Development of antimycobacterial tetrahydrothieno[2,3-c]pyridine-3-carboxamides and hexahydrocycloocta[b]thiophene-3-carboxamides: Molecular modification from known antimycobacterial lead

• We designed series of compounds by molecular modification of known TB molecules.
• We synthesize and characterized thirty molecules.
• Seven compounds inhibited MTB with MIC of <10 μM.
• Compound 12f showed MIC of 1.23 μM in presence of efflux pump inhibitor verapamil.

Twenty derivatives of 2,6-disubstituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide and ten of 2-substituted 4,5,6,7,8,9-hexahydrocycloocta[b]thiophene-3-carboxamide were synthesized by molecular modification of a known antimycobacterial molecule. Compounds were evaluated in vitro against Mycobacterium tuberculosis (MTB), and cytotoxicity against RAW 264.7 cell line. Among the compounds, 2-(4-phenoxybenzamido)-4,5,6,7,8,9-hexahydrocycloocta[b]thiophene-3-carboxamide (12f) was found to be the most active compound against MTB with MIC of 3.70 μM and was more potent than Ethambutol (MIC of 7.64 μM), Ciprofloxacin (MIC of 9.41 μM) and standard lead compound SID 92097880 (MIC of 9.15 μM). Compound 12f also showed MTB MIC of 1.23 μM in the presence of an efflux pump inhibitor verapamil, and showed no cytotoxicity at 50 μM.

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