ABSTRACT
Several new semi-synthetic coumermycin analogs, which carry a polar substituent at the C-3 amide moiety have been prepared. In vitro antibacterial activity of these new analogs against Gram-positive organisms, particularly methicillin-resistant strains of Staphylococci species has been described.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Aminocoumarins , Anti-Bacterial Agents/pharmacology , Chemical Phenomena , Chemistry , Coumarins/chemical synthesis , Coumarins/pharmacology , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , 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/pharmacologySubject(s)
Acetamides/chemical synthesis , Cephalosporins/chemical synthesis , Acetamides/pharmacology , Cephalosporins/pharmacology , Escherichia coli/drug effects , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests , Pyridines/chemical synthesis , Pyridines/pharmacology , Salmonella enteritidis/drug effects , Staphylococcus/drug effects , Streptococcus pneumoniae/drug effects , Streptococcus pyogenes/drug effects , Structure-Activity Relationship , Sulfides/chemical synthesis , Sulfides/pharmacologyABSTRACT
Structure-activity relationships were examined for a number of 7-[alpha-(N,N'-substituted-amidinothio)-acetamido] cephalosporanic acids, including several wherein the amidino group was cyclized into six, seven, and eight-membered rings and a series wherein alkyl, cycloalkyl, alkenyl, and alkynyl radicals were substituted on the nitrogens of the noncyclized amidino group. Derivatives containing an unsubstituted cyclized amidino group had comparable antibacterial activity in vitro and in general had a spectrum of activity broader than that of cephalothin, especially against cephalothin-resistant strains of Escherichia, Klebsiella, and Proteus. When administered parenterally, the cephalosporin with the six-membered cyclized amidino group was as effective as cephalothin in experimental infections of mice produced by cephalothin-sensitive gram-negative organisms and more efficacious in infections caused by cephalothin-resistant strains. Among the cephalosporins with noncyclized amidino groups, those with an ethyl substituent on one of the nitrogens and a C(2)-C(4) alkyl radical, particularly propyl on the other, were the most active. They not only had a better profile of activity in vitro than cephalothin and the cephalosporin derivatives having a cyclized amidino group, but were also more efficacious in infections of mice.
