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Published September 15, 2019 | Accepted Version
Journal Article Open

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


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.

Additional Information

© 2019 Elsevier Ltd. Received 7 April 2019, Revised 8 July 2019, Accepted 13 July 2019, Available online 16 July 2019. A.W.S. and B.M.S conceived of the project. A.W.S., B.M.O, M.D.B., and S.C.V. performed experimental chemistry. P.L.B., P.A.J., and WuXi AppTec performed biological assays. M.D.B. performed VCD experiments. A.W.S., P.L.B., M.D.B., P.A.J., B.M.O., J.F.M., and B.M.S. wrote the manuscript. The NIH-NIGMS (R01GM080269), Caltech, the Paul and Daisy Soros Foundation, the Cystic Fibrosis Foundation, and the UCLA-Caltech Medical Scientist Training Program are thanked for support of our research program. (Grants R01GM080269 to B.M.S., F30GM120836 and T32GM008042 to A.W.S., F30AI118342, T32GM008042 and P.D. Soros Fellowship to P.L.B., and a Cystic Fibrosis Foundation Fellowship to P.A.J.). Dr. David VanderVelde is thanked for assistance with structural assignments via NMR analysis. Dr. Justin Hilf is thanked for helpful discussions. Professor Dianne K. Newman is thanked for MIC testing. The CO-ADD is thanked for MIC testing. The UCLA Microbiology Laboratory is thanked for providing bacterial strains.

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Accepted Version - nihms-1537091.pdf


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