Development of Functionalized 1,2,4-Triazole Derivatives as Potential Aromatase Inhibitors in Breast Cancer

Research Article

Abstract

Breast cancer is characterized by high morbidity and mortality rates largely driven by estrogen-dependent tumor proliferation. The enzyme aromatase, a member of the cytochrome P450 superfamily, catalyzes the rate-limiting step in estrogen production, rendering it a critical focal point for therapeutic intervention. While existing clinical inhibitors offer efficacy, their long-term administration is frequently compromised by systemic toxicity and the acquisition of drug resistance. This research details the rational design and microwave-accelerated preparation of a novel series of 1,2,4-triazole analogues (4a-f). Structural elucidation of the resulting derivatives was achieved through rigorous spectroscopic analysis, including FTIR, NMR, and Mass spectrometry. The pharmacological potential was characterized via DPPH radical scavenging and MTT cytotoxicity assays against the MCF-7 human breast adenocarcinoma cell line. Computational insights were garnered through molecular docking simulations utilizing human placental aromatase (PDB ID: 3S79) to map the binding orientation and energetic stability. Experimental data identified compound 4c as the most potent candidate, exhibiting an IC50 of 24.78 ± 0.87 µM in antioxidant assays and superior growth inhibition in MCF-7 cells. Structure-activity relationship assessments indicate that electron-donating functionalities on the aromatic ring significantly enhance biological potency. Molecular docking correlated with these findings, as compound 4c demonstrated a MolDock score of -151.841 kcal/mol, indicating a higher binding affinity than the reference drug Letrozole. These observations position the triazole-based scaffold as a viable lead for the progression of next-generation aromatase inhibitors in oncology