ABSTRACT
Synthesis and derivatization of a series of substituted tetrahydrofluorenone analogs giving potent, ERbeta subtype selective ligands are described. Several analogs possessing ERbeta binding affinities comparable to 17beta-estradiol but with greater than 75-fold selectivity over ERalpha are reported.
Subject(s)
Estrogen Receptor beta/drug effects , Fluorenes/chemical synthesis , Fluorenes/pharmacology , Cell Line , Crystallography, X-Ray , Estrogen Receptor alpha/chemistry , Estrogen Receptor alpha/drug effects , Estrogen Receptor beta/chemistry , Fluorenes/classification , Humans , Ligands , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.
Subject(s)
Bacterial Proteins , Carbapenems/chemical synthesis , Gram-Positive Bacteria/drug effects , Hexosyltransferases , Peptidyl Transferases , Carbapenems/chemistry , Carbapenems/pharmacology , Carrier Proteins/drug effects , Carrier Proteins/metabolism , Drug Resistance, Microbial , Microbial Sensitivity Tests , Muramoylpentapeptide Carboxypeptidase/drug effects , Muramoylpentapeptide Carboxypeptidase/metabolism , Penicillin-Binding ProteinsABSTRACT
A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.
Subject(s)
Carbapenems/chemical synthesis , Gram-Positive Bacteria/drug effects , Lactams/pharmacology , Thiazoles/pharmacology , Animals , Carbapenems/chemistry , Carbapenems/pharmacology , Carbapenems/toxicity , Drug Resistance, Microbial , Humans , Lactams/chemistry , Lactams/pharmacokinetics , Mice , Microbial Sensitivity Tests , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacokineticsABSTRACT
A carbapenem antibiotic, L-786,392, was designed so that the side chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain upon opening of the beta-lactam ring retained antibacterial activity while safely expelling the immunodominant epitope. L-786,392 was well tolerated in animal safety studies and had significant in vitro and in vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.
Subject(s)
Bacterial Proteins , Carbapenems/immunology , Carbapenems/pharmacology , Drug Design , Hexosyltransferases , Lactams/pharmacology , Peptidyl Transferases , Thiazoles/pharmacology , Animals , Antibodies/blood , Carbapenems/chemistry , Carbapenems/metabolism , Carbapenems/toxicity , Carrier Proteins/metabolism , Dipeptidases/metabolism , Drug Resistance, Microbial , Drug Resistance, Multiple , Enterococcus/drug effects , Erythrocytes/immunology , Haptens , Humans , Immunodominant Epitopes , Immunoglobulin G/blood , Lactams/chemical synthesis , Lactams/chemistry , Lactams/metabolism , Lymphocyte Activation , Macaca mulatta , Mice , Mice, Inbred DBA , Microbial Sensitivity Tests , Muramoylpentapeptide Carboxypeptidase/metabolism , Penicillin-Binding Proteins , Staphylococcal Infections/drug therapy , Staphylococcus/drug effects , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/metabolismABSTRACT
The syntheses of five thiols, including three dihydropyrrolotriazoliumthiol salts, 1,4-dimethyl-5-mercaptomethyl-1,2,4-triazolium trifluoromethanesulfonate, and 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride; and the addition of these thiols to 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]-1-met hylcarbapen-2-em-3-carboxylate and the subsequent hydrogenolysis of the addition products is described. The latter thiol provides a new route towards the preparation of L-627 (LJC 10,627). The compounds were evaluated in vitro against a panel of Gram-positive and Gram-negative bacteria and their antibacterial activities compared with imipenem. The compounds were measured for their hydrolytic stability to dehydropeptidase I (DHP-I) relative to imipenem. The five compounds generally had poorer Gram-positive and Pseudomonas activity than imipenem, although their Gram-negative activity was variably improved. The monocyclic triazolium analog was nearly comparable in overall activity to the four bicyclic heterarylium analogs evaluated, including L-627 (LJC 10,627). All compounds were more stable to DHP-I than imipenem, although minor differences existed among them.
