ABSTRACT
Beta-lactamases are serine- and metal-dependent hydrolases, produced by the bacteria as defense against beta-lactam antibiotics. Commercially available inhibitors such as clavulanic acid, sulbactam, and tazobactam, which are currently used in the hospital settings, have reduced activity against newly emerging beta-lactamases. Bacterial production of diverse beta-lactamases including class-A, class-C, and ESBLs has motivated several research groups to search for inhibitors with a broader spectrum of activity. Previously, several novel 6-methylidene penems bearing, [5,5] [5,6] and [5,5,5] heterocycles have been synthesized in our laboratory and were shown to be potent and broad-spectrum beta-lactamase inhibitors. As a continuation of our previous work and in order to extend the structure-activity relationships, in this paper, we describe herein the synthesis and in vitro, in vivo activities of several novel 5,5,6-fused tricyclic heterocycles attached to the 6-methylidene penem core. The compounds presented in the current paper are potent and broad-spectrum inhibitors of the TEM-1 and AmpC beta-lactamases. In combination with piperacillin, their in vitro activities showed enhanced susceptibility to class A- and C-resistant strains studied in various bacteria. Some of the newly synthesized compounds such as 12a-c were shown to have in vivo activity in the acute lethal infection model against TEM-1 producing organisms. The 5,5,6-fused heterocyclic ring cores such as 21, 25, and 35 reported here are hitherto unknown in the literature.
Subject(s)
Anti-Bacterial Agents/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Lactams/pharmacology , beta-Lactamase Inhibitors , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemistry , Imidazoles/chemistry , Imidazoles/pharmacology , Lactams/chemistry , Microbial Sensitivity Tests , Pyrazoles/chemistry , Pyrazoles/pharmacology , Structure-Activity Relationship , beta-LactamasesABSTRACT
The design and synthesis of a series of 6-methylidene penems containing [6,5]-fused bicycles (thiophene, imidazole, or pyrazle-fused system) as novel class A, B, and C beta-lactamase inhibitors is described. These penems proved to be potent inhibitors of the TEM-1 (class A) and AmpC (class C) beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. Their in vitro and in vivo activities in combination with piperacillin are discussed. On the basis of the crystallographic structures of a serine-bound reaction intermediate of 2 with SHV-1 (class A) and GC1 (class C) enzymes, compounds 14a-l were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C beta-lactamases. The interaction energy calculation for the enzyme-bound intermediates favor the formation of the C7 R enantiomer over the S enantiomer of the 1,4-thiazepine in both beta-lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.
Subject(s)
Anti-Bacterial Agents/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Models, Molecular , Thiazepines/chemistry , beta-Lactamase Inhibitors , Aldehydes/chemistry , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enterobacter aerogenes , Enterobacteriaceae Infections/drug therapy , Enterobacteriaceae Infections/mortality , Escherichia coli Infections/drug therapy , Escherichia coli Infections/mortality , Gram-Negative Bacteria/drug effects , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacology , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Mice , Microbial Sensitivity Tests , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacology , beta-Lactam Resistance , beta-Lactamases/chemistryABSTRACT
Deprotection of p-nitrobenzyl esters and valyl carbamates in carbapenem CL 192,276 produced the active compound OCA-983 in excellent yields. Straight chain alkanols such as 1-butanol, 1-pentanol and 1-hexanol in water at certain ratios were effective solvent systems. Alkyl acetates in water also resulted in simultaneous deprotection of PNB and PNZ side-chains albeit at slower rates. The deprotected carbapenem was isolated in excellent yield and purity after removal of the aqueous media. This procedure is applicable to sensitive compounds that are soluble in water without the need to use a buffer and allows for ease of isolation from the aqueous phase.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Carbamates/chemistry , Carbapenems/chemical synthesis , Hydrogen/chemistry , Nitrobenzenes/chemistry , Acetates/chemistry , Alcohols/chemistry , Anti-Bacterial Agents/pharmacology , Carbapenems/pharmacology , Esters/chemistry , Molecular Structure , Solvents/chemistry , Water/chemistryABSTRACT
Over 50 phenyl thiazolyl urea and carbamate derivatives were synthesized for evaluation as new inhibitors of bacterial cell-wall biosynthesis. Many of them demonstrated good activity against MurA and MurB and gram-positive bacteria including MRSA, VRE and PRSP. 3,4-Difluorophenyl 5-cyanothiazolylurea (3p) with clog P of 2.64 demonstrated antibacterial activity against both gram-positive and gram-negative bacteria.
Subject(s)
Anti-Bacterial Agents/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Peptidoglycan/biosynthesis , Phenylthiazolylthiourea/analogs & derivatives , Phenylthiazolylthiourea/pharmacology , Cell Wall/drug effects , Cell Wall/enzymology , Enterococcus faecalis/drug effects , Enterococcus faecalis/enzymology , Escherichia coli/drug effects , Escherichia coli/enzymology , Microbial Sensitivity Tests , Staphylococcus/drug effects , Staphylococcus/enzymologyABSTRACT
Twenty-five 2-phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives were synthesized for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC and MurD enzymes in vitro and antimicrobial activity against gram-positive bacteria including MRSA, VRE and PRSP. However, when they were tested in the presence of 4% bovine serum albumin, the MIC values increased to greater than 128 microg/mL against PRSP. None of the compounds demonstrated activity against gram-negative bacteria at MIC <32 microg/mL.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Cell Wall/metabolism , Staphylococcus aureus/metabolism , Anti-Bacterial Agents/pharmacology , Cell Wall/drug effects , Drug Resistance, Bacterial , Genes, Bacterial/genetics , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Staphylococcus aureus/enzymologyABSTRACT
Class A-class C mechanism-based beta-lactamase inhibitors were designed on the basis of the intermediacy of an oxycarbenium species capable of cross-linking with amino acids residues in the active site. Penams 24 and 27 were very potent against AmpC in vitro. The MIC values of 24 in combination with piperacillin against class A and class C producing organisms showed improvement over clinically used tazobactam.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins , Cyclopropanes/chemical synthesis , Diazonium Compounds/chemistry , Enzyme Inhibitors/chemical synthesis , Rhodium , Serine/chemistry , Spiro Compounds/chemical synthesis , Sulbactam/chemistry , beta-Lactamase Inhibitors , beta-Lactams/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Catalysis , Crystallography, X-Ray , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Microbial Sensitivity Tests , Models, Molecular , Pseudomonas aeruginosa/drug effects , Serratia marcescens/drug effects , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship , Sulbactam/analogs & derivatives , beta-Lactamases/chemistry , beta-Lactams/chemistry , beta-Lactams/pharmacologyABSTRACT
Sixteen muraymycin derivatives 2-17 were synthesized based on selective reactions of the primary and secondary amino groups of muraymycin C1 (1) with isocyanates and aldehydes. Disubstituted derivatives 3-9 demonstrated no activity against either MraY or MurG at Subject(s)
Anti-Bacterial Agents/chemical synthesis
, Bacterial Proteins/antagonists & inhibitors
, Peptidoglycan/drug effects
, Transferases/antagonists & inhibitors
, Anti-Bacterial Agents/pharmacology
, Cell Wall/enzymology
, Hydrophobic and Hydrophilic Interactions
, Nucleotides
, Peptides
, Peptidoglycan/analogs & derivatives
, Peptidoglycan/biosynthesis
, Peptidoglycan/pharmacology
, Staphylococcus epidermidis/enzymology
, Staphylococcus epidermidis/ultrastructure
, Structure-Activity Relationship
, Transferases (Other Substituted Phosphate Groups)
, Urea