Novel 3-Aminothieno[2,3-<i>b</i>]pyridine-2-carboxamides with Activity against <i>Mycobacterium tuberculosis</i>

We conducted an exploration of the 3-aminothieno[2,3-b]pyridine-2-carboxamide (TPA) series for its potential as a drug scaffold against Mycobacterium tuberculosis. Existing analogs were active against a recombinant strain of M. tuberculosis with reduced expression of the sole signal peptidase LepB, but with poor activity against the wild-type strain. Our aim was to improve potency and explore the structure–activity relationship of the series. We identified two subsets of TPA. The first subset of compounds had equipotent activity against wild-type and LepB hypomorph strains and may represent a series with a different target. The second subset of compounds had increased activity against the LepB hypomorph strain and thus appears to be pathway-specific. Among this latter set we identified 17af as a potent inhibitor (IC90 = 1.2 μM) with some cytotoxicity (IC50 = 19 μM) and which retained increased activity against the LepB hypomorph (IC90 = 0.41 μM).