Influence of alkyl linkers on the anti-breast cancer activity of dihydroartemisinin-isatin hybrids

To investigate the impact of alkyl linkers of different lengths between dihydroartemisinin and isatin moieties on the anti-breast cancer activity, a series of twenty dihydroartemisinin-isatin hybrids with three- and four-carbon alkyl linkers were synthesized and screened against drug-sensitive MCF-7 and MDA-MB-231 breast cancer cell lines, as well as their multidrug-resistant counterparts MCF-7/ADR and MDA-MB-231/ADR cell lines. The results showed that the length of the carbon spacer had a significant effect on the anti-breast cancer activity, with hybrids tethered through a four-carbon linker exhibiting greater potency than their three-carbon analogs. Additionally, substituents at C-3 and C-5 positions of isatin moiety also greatly influenced the activity, with fluoro at C-3 position and methoxime/ethoxime at C-5 position being favorable for activity. These enriched structure–activity relationships may facilitate the rational design of future compounds. Graphical Abstract