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 (10 alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs less than or equal to 0.5-1 mug/mL and moderate Gramnegative activity with MICs = 2-8 mug/mL against Haemophilus influence and Moraxella catarrhalis. This analogue was also found to have potent in vivo activity with an ED50 = 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 10 alpha. 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 less than or equal to 0.06-0.25 kg/mL against Gram-positive pathogens and with MICs of 1 mug/mL against fastidious Gram-negative pathogens. (C) 2001 Elsevier Science Ltd. All rights reserved.