Carbon-carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria
Cs. Lee et al., Carbon-carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria, BIO MED CH, 9(12), 2001, pp. 3243-3253
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 exhibite
d very good Gram-positive activity with MICs less than or equal to 0.5-1 mu
g/mL and moderate Gramnegative activity with MICs = 2-8 mug/mL against Haem
ophilus influence and Moraxella catarrhalis. This analogue was also found t
o 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 sim
ilar 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 le
ading to compounds several times more potent than eperezolid. linezolid and
vancomycin. The thioamide of the N-cyanomethyl pyrazole analogue (34) exhi
bited 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 ag
ainst fastidious Gram-negative pathogens. (C) 2001 Elsevier Science Ltd. Al
l rights reserved.