Structure–Activity Relationship Study of Benzamides as Mycobacterium tuberculosis 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.