ABSTRACT
p-Nitrobenzyl 2 beta-[(benzoyloxy)methyl]-2 alpha-methylpenam-3 alpha-carboxylate was prepared by reaction of p-nitrobenzyl 2-[2-oxo-3 alpha-bromo-4-(benzothiazol-2-yldithio)azetidin-1-yl] -2-isopropenylacetate with silver benzoate in the presence of iodine. The resulting diester was oxidized to the sulfone with potassium permanganate and hydrogen peroxide, and the bromine and p-nitrobenzyl groups were removed by hydrogenolysis to give potassium 2 beta-(benzoyloxy)methyl 2 alpha-methylpenam-3 alpha-carboxylate 1,1-dioxide. A series of related compounds, including the pivaloyl, methoxybenzoyl, p-fluorobenzoyl, and p-aminobenzoyl derivatives, were prepared in a similar way. All of these compounds were potent beta-lactamase inhibitors in vitro against the TEM beta-lactamase from Klebsiella pneumoniae A22695 and Bacteroides fragiles A22695 but less active against the beta-lactamase from Staphylococcus aureus A9606. All compounds when administered orally in a 1:1 combination with amoxicillin did not show any significant protection of mice infected with S. aureus A9606. 2 beta-(Bromomethyl)-2 alpha-methylpenam-3 alpha-carboxylic acid was prepared and reacted with silver nitrate to give the nitrate ester. Oxidation with potassium permanganate and catalytic reduction afforded 2 beta-(hydroxymethyl)-2 alpha-methylpenam-3 alpha-carboxylic acid 1,1-dioxide. 2 beta-(Bromomethyl)-2 alpha-methylpenam-3 alpha-carboxylic acid 1,1-dioxide was found to be a strong beta-lactamase inhibitor, while the 2 beta-hydroxymethyl compound showed only weak beta-lactamase-inhibiting properties.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Penicillins/chemical synthesis , beta-Lactamase Inhibitors , Amoxicillin/pharmacology , Bacteria/drug effects , Penicillins/pharmacology , Structure-Activity RelationshipABSTRACT
Potassium 2 beta-(chloromethyl)-2 alpha-methylpenam-3 alpha-carboxylate 1,1-dioxide (BL-P2013) and its pivaloyloxymethyl ester were prepared by the conversion of 6-aminopenicillanic acid to p-nitrobenzyl 6 alpha-bromo-2,2-dimethylpenam-3 alpha-carboxylate 1-oxide, which was rearranged with benzoyl chloride and quinoline to p-nitrobenzyl 6 alpha-bromo-2 beta-(chloromethyl)-2 alpha-methylpenam-3 alpha-carboxylate in 65% yield. Oxidation and catalytic hydrogenation afforded BL-P2013, which was found to be a potent inhibitor of various bacterial beta-lactamases and has been found to protect amoxicillin from beta-lactamases in both in vitro and in vivo systems.
Subject(s)
Penicillanic Acid/chemical synthesis , beta-Lactamase Inhibitors , Amoxicillin/pharmacology , Animals , Chemical Phenomena , Chemistry , Clavulanic Acid , Escherichia coli Infections/drug therapy , Mice , Mice, Inbred ICR , Penicillanic Acid/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , beta-Lactams/pharmacologyABSTRACT
Hetacillin was oxidized with m-chloroperbenzoic acid to give the corresponding (R)- and (S)-sulfoxides. Ozonization of hetacillin not only oxidized the sulfide but caused unexpected oxidation of the imidazolidine ring to a 2H-imidazoline. The biological spectrum showed the (R)-sulfoxide to be appreciably more active than the (S)-sulfoxide.
Subject(s)
Penicillins/chemical synthesis , Animals , Mice , Microbial Sensitivity Tests , Penicillins/pharmacology , Penicillins/therapeutic use , Stereoisomerism , Streptococcal Infections/drug therapy , Streptococcus pyogenes , Structure-Activity Relationship , Sulfoxides/chemical synthesis , Sulfoxides/pharmacology , Sulfoxides/therapeutic useABSTRACT
The synthesis of 7-(2-aminomethylphenylacetamido)-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (BL-S786) is described and the antimicrobial activities are compared with cefazolin and cefamandole. The compound exhibits broad antimicrobial spectrum, produces high intramuscular blood levels in mice and demonstrates a high degree of therapeutic efficacy in experimental bacterial infections in rodents.
