Piperazinyl Oxazolidinone Antibacterial Agents Containing a Pyridine, Diazene, or Triazene Heteroaromatic Ring

Abstract

Oxazolidinones are a novel class of synthetic antibacterial agents active against gram-positive organisms including methicillin-resistant Staphylococcus aureus as well as selected anaerobic organisms. Important representatives of this class include the morpholine derivative linezolid 2, which is currently in phase III clinical trials, and the piperazine derivative eperezolid 3. As part of an investigation of the structure-activity relationships of structurally related oxazolidinones, we have prepared and evaluated the antibacterial properties of a series of piperazinyl oxazolidinones in which the distal nitrogen of the piperazinyl ring is substituted with a six-membered heteroaromatic ring. Compounds having MIC values </= 2 microg/mL vs selected gram-positive pathogens were discovered among each of the pyridine, pyridazine, and pyrimidine structural classes. Among these the cyanopyridine 17, the pyridazines 25 and 26, and the pyrimidine 31 exhibited in vivo potency vs S. aureus comparable to that of linezolid.

Development of nitroimidazopyrans and nitroimidaoxazoles for tuberculosis chemotherapy

“…One of the compounds, PA-824 has emerged as a lead molecule as it is effective against both replicating and latent Mtb cells with a minimum inhibitory concentration (MIC) ranging from 0.015 to 0.25 μg/mL. Poly and MDR strains are susceptible to PA-824, indicating that there is no crossresistance with current drugs [26]. Another orally active analog PA 1343 has been developed and is in preclinical studies with MIC of 0.015 μg/mL.…”

“…Some of the morpholine and thiomorpholine analogs of oxazolidinones like linezolid and U-100480 have shown potent in vitro activity against Mtb, whereas the other oxazolidinone derivatives displays lethal toxicity in the rat models [26].…”

Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

“…Oxazolidinones are totally synthetic, orally active anti-bacterial agents developed by DuPont (71,72). They are bacterial protein synthesis inhibitors, with inhibition uniquely in the initiation phase of protein synthesis.…”

Synthesis and Evaluation of Urea and Thiourea Derivatives of Oxazolidinones as Antibacterial Agents

“…1) potent in vitro and in vivo antibacterial agents. [6][7][8][9] In 1987, DUP 721 was selected as an antibacterial new candidate for clinical trials. However, its further development was discontinued due to toxicity observed in phase-I clinical trials.…”

“…Chemistry The synthesis of oxazolidinone basic moiety (compound A) was accomplished by the procedures, which have been described previously 8,10) (Chart 1). The thioanisole (0.264 g, 2.12 mmol) was added to a solution of compound A (0.250 g, 0.51 mmol) in dichloromethane (15 ml) under stirring at 0°C and continued the stirring for 6 h. To the resulted reaction mass trifluoroacetic acid (0.96 g, 8.4 mmol) in DCM (10 ml) was added drop wise under stirring at the same condition.…”