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. Epub 2019 Jul 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Linezolid / chemical synthesis
  • Linezolid / chemistry
  • Linezolid / pharmacology*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Proteins / antagonists & inhibitors*
  • Mitochondrial Proteins / metabolism
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Heterocyclic Compounds
  • Mitochondrial Proteins
  • Linezolid