ABSTRACT
A series of 3-[(2,5-dihydro-6-hydroxy-2-methyl)-5-oxo-cis-triazin-3-yl]-thiomethyl-cefalosporins with various 3-phenyl-2-propenoyl substituted groups at the 7beta-position were synthesized, structurally characterized and evaluated for antibacterial activity in vitro. To prepare these derivatives by the Vilsmeier's reagent method, it was necessary to carefully control the reaction conditions in order to avoid the formation of the biologically inactive alpha epimer. The NMR studies showed that the 3-phenyl-2-propenoyl moiety has little effect on chemical shifts of cephem nucleus protons and carbon atoms. Some of these cephalosporin derivatives showed good in vitro activity against methicillin sensible strains of Staphylococcus aureus (MSSA) and coagulase negative Staphylococcus (MSCoNS). Particularly effective were the compounds carrying a 3-(2'-chlorophenyl)-2-propenoyl or 2-methyl-3-phenyl-2-propenoyl moiety at 7beta-position, both with an antibacterial potency close to cefazoline and higher than cefuroxime. All the synthesized cephalosporins were inactive against methicillin resistant strains of Staphylococcus aureus (MRSA) and coagulase negative Staphylococcus (MRCoNS).
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Anti-Bacterial Agents/chemistry , Bacteria/drug effects , Cephalosporins/chemistry , Magnetic Resonance Spectroscopy , Microbial Sensitivity TestsABSTRACT
(13)C NMR spectroscopic data for 25 cephalosporin derivatives were assigned by combination of one- and two-dimensional experiments. The effect of the substitution at C-3, C-7 and C-4 acid group positions on the chemical shifts of the cephem nucleus is discussed.
Subject(s)
Cephalosporins/chemistry , Magnetic Resonance Spectroscopy/methods , Carbon Isotopes , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Reference Standards , Sensitivity and SpecificityABSTRACT
The (1)H and (13)C spectroscopic data for 7beta-(cinnamoyl-substituted)amino-3-acetoxymethyl-cephalosporins were fully assigned by a combination of one- and two-dimensional experiments. Substitution on the aromatic ring and on the double-bond alpha-position of the cinnamoyl moiety has little influence on the spectroscopic properties of the 7beta-aminocephalosporanic acid parent moiety.
Subject(s)
Carbon Isotopes , Cephalosporins/chemistry , Cephalosporins/standards , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Protons , Reference Values , Cephalosporins/analysis , Cephalosporins/classification , ItalyABSTRACT
Twenty 3-acetoxymethyl cephalosporin derivatives, with various cinnamoyl (3-phenyl-2-propenoyl) substituted groups at the 7beta-position, were synthesized and evaluated for antibacterial activity in vitro. Some of these cephalosporin derivatives showed good selective activity against Gram-positive bacteria. Although substitution on the aromatic ring of cinnamoyl moiety generally reduced antimicrobial activity against Staphylococcus sp. and Enterococcus sp., a hydroxy group at the para position, and particularly ortho, para di-chloro substitution, improved the activity against methicillin resistant strains of Staphylococcus aureus (MRSA). Substitution on the double bond alpha position of the cinnamoyl moiety also affected the antimicrobial activity. A cyano group attached to this position increased activity against both negative coagulase Staphylococcus and Enterococcus sp. and extended the antibacterial spectrum towards Gram-negative bacteria.
Subject(s)
Anti-Bacterial Agents/chemistry , Cephalosporins/chemistry , Cinnamates/chemistry , Anti-Bacterial Agents/pharmacology , Cephalosporins/pharmacology , Cinnamates/pharmacology , Humans , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Staphylococcus aureus/physiology , Structure-Activity RelationshipABSTRACT
Cefpodoxime proxetil, a third-generation cephalosporin for oral administration, was synthesized by a method based on the following sequence of reactions: acylation of 7-aminocephalosporanic acid (7-ACA) with S-benzothiazol-2-yl(2-amino-4-thiazolyl)(methoxyimino)thioacetate (MAEM), chloroacetylation of the cefotaxime formed with chloroacetyl chloride, esterification of the acid function with 1-iodoethyl isopropyl carbonate and final cleavage of chloroacetamide protective group by treatment with thiourea in N,N-dimethylacetamide. The developed procedure allows us to obtain better yields of cefpodoxime proxetil and to eliminate the final purification step by column chromatography, necessary during the synthesis of this antibiotic by the previously reported methods.
Subject(s)
Acetates/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Ceftizoxime/analogs & derivatives , Ceftizoxime/chemical synthesis , Thiazoles/chemical synthesis , Acylation , Administration, Oral , Benzothiazoles , Cephalosporins/chemistry , Chemistry, Pharmaceutical , Drug Compounding , Cefpodoxime ProxetilABSTRACT
Cefdinir, a broad spectrum third-generation cephalosporin for oral administration, was prepared by the following synthetic pathway: synthesis of diphenylmethyl 7beta-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride from 7-aminocephalosporanic acid (7-ACA), preparation of sodium 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(tritylhydroxyimino) acetate from ethyl acetoacetate, coupling of both intermediaries to obtain diphenylmethyl 7beta-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-tritylhydroxyimino-3-vinyl-3-cephem-4-carboxylate and final cleavage of trityl and diphenylmethyl protective groups. This procedure allows to obtain better yields of cefdinir and to avoid the use of diketene during the synthesis of this antibiotic by the previously reported method.
