Designing ESR1 inhibitors for breast cancer: Synthesis and characterization of novel 1,2,3-triazole-salicylaldehyde conjugates <i>via in silico</i> approaches.

Breast cancer remains a global health priority. Phenolic compounds, like salicylaldehyde and 1,2,3-triazoles, show significant anticancer potential. This study reports the synthesis and characterization (high resolution mass spectrometry-HRMS and nuclear magnetic resonance-NMR) of a novel series of 1,2,3-triazole-salicylaldehyde conjugates. Network pharmacology analysis identified ESR1 as a major target. Density functional theory (DFT) calculations characterized the electronic properties, and Hirschfeld surface analyses evaluated intermolecular interactions. Compound 9d exhibited the most favorable electronic characteristics. Furthermore, all derivatives 9a-d underwent ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling and molecular docking with ESR1. A 100 ns molecular dynamics simulation confirmed the stability of compound 9d . Overall, all synthesized derivatives showed favorable physicochemical and ADMET properties, with 9d and 9a standing out as promising lead candidates for ESR1 inhibition.