Novel, Achiral 4‑Nitroimidazole Compounds with Potent Antitubercular Activity.

4-Nitroimidazole compounds (delamanid and pretomanid) have been approved for the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. Besides toxicity reported for these compounds, they are chiral molecules which must be separated into pure forms; thus reducing synthetic accessibility. Herein, we report the syntheses of easily accessed achiral 4-nitroimidazoles. These compounds were tested in vitro for antitubercular and cell toxicity properties. While 4-nitroimidazoles derivatized with hydrazide were generally inactive, replacing the hydrazide with tetrazole generally led to compounds with potent antitubercular activity. A good number of 4-nitroimidazole incorporating tetrazole compounds exhibited potent antitubercular activity, with two of them (7e, 0.24 μM, and 7q, 0.92 μM) showing MIC90 values which are submicromolar and without displaying cell toxicity. These compounds show good metabolic stability in the presence of human liver microsomes.