Breast cancer (BC) is a multifactorial disease that poses a significant threat to women’s health [1]. In 2023, an estimated 3.00 million new cases of BC will occur, followed by lung cancer (2.38 million) [2]. Understanding BC molecular subtypes is crucial for tailoring treatment approaches. These subtypes are categorized according to the presence or absence of certain proteins, namely estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [3]. ER-positive (ER+) BC, characterized by over-expressed ERs, constitutes more than 70 % of BC cases [4]. There are two main subtypes of the estrogen receptor: ER-alpha (ER-α) and ER-beta (ER-β). ER-α is a ligand-dependent transcription factor that regulates the genes associated with cell proliferation, differentiation, and migration [5]. ER-β typically antagonizes the cell hyperproliferation promoted by ER-α, particularly in tissues like the breast and uterus [6]. In normal breast cells, both ER-α and ER-β are present at comparable low levels. However, in BC cells, ER-α expression surpasses that of ER-β. As normal breast tissue becomes tumorigenic, the amount of ER-α increases, whereas the amount of ER-β decreases [7], [8]. When estrogen binds to ER-α on BC cells, it can promote the growth and development of cancerous cells [6]. To counteract the effect of estrogen, selective estrogen receptor modulators (SERMs) have been developed [9]. SERMs modify the effect of estrogen by binding to ERs. Tamoxifen, a first-generation SERM, has long been used to treat BC but is associated with adverse effects such as an increased risk of thrombosis and endometrial cancer [10]. Second-generation SERMs like raloxifene and lasofoxifene were subsequently introduced to mitigate these side effects but still pose risks such as blood clot formation, deep vein thrombosis, the onset of hot flashes, and pulmonary embolism [11]. During recent developments in SERMs, 2-phenylindole analogs bazedoxifene and pipendoxifene were moved to clinical evaluations. Bazedoxifene demonstrates a higher affinity for binding to ER-α than ER-β [12]. Studies have indicated that the inhibitory impact of bazedoxifene is linked to the downregulation of ER-α and the arrest of the cell cycle. Recently, a combination therapy involving bazedoxifene and palbociclib has been employed for the treatment of stage IV metastatic BC [13].

The development of new SERMs with simple structure and improved efficacy is imperative. It has been reported that nitrogen-containing heterocyclic rings confer a polarized character, facilitating effective interaction with ER-α [14], [15]. Indole-fused heterocyclic ring structures have emerged as promising candidates for cancer treatment due to their potent anti-cancer properties [16], [17], [18]. Fusing two or more heterocyclic rings into a single molecular structure can result in synergistic effects, augmentation, or modulation of the desired characteristics in the individual components [19].

1,3,4-Oxadiazoles are important five-membered heterocyclic compounds with an oxygen atom and two nitrogen atoms, as they have attracted significant interest in medicinal and pharmaceutical chemistry [20]. Considering the importance of indole and oxadiazole nuclei in the pharmaceutical field, we have developed a series of indole-oxadiazoles and evaluated them against ER + BC cell lines (T-47D and MCF-7). To target BC via the ER-α pathway, compounds must exhibit a binding affinity towards ER-α [21]. Two molecules with the best antiproliferative activity against the T-47D cell line were chosen to determine their binding affinity towards ER-α. Polar Screen ER-α Competitor Assay Kit, Green, Life Technology was used for this purpose. The effect of these derivatives on ER-α protein level was determined using Western blotting. Molecular docking was employed to explore potential binding modes of interaction between the synthesized compounds and ER-α. Further, ADME calculations were performed to study their pharmacokinetic profiles. Further, these molecules were subjected to molecular dynamics simulations and density functional theory calculations in search of potential anticancer agents for managing BC.