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Synthesis of Zoliflodacin
Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N-Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914).
J. Med. Chem. 2015;
21 July 2020 (online)
Zoliflodacin is an oral antibiotic with a unique mode of inhibition against type II topoisomerases with binding sites in bacterial gyrase. It has entered phase 3 clinical trials for the treatment of gonorrhea (P. A. Bradford, A. A. Miller, J. O’Donnell, J. P. Mueller ACS Infect. Dis. 2020, 6, 1332). Zoliflodacin also has activity against Gram-positive, Gram-negative, and atypical pathogens including multidrug-resistant strains.
In 2015, Basarab and co-workers reported the discovery of this DNA gyrase inhibiting spiropyrimidinetrione fused to a benzisoxazole scaffold. In the key spirocyclization reaction, intermediate (2R,6R)-morpholine L underwent a 1,5-hydrogen shift to generate intermediate M that epimerized before cyclization to the spiropyrimidinedione in zoliflodacin (dr = 9:1).