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

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.

Figure 1.

Biological properties altered by hypothetical gem-disubstitution of the antibiotic linezolid

Figure 2.

gem-Disubstituted linezolid analogues synthesized via Ullmann coupling

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.

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.

Synthesis of gem-disubstituted morpholines by benzoyl cleavage and reduction of morpholinone decarboxylative alkylation products

Scheme 3.

Additional analogues synthesized by derivatization