Kevin C. Grega

Carbon–carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria

In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole (10alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs <or=0.5-1 microg/mL and moderate Gram-negative activity with MICs=2-8 microg/mL against Haemophilus influenzae and Moraxella catarrhalis. This analogue was also found to have potent in vivo activity with an ED(50)=1.9 mg/kg. Beta-substitution at the C3-linked pyrazole generally results in a loss of activity. The C4-linked pyrazoles are slightly more potent than their counterparts in the C3-linked series. Most of the analogues in the C4-linked series exhibited similar levels of activity in vitro, but lower levels of activity in vivo than 10alpha. In addition, incorporation of a thioamide moiety in selected C4-linked pyrazole analogues results in an enhancement of in vitro activity leading to compounds several times more potent than eperezolid, linezolid and vancomycin. The thioamide of the N-cyanomethyl pyrazole analogue (34) exhibited an exceptional in vitro activity with MICs of <or= 0.06-0.25 microg/mL against Gram-positive pathogens and with MICs of 1 microg/mL against fastidious Gram-negative pathogens.

Synthesis and antibacterial activity of new tropone-substituted phenyloxazolidinone antibacterial agents 2. Modification of the phenyl ring — the potentiating effect of fluorine substitution on in vivo activity

Abstract Various electron-withdrawing groups were incorporated into the meta position of tropone-substituted 3-phenyl-2-oxazolidinones and their influence on antibacterial activity examined. Consideration of in vitro and in vivo test results indicated that one or two fluorine atoms flanking the para tropone appendage is the optimum arrangement for these compounds. Synthetic routes to enantiomerically enriched analogues are reported.

Design, Synthesis, and Evaluation of Novel Oxazolidinone Antibacterial Agents Active Against Multidrug-Resistant Bacteria

Throughout the human experience, diseases caused by pathogenic bacteria have exerted an enormous negative impact on society. Today, for example, approximately one third of the world’s population is infected with Mycobacterium tuberculosis and tuberculosis remains the leading cause of death in the world from infectious disease (Bloom, 1994). The emergence of effective antibacterial agents, from penicillin to more contemporary drugs, was initially thought to mark an end to the burden of microbial disease. However, subsequent events have illustrated the resiliency of bacteria to environmental pressures, including the threat of antibacterial agents.

Synthesis and antibacterial activity of new tropone-substituted phenyloxazolidinone antibacterial agents 1. Identification of leads and importance of the tropone substitution pattern

Abstract Incorporation of a substituted tropone moiety into the para position of suitably functionalized 3-phenyl-2-oxazolidinones affords novel and potent antibacterial agents. The effect of the tropone regioisomer and its attendant substituents on antibacterial activity is discussed. Analogues such as 11c and 13b display in vitro and in vivo activity approaching that of the current clinical benchmark, vancomycin.