Abstract:A panel of 1,3‐diynyl‐noscapinoids (20–22) were strategically designed to increase the anticancer activity of the lead molecule, noscapine. Structure‐activity analyses revealed strong predicted free energy of binding (ΔGbind,pred) of −6.694, −7.294 and −7.468 kcal/mol, for 20–22 respectively compared to noscapine (experimental free energy of binding (ΔGbind,expt) is −5.246 kcal/mol). These novel derivatives were demonstrated to bind tubulin by fluorescence quenching assay and Far‐UV circular dichroism. Further, they were tested to exhibit potent cytotoxic activity compared to noscapine using two human breast cancer cell lines. The IC50 value for noscapine, 20, 21 and 22 has been derived to be 35.2, 27.3, 18.7 and 12.7 μM using MCF7 and 39.6, 31.4, 22.5 and 16.1 μM using MDAMB‐231. These derivatives were found to arrest cell cycle in the G2/M‐phase followed by apoptosis and appearance of TUNEL‐positive cells. Thus, we conclude that 1,3‐diynyl derivatives of noscapine have great potential to be a novel therapeutic agent for breast cancers.