Identification of Novel Coumarin-Based Chalcones as Estrogen Receptor α Inhibitors through Experimental and Computational Approaches

<title>Abstract</title> <p> This study reports the synthesis of fifteen (15) coumarin-based chalcone compounds, of which ten (10) were confirmed to be novel by Reaxys and ChemSpider. The compounds were subjected to experimental (antioxidant and cytotoxicity) and computational analyses to investigate their biological efficacy against breast cancer. Notably, compounds 1b, 1d, 2c, 2d, 3a, 3c, and 3d exhibited consistently pronounced activity against the breast cancer cell line MCF-7 and in the DPPH radical scavenging assay. They exhibited greater activity than the reference standards, tamoxifen and Trolox. Compound 2c emerged as the most effective, with an IC ₅₀ of 0.65 µg/ml in the MCF-7 assay and 20.49 µg/ml in the DPPH assay. The remaining compounds displayed activity above 50 µg/ml for the MCF-7 cell line and 100 µg/ml for the radical scavenging assay. Furthermore, these compounds were computationally analyzed to determine their binding affinity toward estrogen receptor alpha (ERα). Compound <bold>2c</bold> also demonstrated a good binding affinity of -8.78 kcal/mol, with a Ki value of 0.36 µg/ml, and interacted hydrophobically with Ala350, His524, Leu346, Leu387, Leu525, Met388, Met421, and Phe404 amino acid residues. Finally, the compounds met the physicochemical, pharmacokinetic, and drug-like property requirements. Hence, they may be considered potential anti-breast cancer agents. </p>