Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity
| Autor: | O'boyle Brendan M, Peter Jorth, Philip L. Bulterys, Michael D. Bartberger, Alexander W. Sun, Scott C. Virgil, Brian M. Stoltz, Jeff F. Miller |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
endocrine system diseases
medicine.drug_class Clinical Biochemistry Antibiotics Pharmaceutical Science Mitochondrion 01 natural sciences Biochemistry Article Mitochondrial Proteins chemistry.chemical_compound Structure-Activity Relationship Heterocyclic Compounds Morpholine Drug Discovery medicine Humans Molecular Biology biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Linezolid medicine.disease biology.organism_classification Combinatorial chemistry Small molecule In vitro 0104 chemical sciences Anti-Bacterial Agents Mitochondria 010404 medicinal & biomolecular chemistry Mitochondrial toxicity Molecular Medicine Bacteria |
| Zdroj: | Bioorg Med Chem Lett |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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