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1.
Bioorg Med Chem ; 16(4): 1890-902, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18061461

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-Lactamases
2.
J Med Chem ; 49(15): 4623-37, 2006 Jul 27.
Article in English | MEDLINE | ID: mdl-16854068

ABSTRACT

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/chemistry
3.
Med Chem ; 2(1): 21-5, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16787352

ABSTRACT

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/chemistry
4.
Bioorg Med Chem Lett ; 14(1): 235-8, 2004 Jan 05.
Article in English | MEDLINE | ID: mdl-14684334

ABSTRACT

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/enzymology
5.
Bioorg Med Chem Lett ; 13(15): 2591-4, 2003 Aug 04.
Article in English | MEDLINE | ID: mdl-12852973

ABSTRACT

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/enzymology
6.
J Med Chem ; 46(13): 2569-71, 2003 Jun 19.
Article in English | MEDLINE | ID: mdl-12801220
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