A novel series of parenteral cephalosporins exhibiting potent activities against both Pseudomonas aeruginosa and other Gram-negative pathogens. Part 2: Synthesis and structure-activity relationships
ABSTRACT A novel series of 7beta-[2-(2-amino-5-chloro-thiazol-4-yl)-2(Z)-((S)-1-carboxyethoxyimino)acetamido]cephalosporins bearing various pyridinium groups at the C-3' position were synthesized and their in vitro antibacterial activities against gram-negative pathogens including Pseudomonas aeruginosa and several gram-positive pathogens were evaluated. Among the cephalosporins prepared, we found that a cephalosporin bearing the 2-amino-1-(3-methylamino-propyl)-1H-imidazo[4,5-b]pyridinium group at the C-3' position (8a) showed potent and well-balanced antibacterial activities against P. aeruginosa and other gram-negative pathogens including the strains which produce class C beta-lactamase and extended spectrum beta-lactamase (ESBL). Compound 8a also showed efficacious in vivo activity and high stability against AmpC beta-lactamase. These findings indicate that 2-aminoimidazopyridinium having an aminoalkyl group at the 1-position as a C-3' side chain is suitable for cephalosporins bearing an aminochlorothiazolyl moiety and a carboxyethoxyimino moiety on the C-7 side chain.
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ABSTRACT: In vivo expression of colored proteins without post-translational modification or chemical functionalization is highly desired for protein studies and cell biology. Cell-permeable tryptophan analogues, such as azatryptophans, have proved to be almost ideal isosteric substitutes for natural tryptophan in cellular proteins. Their unique spectral features, such as markedly red-shifted fluorescence, are transmitted into protein structures upon incorporation. Among the azaindoles under study (2-, 4-, 5-, 6-, and 7-azaindole) 4-azaindole has exhibited the largest Stokes shift (approximately 130 nm) in steady-state fluorescence measurements. It is also highly biocompatible and as 4-azatryptophan it can be translated into target protein sequences. However, its quantum yield and fluorescence intensity are still significantly lower when compared with natural indole/tryptophan. Since azatryptophans are hydrophilic, their presence in the hydrophobic core of proteins could be harmful. In order to overcome these limitations we have performed nitrogen methylation of azaindoles and generated mono- and dimethylated azaindoles. Some of these methyl derivatives retain the pronounced red shift present in the parent 4-azaindole, but with much higher fluorescence intensity (reaching the level of indole/tryptophan). Therefore, the blue fluorescence of azaindole-containing proteins could be further enhanced by the use of methylated analogues. Further substitution of any azaindole ring with either endo- or exocyclic nitrogen will not yield a spectral fluorescence maximum shift beyond 450 nm under steady-state conditions in the physiological milieu. However, green fluorescence is a special feature of tautomeric species of azaindoles in various nonaqueous solvents. Thus, the design or evolution of the protein interior combined with the incorporation of these azaindoles might lead to the generation of specific chromophore microenvironments that facilitate tautomeric or protonated/deprotoned states associated with green fluorescence.ChemBioChem 02/2010; 11(3):305-14. DOI:10.1002/cbic.200900651 · 3.06 Impact Factor
Chapter: β-Lactams[Show abstract] [Hide abstract]
ABSTRACT: Natural β-lactams occupy a prominent place in the realm of organic synthesis and medicinal chemistry. The discovery of antibacterial activity in penicillin led the foundation of research in design, synthesis, and evaluation of biological activity profile of these compounds and analogs. A huge development has taken place in this area since then and currently, β-lactam antibiotics share a major chunk of market of antibiotics. β-Lactams are also in use for cholesterol absorption inhibition, and as β-lactamase inhibitor. These include penicillins, cephalosporins, carbapenems, clavulanic acid, ezitimibe, and spiro-fused β-lactams. This chapter describes briefly the discovery of natural compounds followed by a brief discussion of their biosyntheses. The recent synthetic approaches to the skeletons are described in detail. Several methods recently employed for the construction of monocyclic β-lactam ring are also described. An effort has been made to discuss the recently reported biological activities of β-lactams.Natural Lactones and Lactams, 10/2013: pages 101-145; , ISBN: 9783527334148