Michael J. Genin

The oxazolidinone class of antibiotics represents a promising advance in the battle against multiply resistant Gram-positive bacterial infections. Numerous companies have been involved in this area of research and Pharmacia has recently brought the first member of this class, linezolid (Zyvox®), to market for the treatment of sensitive and resistant Gram-positive bacterial infections. During the last few years, advancements have been made by several firms in expanding oxazolidinone SAR as well as the spectrum of activity to include the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis.

A series of new nitrogen−carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, 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-negative organisms Haemophilusinfluenzae and Moraxellacatarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 μg/mL and M. catarrhalis = 2 μg/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 differences in activity were observed for many analogues that cannot be rationalized 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 against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting 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 ≤ 0.5−1 μg/mL and H. influenzae and M. catarrhalis MICs = 2−4 μg/mL. These analogues are also very effective versus S. aureus and S. pneumoniae in mouse models of human infection with ED₅₀s in the range of 1.2−1.9 mg/kg versus 2.8−4.0 mg/kg for the eperezolid (1) control.

Through computationally directed broad screening, a novel 1,5-diphenylpyrazole (DPP) class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered. Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC₅₀ = 2.3 μM) and delavirdine-resistant P236L (IC₅₀ = 1.1 μM) reverse transcriptase (RT). Also, PNU-32945 has an ED₅₀ for inhibition of viral replication in cell cultures of 0.1 μM and was shown to be noncytotoxic with a CC₅₀ > 10 μM. Structure−activity relationship studies on the 3- and 4-positions of PNU-32945 led to interesting selectivity and activity within the class. In particular, the 3-hydroxyethyl-4-ethyl congener 29 is a potent inhibitor of the P236L mutant (IC₅₀ = 0.65 μM), whereas it is essentially inactive versus the wild-type enzyme (IC₅₀ > 50 μM). Furthermore, this compound was significantly more active versus the P236L mutant than delavirdine. The synthesis and RT inhibitory activity of various 3- and 4-substituted analogues are discussed.