Structure–Activity Relationship Study of Benzamides as <i>Mycobacterium tuberculosis</i> QcrB Inhibitors

We previously identified a morpholinobenzamide series with potent activity against Mycobacterium tuberculosis. We conducted structure–activity relationship studies focusing on removing the metabolically labile morpholine group while retaining antibacterial activity. We identified potent benzamides 16 (IC90 = 0.13 μM) and 22f (IC90 = 0.09 μM) with a thiophene and methyl substituents replacing the morpholine at the C-5 position. These analogs had high selectivity (selectivity index = 300 and 278, respectively) and low cytotoxicity (HepG2 CC50 of 39 and 25 μM, respectively). Compound 16 demonstrated a good metabolic stability in human liver microsomes.