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

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).