Discovery of a Teraryl Oxazolidinone Compound (S)-N-((3-(3-Fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide Phosphate as a Novel Antimicrobial Agent with Enhanced Safety Profile and Efficacies

Abstract

A series of novel teraryl oxazolidinone compounds was designed, synthesized, and evaluated for their antimicrobial activity and toxicities. The compounds with aromatic N-heterocyclic substituents at the 4-position of pyrazolyl ring showed better antibacterial activity against the tested bacteria than other compounds with different patterns of substitution. Among all potent compounds, 10f exhibited promising safety profile in MTT assays and in hERG K(+) channel inhibition test. Furthermore, its phosphate was found to be highly soluble in water (47.1 mg/mL), which is beneficial for the subsequent in vivo test. In MRSA systemic infection mice models, 10f phosphate exerted significantly improved survival protection compared with linezolid. The compound also demonstrated high oral bioavailability (F = 99.1%). Moreover, from the results of in vivo toxicology experiments, 10f phosphate would be predicted to have less bone marrow suppression.

Regioselective Synthesis, NMR, and Crystallographic Analysis of N1-Substituted Pyrazoles

“…The current literature provides few examples on the N-substitution reactions of pyrazoles, including N-alkylation and N-arylation . Further, thorough regioselectivity studies are nonexistent.…”

Design, Synthesis, and Antibacterial Evaluation of Oxazolidinones with Fused Heterocyclic C-Ring Substructure

“…Of late, research on oxazolidinone antibacterials is focused on overcoming the linezolid-resistance, 17 broadening of antibacterial spectrum against Gram-negative strains, 18−20 exploring the utility in diseases of central nervous system (CNS), 21 and reducing the toxic side effects. 22 To achieve these objectives, extensive structural modification of oxazolidinone pharmacophore has been done. Modification at C-ring portion with various heterocycles has been the most successful, and many compounds have been recognized as clinical candidates.…”

“…Oxazolidinones such as MRX-1 developed by MicuRx Pharmaceuticals and LCB01-037 developed by LegoChem Biosciences are currently undergoing the phase III and phase II clinical trials, respectively. Of late, research on oxazolidinone antibacterials is focused on overcoming the linezolid-resistance, broadening of antibacterial spectrum against Gram-negative strains, − exploring the utility in diseases of central nervous system (CNS), and reducing the toxic side effects . To achieve these objectives, extensive structural modification of oxazolidinone pharmacophore has been done.…”

Ribosome‐targeting antibacterial agents: Advances, challenges, and opportunities

“…In addition, in our previous work, an improved oxazolidinone, pyrinezolid, was developed by modifying the C ring of linezolid (Figure 10C). Compared with linezolid, this compound caused less severe symptoms of leukopenia, thrombocytopenia, and bone marrow granulocytopenia in mice over linezolid 112 …”