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A series of new Coumarin hydrazone oxime scaffolds were synthesised as potential anti‐TB agents. The structures of the scaffolds were confirmed by spectroscopic and analytical techniques. X‐ray crystallography confirmed the structure of compound 6‐methyl‐4‐((((Z)‐((E)‐3‐(2‐phenylhydrazono)butan‐2‐ylidene)amino)oxy)methyl)‐2H‐chromen‐2‐one (5a). The coumarin hydrazone oxime scaffolds were tested in‐vitro against the Mycobacterium tuberculosis H37Rv strain, and Vero cells were used to assess cytotoxicity. Compound 5b was obtained as the hit candidate, exhibiting MIC 0.78 μg/mL, showing more potent anti‐TB activity than Rifamycin and comparable activity to Isoniazid. There was minimal cytotoxicity observed against Vero cells for the most active compounds, indicating a good safety‐profile.In addition, the most diligent compound 5b demonstrated substantial binding interactions at the PDB:4DQU enzyme's active site and also displayed greater C‐score value than that of 4DQU ligand which validates the observed results. [ABSTRACT FROM AUTHOR]

• Novel coumarin-thioether conjugates were synthesised and characterised. • The synthesised compounds are assessed for in vitro anti-TB activity (H 37 Rv strain). • Compound 6b (MIC = 0.39 µg/mL) was twofold more active than Rifampin (0.8 µg/mL). • Compounds 6b and 6f possessed low level of cytotoxicity against Vero cells. • Molecular docking study revealed higher C-score values that supports the findings. In this work, we report a series of 4-(2,6-dimethylphenyl)thio)methyl)-2H-chromen-2-one conjugates as promising leads to treat tuberculosis. Spectroscopic and other analytical methods were used to validate the synthesised compounds. The compounds were assessed for in vitro anti-tubercular activity with the H 37 Rv strain of Mycobacterium tuberculosis. Further, cytotoxicity studies were performed using Vero cells. Most of the synthesised conjugates were effective and displayed notable activity with MIC values in the range 0.39–12.5 µg/mL.The most diligent compound 6b (MIC = 0.39 µg/mL) was twofold more active than standard anti-TB drug Rifampin (0.8 µg/mL) and was comparable to Isoniazid (0.1 µg/mL). Compound 6f also displayed exemplary activity (MIC 0.78 µg/mL). Both compounds 6b and 6f possessed low levels of cytotoxicity, Molecular docking evaluation of the synthesised conjugates and 4DQU ligand demonstrated that the synthesised conjugates had higher C-score values that further supports the obtained results. It indicates compound 6b and 6f are promising lead compounds in search of novel antitubercular drug-like molecules. [Display omitted] [ABSTRACT FROM AUTHOR]