Antitubercular Nitroimidazoles Revisited: Synthesisand Activity of the Authentic 3-Nitro Isomer of Pretomanid

摘要

A published study of structural features associated with the aerobic and anaerobic activities of 4- and 5-nitroimidazoles had found that the 3-nitro isomer of pretomanid, >8, displayed interesting potencies, including against nitroreductase mutant Mycobacterium tuberculosis. However, recent nuclear magnetic resonance analyses of two trace byproducts, isolated from early process optimization studies toward a large-scale synthesis of pretomanid, raised structural assignment queries, particularly for >8, stimulating further investigation. Following our discovery that the reported compound was a 6-nitroimidazooxazole derivative, we developed a de novo synthesis of authentic >8 via nitration of the chiral des-nitro imidazooxazine alcohol >26 in trifluoroacetic or acetic anhydride, and verified its identity through an X-ray crystal structure. Unfortunately, >8 displayed no antitubercular activity (MICs > 128 μM), whereas the second byproduct (3′-methyl pretomanid) was eight-fold more potentthan pretomanid in the aerobic assay. These findings further clarifytarget specificities for bicyclic nitroimidazoles, which may becomeimportant in the event of any future clinical resistance.