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. 2019 Sep 15;29(18):2686-2689.
doi: 10.1016/j.bmcl.2019.07.024. Epub 2019 Jul 16.

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

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

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

Alexander W Sun et al. Bioorg Med Chem Lett. .

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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Figures

Figure 1.
Figure 1.
Biological properties altered by hypothetical gem-disubstitution of the antibiotic linezolid
Figure 2.
Figure 2.
gem-Disubstituted linezolid analogues synthesized via Ullmann coupling
Figure 3.
Figure 3.
Diastereomers of analogue 19. Absolute configuration of the spirocyclic stereocenter determined by both VCD and optical rotations (See supporting information for details).
Scheme 1.
Scheme 1.
Synthesis of gem-disubstituted linezolid analogues via Cu-catalyzed Ullmann coupling. a. (S)-epichlorohydrin, NH4OH (aq). THF, 40 °C, 12 h, 55% yield; b. LiOt-Bu, CH2Cl2, rt to 40 °C, 87% yield; c.1N HCl, H2O/EtOAc; d. Ac2O, CH2Cl2, 96% yield over 2 steps; e. NIS, TFA, rt, 92% yield; f. Substituted morpholine 11a-p, CuBr (10 mol %), BINOL (20 mol %), K3PO4, DMF, 80 °C.
Scheme 2.
Scheme 2.
Synthesis of gem-disubstituted morpholines by benzoyl cleavage and reduction of morpholinone decarboxylative alkylation products
Scheme 3.
Scheme 3.
Additional analogues synthesized by derivatization
See this image and copyright information in PMC

References

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