A series of new noscapinoids designed; synthesized and assessed whether its 3‐ylidenephthalide and isocoumarin conjugates improved cytotoxicity. Cu‐catalysed Sonogashira coupling of N‐propargyl noscapine with 2‐bromobenzoic acids followed by in‐situ substrate‐directed 5‐exo‐dig or 6‐endo‐dig cyclization produced 3‐ylidenephthalide 6 a–6 f and isocoumarin 7 a–7 h analogues in very good yields. In comparison to the lead drug, noscapine, all the newly synthesised derivatives exhibited strong cytotoxic potential in vitro with IC50 ranging from 5.4 μM to 39.5 μM across the evaluated panel of cancer cell lines, without harming normal cells (IC50 >300 μM).

Noscapine an FDA-approved antitussive agent. With low cytotoxicity with higher concentrations, noscapine and its derivatives have been shown to have exceptional anticancer properties against a variety of cancer cell lines. In order to increase its potency, in this study, we synthesized a series of new amido-thiadiazol coupled noscapinoids and tested their cytotoxicity in vitro. All of the newly synthesised compounds demonstrated potent cytotoxic potential, with IC 50 values ranging from 2.1 to 61.2 μM than the lead molecule, noscapine (IC 50 value ranges from 31 to 65.5 μM) across all cell lines, without affecting normal cells (IC 50 value is > 300 μM). Molecular docking of all these molecules with tubulin (PDB ID: 6Y6D, resolution 2.20 Å) also revealed better binding affinity (docking score range from À 5.418 to À 9.679 kcal/mol) compared to noscapine (docking score is À 5.304 kcal/ mol). One of the most promising synthetic derivatives 6aa (IC 50 value ranges from 2.5 to 7.3 μM) was found to bind tubulin with the highest binding affinity (ΔG binding is À 28.97 kcal/mol) and induced apoptosis in cancer cells more effectively.

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