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.