Antibacterial oxazolidinones

Antibacterial dendrimers, 26 799 Antibacterial oxazolidinones, 17 728-746 evolution of, 17 744 mode of action of, 17 735-736 structure-activity of, 17 732-735 synthesis of, 17 736-743 therapeutic spectrum of, 17 734—735... 

See also Antibacterial oxazolidinones antibacterials, 3 8 binding sites in, 77 736 optically pure, 77 740 preparation and manufacture, 3 13-14 therapeutic utility, 3 18 world market for, 3 16t Oxazolidone products, 70 410 Oxichromic developers, dye images from, 79 287-288... 

Reck F, Zhou F, Girardot M, Kern G, Eyermann CJ, Hales NJ, et al. Identification of 4-substituted 1,2,3-triazoles as novel oxazolidinone antibacterial agents with reduced activity against monoamine oxidase A. J Med Chem 2005 48 499-506. 

Keywords Antibacterials LpxC inhibitors Oxazolidinones PDF inhibitors ... 

Further development in the chemistry of oxazolidinone antibacterials was based mainly on the assumption that the 4-pyridyl moiety of one of Dupont s lead compounds, E-3709, might be amenable to replacement by suitably saturated heterocyclic bioisosteres [48]. This assumption was based on an example in which successful replacement of the piperazine ring system in the quinolone antibacterials, such as ciprofloxacin, with a pyridine fragment, such as seen in Win-57273, results in improvement of both the antibacterial and the pharmacokinetic profiles of the compounds. Similarly, as in the case of ciprofloxacin and Win-57273, it was predicted that the presence of a small but highly electron-withdrawing fluorine atom would be tolerated at the meta position(s) of the central phenyl ring, and would confer enhanced antibacterial activity and/or other desirable properties to the targeted oxazolidinones, as shown in Fig. 3. 

This class of rigid tricyclic fused oxazolidinones was synthesized in order to gain an understanding of the importance of the spatial relationship and torsional angle between the aryl and oxazolidinone rings with regard to antibacterial activity [51,65]. Considering the structure of an early lead compound,... 

Hegedus and co-workers8 reported the synthesis of (4S,5R)-4,5-diphenyl-3-vinyl-2-oxazolidinone (the enantiomer of the compound prepared here) via the chromium carbene complex in a fair yield. This is an interesting method, but the procedure is complicated (e.g., low temperature, argon atomsphere) and the chromium waste must be disposed of in an appropriate way. On the other hand, this procedure, consisting of transacetalization9 and pyrolysis,10 is simple and safe. Optically active 3-vinyl-2-oxazolidinone is also used for the synthesis of (1 R,2S)-2-fluorocyclopropylamine11a b that is the key intermediate for novel antibacterial quinolonecarboxylic acids. 

Linezohd (Zyvox) is an oxazolidinone, a tive-membered heterocychc ring that forms the core of the hnezohd structure. The approval of hnezohd by the FDA in 2000 marked the first new structural class of antibacterial introduced into medical practice in the United States in 40 years. It is notable for its activity against methicillin-resistant Staph aureus, MRSA, and vancomycin-resistant Enterococcus faecium, VRE. It is bacteriostatic rather than bactericidal but finds significant use in patients with an intact immune system. Like several other classes of antibacterials, linezolid is an inhibitor of protein synthesis. It interacts specifically with the RNA component of a bacterial ribosome subunit to prevent initiation of protein synthesis. 

Pharmacology Linezolid is a synthetic antibacterial agent of oxazolidinones. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of strains. 

In many ways, mitochondria resemble bacteria for example, the mitochondrial ribosomal RNA genes of all eukaryotes have been traced back to the eubacteria [10]. This can explain why some antibacterial compounds with the target of inhibiting bacterial protein synthesis also inhibit mitochondrial protein synthesis [6, 11, 12], resulting in hematotoxicity. Tetracycline, chloramphemcol and some oxazolidinone antibiotics have been shown to induce hematotoxicity by inhibiting mitochondrial protein synthesis [13]. 

The genesis of linezolid (2) began in 1978 when a DuPont patent described a novel oxazolidinone antibacterial agent S-6123 (37). This compound and two subsequently optimized drug candidates DuP 721 and DuP 105 did not materialize as marketed drugs due to unacceptable toxicity. Inspired by this innovation, scientists at Upjohn further developed this class of compounds via intensive SAR studies, obtaining linezolid (2), a compound with favorable pharmacological, pharmacokinetic, and safety profiles. 

ANTIBACTERIAL AGENTS SYNTHETIC - NITROFURANS] (Vol 2) 3-[(5-Nitro-2-furanyl)methyleneamino]-2-oxazolidinone... 

The oxazolidinone-based compounds are the most common (Figure 23.1), and examples include antibacterial,27-28 adhesion receptor antagonists,29-30 tumor necrosis factor inhibitors,31 platelet aggregation inhibitors,32 antimigraine drugs,33 and monoamine oxidase inhibitors.3435 In one case, an oxazolidinone has been used as a transdermal drug delivery agent.36... 

Finally, it has to be noted that glycopeptides only represent one option to combat infections by gram-positive bacteria. Current research is focused on other cell wall biosynthesis inhibitors (e.g., (3-lactams, cephalosporins) or even on the development of antibacterial agents (e.g., tetracyclines, ketohdes, and quinolone antibiotics) against other targets.An important drug candidate in this context is hnezolid (Zyvox), which is an entirely synthetic oxazolidinone antibiotic with in vitro and in vivo efficiency against MRS A and VRE. ... 

Starting from 4- or 5-tributylstannanyl isoxazoles, prepared via 1,3-DC with chlorooximes and tributylethynyltin in the presence of base, a series of isoxazolyl tetrahydropyridinyl oxazolidinones 42 were synthesised and their in vitro antibacterial activity evaluated <03BMCL4117>. 

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