Oxazolidinone, antibacterial

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. 

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. 

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... 

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. 

Stalker D, jungbluth G. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmacokinet 2003 42 1129-1140. 

Vinyl sulfones can function as acetylene equivalents through the elimination of sulfinic acid. Reck and coworkers prepared a series of vinyl sulfones for cycloaddition reactions with azides to prepare 1,2,3-triazole derivatives to be incorporated into new oxazolidinone antibacterial agents. Included in the series was the cycloaddition of l-fluoro-l-(phenylsulfonyl)ethylene with the oxizolidinone 156 to give, after elimination of phenylsulfonic acid, a 28% yield of a 1 7 mixture of the regioisomeric 4-and 5-fluorotriazoles (157 and 158) (Fig. 3.91). 

Renslo, A. R., Luehr, G. W, Gordeev, M. F. Recent develr ments in the identification of novel oxazolidinone antibacterial agents. Bioorg. Med. Chem. 2006, 24(12), 4227 240. 

In 1996, Schaus and Jacobsen reported the DKR of epichlorohydrin via enan-tioselective ring opening with TMSN3 catalysed by a chiral (salen)Cr(iii)N3 complex. The resulting 3-azido-l-chloro-2-trimethylsiloxypropane product was obtained in 47% yield and enantioselectivity of 95% ee. This chiral product was used in the total synthesis of an aryl oxazolidinone antibacterial agent, U-100592, as shown in Scheme 2.76. 

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