2. Academic Validation
  3. Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity

Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity

  • Bioorg Med Chem Lett. 2019 Sep 15;29(18):2686-2689. doi: 10.1016/j.bmcl.2019.07.024.
Alexander W Sun 1,  Philip L Bulterys 2,  Michael D Bartberger 1,  Peter A Jorth 3,  Brendan M O'Boyle 1,  Scott C Virgil 1,  Jeff F Miller 2,  Brian M Stoltz 4
Affiliations

Affiliations

  • 1 The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
  • 2 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
  • 3 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, United States.
  • 4 The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States. Electronic address: stoltz@caltech.edu.
PMID: 31383589 DOI: 10.1016/j.bmcl.2019.07.024
Abstract

gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing Oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding Oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.

Keywords

Allylic alkylation; Antibiotic; Heterocycle; Linezolid; Mitochondria.

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