Background: Breast cancer, a common and potentially fatal disease, has several subtypes, with the frequent being hormone receptor-positive breast cancer. This study addresses the critical need to tackle this subtype by focusing on the estrogen receptor alpha (ERα), a crucial factor in its development and progression.

Methods: We used computational approaches to create and improve new pyrazole-substituted 9-anilinoacridine compounds with ERα inhibition potential. This included ligand preparation, receptor grid generation, Glide molecular docking and Prime/ Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) binding free energy calculations. We tested the ligand–protein interactions and binding affinities using these approaches. The lead compounds were tested for anti-breast cancer efficacy in vitro by utilising MDA-MB-231 cell lines.

Results: Our computational research showed numerous chemicals with strong ERα receptor binding sites as evidenced by favourable interactions involving hydrogen bonding, hydrophobic interactions and van der Waals forces. These molecules were subsequently synthesised and structurally characterised. Compound 1z displayed considerable cytotoxicity in in-vitro cytotoxicity studies using the MDA-MB-231 cell line, with concentration required for 50% inhibition of cell growth (IC50) value of 23.86 g/mL indicating a good potential against breast cancer. Despite having high docking scores and binding free energy, compound 1x had a high IC50 value (36.08 g/mL). This emphasises the importance of experimental validation in supplementing computer predictions.

Conclusions: Thus, pyrazole-substituted 9-anilinoacridine derivatives show promise as possible ERα inhibitors for breast cancer therapy. While our computational analysis provides a solid foundation, more research is needed to ensure their safety and efficacy as prospective therapies for ERα breast cancer, including in-vivo evaluations and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profiling.