple method for the synthesis of carbamate-protected guanidines from primary amines is described. A variety of thioureas derived from primary amines and isothiocyanates react with the Burgess reagent to give the corresponding guanidines via either a stepwise or one-pot procedure. By tuning the carbamoyl units of isothiocyanates and the Burgess reagent, differentially N,N'-diprotected guanidines can be obtained. Selective deprotection of the products affords N-monoprotected guanidines.
Subject(s)
Amines/chemistry , Carbamates/chemistry , Guanidines/chemical synthesis , Guanidines/chemistry , Indicators and Reagents , Isothiocyanates/chemistry , Molecular Structure , Thiourea/chemistryABSTRACT
Oxazolidinones bearing a seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane heterocycle substituted with an amide or urea functionality as the C-ring and having a [1,2,3]triazole, a thiocarbamate, an isoxazole-3-ylamino, or a thioacetamide C-5 side chain unit on the A-ring instead of the typical acetamide were synthesized and their in vitro antibacterial activities towards various pathogens were evaluated. Several derivatives exhibited potent in vitro antibacterial activity toward not only Gram-positive, but also Gram-negative and linezolid-resistant pathogens. The in vivo therapeutic effects of amide 11a and ureas 16e, 17a were 2- to 3-fold greater than that of linezolid in a systemic mouse infection model treated by intravenous administration. Furthermore, compounds 11a and 17a showed lower monoamine oxidase (MAO)-inhibitory activity than our previously reported potent oxazolidinone antibacterials 3a and 3b.
Subject(s)
Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/pharmacology , Oxazepines/chemistry , Oxazolidinones/pharmacology , Thiocarbamates/chemistry , Amides/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Microbial Sensitivity Tests , Monoamine Oxidase/analysis , Monoamine Oxidase/metabolism , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Structure-Activity Relationship , Urea/chemistryABSTRACT
We synthesized a series of oxazolidinone analogues bearing a N-hydroxyacetyl-substituted [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring unit as homologues of an earlier drug candidate, eperezolid. Several of these compounds exhibited potent in vitro antibacterial activities towards not only Gram-positive, but also Gram-negative and linezolid-resistant pathogens. Compounds 21a and 21b, bearing a thiocarbamate side chain, showed high in vivo activity against methicillin-resistant Staphylococcus aureus SR3637, together with a promising safety profile in terms of weak inhibition of monoamine oxidase and cytochrome P450 isozymes.
Subject(s)
Anti-Bacterial Agents/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Oxazolidinones/pharmacology , Staphylococcal Infections/prevention & control , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 CYP1A2/metabolism , Cytochrome P-450 CYP1A2 Inhibitors , Cytochrome P-450 CYP2C9 , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2D6 Inhibitors , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Models, Chemical , Molecular Structure , Monoamine Oxidase/metabolism , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Prosencephalon/drug effects , Prosencephalon/enzymology , Rats , Staphylococcal Infections/microbiology , Structure-Activity RelationshipABSTRACT
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
A new type of ketolides, bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and a cyclic carbonate at the C-11,12 position was prepared and the antibacterial activities of the compounds were evaluated. Some of the derivatives showed potent antibacterial activity against both Haemophilus influenzae and Streptococcus pneumoniae, which are clinically important respiratory tract pathogens. Among the derivatives prepared, compound 5s with a quinolin-4-yl moiety was found to have potent and well-balanced activity against S. pneumoniae and H. influenzae including erythromycin-resistant strains.
Subject(s)
Acetamides/chemistry , Ethers/chemistry , Ketolides/chemistry , Ketolides/pharmacology , Alkylation , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Ketolides/chemical synthesis , Lung Diseases/drug therapy , Mice , Rats , Structure-Activity RelationshipABSTRACT
In the search for new types of ketolide antibiotics active against key respiratory pathogens including erythromycin-resistant strains, we conducted an extensive study on the modification at the C-11,12-diol moiety of 9-oxime-3-ketolide derivatives. Among the derivatives prepared, compound 6 with carbonate at the C-11,12 position was found to have potent antibacterial activities against erythromycin-resistant Staphylococcus aureus as well as other erythromycin-susceptible strains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Ketolides/chemistry , Ketolides/pharmacology , Oximes/chemistry , Respiratory System/microbiology , Anti-Bacterial Agents/chemistry , Drug Resistance, Bacterial , Erythromycin/pharmacology , Ketolides/chemical synthesis , Molecular Structure , Staphylococcus aureus/drug effects , Staphylococcus aureus/pathogenicityABSTRACT
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.