Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis

A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibact erial agents has been prepared in an effort to expand the spectrum of activ ity of this class of antibiotics to include Gram-negative organisms. Pyrrol e, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-ne gative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsu bstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MI Cs against N. influenzae = 4 mu g/mL and M. catarrhalis 2 mu g/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differ ences in activity were observed for many analogues that cannot be rationali zed solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity agains t both Gram-positive and Gram-negative bacteria relative to unsubstituted c ounterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl subst ituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with in teresting antibacterial activity in vitro and in vivo. In particular, the 3 -cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs less than or equal to 0.5-1 mu g/mL and H. i nfluenzae and M. catarrhalis MICs = 2-4 mu g/mL. These analogues are also v ery effective versus S. aureus and S. pneumoniae in mouse models of human i nfection with ED(50)s in the range of 1.2-1.9 mg/kg versus 2.8-4.0 mg/kg fo r the eperezolid (1) control.