Design, synthesis, in silico, and pharmacological evaluation of novel quinoline derivatives containing substituted piperazine moieties as potential anti-breast cancer agents

Quinoline derivatives are important heterocyclic compounds with potential medicinal values, especially for treating cancers like breast cancer. However, drug resistance and potential toxicity can limit their effectiveness. New derivatives are needed to specifically target cancer cells, particularly in breast cancer, while minimizing harm to normal cells and side effects for better treatment outcomes. Thus, this study aims to design and synthesize novel quinoline derivatives incorporating substituted piperazine moieties to enhance their anticancer efficacy by inhibiting EGFR, a key therapeutic target for breast cancer. Therefore, in this study, structural elucidation of the synthesized compounds was confirmed by using various analytical techniques, including IR, MASS, and NMR spectral data. Subsequently, these analogs were analyzed for their binding affinity using the molecular docking study, while anticancer efficacy was evaluated against MCF-7 cell lines, followed by an in vivo study in a DMBA-induced rat model. Initially, docking studies of synthesized analogs (8a–i) at the ATP binding site of the EGFR showed better docking scores and MM/GBSA energy, indicating their increased binding affinity to the EGFR. Further, the in vitro evaluation of all compounds (8a–i) showed that the compounds effectively inhibit the EGFR-TK enzyme, with compound 8i showing the highest potency at 87.5%. Moreover, the anti-breast cancer efficacy of compound 8i is attributed to electron-donating groups, which enhance interactions with biological targets. Compound 8i exhibited promising anti-breast cancer activity and was confirmed in vitro and in vivo studies, warranting further investigation as a potential anticancer property.