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Melatonin (N‐acetyl‐5‐methoxytryptamine, MLT) is suggested as a preventive agent and potential therapeutic option for breast cancer via its antioxidant as well as anticancer effects by modulating estrogen dependent and independent pathways. However, its rapid metabolic inactivation led scientists to discover novel MLT analogues. Therefore, a series of new indole‐based hydrazide/hydrazone derivatives were synthesized and characterized as MLT analogues in the present study. The initial aim is to investigate the cytotoxicity of novel 1‐ethyl indole hydrazone derivatives against two human breast cancer cells (MCF‐7 and MDA‐MB‐231) as well as a non‐tumorigenic human breast epithelial cell (MCF‐10A). Selective cytotoxic compounds for cancer cells are further investigated for their effects on selected targets; agonist/antagonist activity on estrogen receptor (ER) and inhibitory effects on aromatase and CYP1B1. Their potential antioxidant activity was also investigated by both cell based and cell free in vitro assays. Possible binding of the compounds to the selected targets is also explored by molecular modelling studies. Nonsubstituted compound E1 inhibited human aromatase and the CYP1B1 enzyme with IC50 values of 0.89 μM and 0.5 μM, respectively. Compounds EI 4 and EI 11 exhibited ER antagonist activity with IC50 values of 2.88 μM and 5.29 μM, respectively. Additionally, both EI 4 and EI 11 inhibited CYP1B1 enzyme within 60–100 nanomolar range. In conclusion among 19 tested derivatives EI 1, EI 4 and EI 11 affected either one or more targets besides their selective cytotoxic effect for MCF‐7 cells suggesting that they can be promising candidates in prevention/treatment of ER‐positive breast cancer. Further studies are needed to elucidate their metabolism, in vivo effects, and safety. [ABSTRACT FROM AUTHOR]