ABSTRACT
Lipopolysaccharides of the seven Fisher immunotypes of Pseudomonas aeruginosa gave cross-precipitation in many antipneumococcal sera. The reaction of Pseudomonas type IV in type 25 antipneumococcal serum was immediate and heavy: 93 micrograms of antibody nitrogen per ml. Correlations are described, mainly between the structures of the O-chains of the immunotypes and their specificities as shown by the cross-reactions.
Subject(s)
Lipopolysaccharides/immunology , Pseudomonas aeruginosa/immunology , Streptococcus pneumoniae/immunology , Antibodies, Bacterial/immunology , Carbohydrate Sequence , Cross Reactions , Pseudomonas aeruginosa/classificationABSTRACT
A series of penicillins and cephalosporins containing the substituted 6-vinyl-1,2-dihydro-2-oxo- and 1,4-dihydro-4-oxo-3-pyridinecarboxylic acid side chains has been prepared and compared to piperacillin and cefoperazone. The compounds show good activity when tested in vitro against an array of Gram-negative bacteria. In vitro activity was also demonstrated against several species of Gram-positive bacteria. Two compounds, 14 and 21, show good in vivo activity when tested against Klebsiella pneumoniae, Enterobacter cloacae, and two strains of Pseudomonas aeruginosa.
Subject(s)
Cephalosporins/chemical synthesis , Penicillins/chemical synthesis , Animals , Bacteria/drug effects , Bacterial Infections/drug therapy , Cephalosporins/pharmacology , Female , Mice , Penicillins/pharmacology , Structure-Activity RelationshipABSTRACT
Several nucleosides modified and chain extended at the 5'-position have been synthesized as follows: N6-benzamido- 9-(2,3-di-O-benzoyl-beta-D-arabino-pentodialdo-1,4-furanosyl)adenine, O=CHR, a leads to (E)-EtOCOCH=CHR (2) b leads to EtOCOCH2CH2R (3) c leads to H2NCOCH2CH2R (6) d leads to 1-(adenin-9- yl)-1,5,6-trideoxy-beta-D-arabino-hepto-1,4-furanuronamide (8); 3 e leads to ethyl 1-(adenin-9-yl)-1,5,6-trideoxy-beta-D-arabino-hepto-1, 4-furanuronate (5) f leads to 1-(adenin-9-yl)-1, 5,6-trideoxy-beta-D-arabino-hepto-1,4-furanuronic acid (4); 5 g leads to 9-(5,6-dideoxy-beta-D-arabino-hepto-1,4-furanosyl)adenine (7) [where a = EtOCOCH=PPh3; b = H2, Pd/C; c = Me2A1NH2; d = NH3/MeOH; e = NaOEt/EtOH; f = NaOH/MeOH; g = LiA1H4]. Both 7 and 8 show activity against herpes simplex virus type 1. The mechanism for such activity is unknown. Compounds 5 and 8 exhibited weak coronary vasodilation effects in dogs.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Coronary Circulation/drug effects , Vidarabine/analogs & derivatives , Adenosine Deaminase/metabolism , Animals , Cattle , Cell Line , DNA Replication/drug effects , Dogs , Indicators and Reagents , Intestinal Mucosa/enzymology , Magnetic Resonance Spectroscopy , Simplexvirus/drug effects , Spectrophotometry , Structure-Activity Relationship , Vascular Resistance/drug effects , Vasodilation/drug effectsABSTRACT
3'-Deoxybutirosin A (4), 5"-amino-3', 5"-dideoxybutirosin A (6), and 5"-amino-4', 5"-dideoxybutirosin A (7) were prepared by deoxygenation of the appropriate hydroxyl in suitably protected derivatives of butirosin A, using sequentially trifluoromethylsulfonylation, displacement with benzenethiolate, and hydrogenolysis. The structures of the compounds were confirmed by NMR spectroscopy, using 13C NMR and 1H NMR at up to 600 MHz. The compounds are broad-spectrum antibiotics active against resistant microorganisms which inactivate butirosin and related aminoglycosides by 3'-phosphorylation.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Aminoglycosides/chemical synthesis , Animals , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Butirosin Sulfate/chemical synthesis , Butirosin Sulfate/pharmacology , Drug Resistance, Microbial , Magnetic Resonance Spectroscopy , Male , Mice , PhosphorylationABSTRACT
A series of 4-acylamino-alpha-oximinobenzeneacetic acids, and 1,2-dihydro-6-methyl-alpha-oximino-2-oxo-3-pyridineacetic acid were prepared and coupled to 7-aminocephalosporanic acid and its 3'-(1-methyltetrazol-5-yl)thiolo analogue. Several coupling methods and oxime protecting groups were thoroughly examined. The best coupling procedure employed dimethylchloroformiminium chloride, and the tetrahydropyranyl (THP) group was selected for oxime protection. The cephalosporins prepared were tested and compared to cefuroxime and cefotaxime. The corresponding alpha-keto acids, and O-methyl oximes were also examined.
Subject(s)
Cephalosporins/chemical synthesis , Anilides/chemical synthesis , Anilides/pharmacology , Bacteria/drug effects , Chemical Phenomena , Chemistry , Imino Acids/chemical synthesis , Imino Acids/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis and biological activities of a series of 12 new semisynthetic penicillins is described. These compounds consisted of acylated amino acid analogs of 6-substituted-1,2-dihydro-2-oxonicotinic acid and 2-substituted-3,4-dihydro-4-oxo-5-pyrimidinecarboxylic acid attached to amoxicillin. The effect of the amino acid substituent, chirality of amino acid and acyl function on biological properties is discussed.
Subject(s)
Amoxicillin/analogs & derivatives , Amoxicillin/pharmacology , Bacteria/drug effects , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
A new broad spectrum semisynthetic cephalosporin (CN-92,982) was prepared from the condensation of an acetylaminoacylaminophenyl pyridone with trans-7-[(D-2-phenylglycyl) amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-delta 3-cephem-4-carboxylic acid. The new cephalosporin displayed an in vitro antibacterial spectrum similar to other cephaloglycine types such as cefoperazone and SM-1652. The compound produced a high and prolonged blood level following a single intramuscular dose in a dog.
Subject(s)
Bacteria/drug effects , Cephalosporins/chemical synthesis , Animals , Cephalosporins/blood , Cephalosporins/pharmacology , Dogs , Drug Resistance, Microbial , Kinetics , MiceABSTRACT
The synthesis and antimicrobial activity of a new semisynthetic penicillin are described. Both in vitro and in vivo, the compound shows promising antibacterial activity when compared with piperacillin and ticarcillin. High activity is shown against Pseudomonas and other Gram-negative bacteria.
Subject(s)
Penicillins/chemical synthesis , Animals , Mice , Microbial Sensitivity Tests , Penicillins/pharmacology , Pseudomonas Infections/drug therapyABSTRACT
A number of 2',3'- and 3',5'-di-O-acyl derivatives of 9-beta-D-arabinofuranosyladenine (1) were prepared and evaluated as antivirals. These compounds, designed as prodrugs of 1, offer a range of solubilities and lipophilicities, as well as a resistance to adenosine deaminase, that render some as being attractive as possibly useful antiviral agents. Of particular note is 9-(2,3-di-O-acetyl-beta-D-arabinofuranosyl)adenine that was found to be effective as a topical agent in a guinea pig model of genital herpes.
Subject(s)
Vidarabine/analogs & derivatives , Animals , Antiviral Agents/chemical synthesis , Chemical Phenomena , Chemistry , Female , Guinea Pigs , Herpes Simplex/drug therapy , Simplexvirus/drug effects , Vidarabine/chemical synthesis , Vidarabine/pharmacologyABSTRACT
A number of 5'-(O-acyl) derivatives of 9-beta-D-arabinofuranosyladenine (ara-A, VIRA-A) (2a-k) were prepared by direct acylation of the parent nucleoside 1 in pyridine-N,N-dimethyliformamide. These compounds, designed as prodrugs for 1, offer a range of solubilities and lipophilicities indicating for several examples improved solubility and the potential for improved membrane transport over 1. All are resistant to deactivation by adenosine deaminase. Of special interest is the 5'-(O-valeryl) derivative 2d that shows a marked increase in antiviral activity over 1.
Subject(s)
Vidarabine/analogs & derivatives , Acylation , Adenosine Deaminase/metabolism , Antiviral Agents/chemical synthesis , Drug Stability , Solubility , Vidarabine/chemical synthesis , Vidarabine/metabolism , Vidarabine/pharmacology , Viral Plaque AssayABSTRACT
Lipopolysaccharide antigens from seven different serotype strains (antigen immunotypes Nos. 1-7 in the classification of Fisher et al.3) of Pseudomonas aeruginosa have been analyzed for neutral carbohydrate, amino sugars, lipid, protein, 3-deoxy-manno-octulosonic acid, and phosphorus. The individual amino sugars were determined for each antigen type; all contained 2-amino-2-deoxy-D-glucose and -D-galactose, together with 2-amino-2,6-dideoxygalactose; the latter as isolated from the type 2 antigen was identified as the DL form. In addition, 2-amino-2,6-dideoxy-D-glucose was present in the types 3, 4, and 5 antigens. Mild, acid hydrolysis of the antigens gave the lipid A component containing all of the lipid and 2-amino-2-deoxy-D-glucose, together with lipid A-free polysaccharides that contained principally carbohydrate. The lipid A-free polysaccharides all contained L-rhamnose and D-glucose, together with 2-amino-2,6-dideoxygalactose in all except those from types 1, 5, and 7; that from type 6 also contained D-xylose.
Subject(s)
Antigens, Bacterial/analysis , Lipopolysaccharides/analysis , Polysaccharides, Bacterial/analysis , Pseudomonas aeruginosa/immunology , Amino Sugars/analysis , Deoxyglucose/analysis , Disaccharides/analysis , Endotoxins/analysis , Fatty Acids/analysis , Fucose/analysis , Magnetic Resonance Spectroscopy , Molecular Conformation , Pseudomonas aeruginosa/analysis , Serotyping , Species SpecificitySubject(s)
Deoxy Sugars/chemical synthesis , Alcohols , Amino Sugars , Methods , Oxidation-ReductionSubject(s)
Arabinonucleotides/metabolism , Vidarabine Phosphate/metabolism , Animals , Dogs , Isotope Labeling , TritiumABSTRACT
Preparation of both a 5'-deuterium and a 5'-tritium-labeled 9-beta-D-arabinofuranosyladenine (6a and 6b) by reduction of the protected 5'-aldehyde 4 is described. Conversion of 6b to the 5'-tritium-labeled 5'-monophosphate 7b was effected directly with a phosphoryl chloride-formic acid reagent. The product 7b exhibited consistently higher blood levels of nonvolatile tritium than the 2-labeled compound when tested in dogs.