Inhibitory effects of thiophene-2-thiazole hybrids against sensitive strains and resistant clinical isolates of Mycobacterium tuberculosis.

Tuberculosis (TB) remains a major global health challenge, particularly due to the rise of drug-resistant Mycobacterium tuberculosis (Mtb). Herein, a focused small library of thiophene-thiazole hybrid derivatives 3a-d bearing an imide linker was designed, synthesized, and evaluated against drug-sensitive (H37Ra and H37Rv) and drug-resistant Mtb clinical isolates. Among them, 3c emerged as the most promising compound, exhibiting MIC values of 10-20 μM, including activity against a katG-mutant strain. Drug combination assays revealed no antagonism with first- and second-line anti-TB agents (FICI 0.75-3.0). In silico studies targeting Mtb KatG (PDB ID: 1SJ2) demonstrated a stable induced-fit binding mode, supported by persistent hydrogen bonding with Asp137 and Tyr229. Compound 3c retained bactericidal activity under nutrient-starvation conditions and outperformed isoniazid (INH) in a dormancy model. Cytotoxicity assays in HepG2 and Vero E6 cells showed low toxicity (IC₅₀ > 100 μM). These findings identify 3c as a promising lead scaffold for anti-TB drug development.