Design, synthesis, and molecular modeling of new 1,2,4-triazole-containing indole compounds as aromatase antagonists for the treatment of breast cancer.

Recently, the incidence of breast cancer has increased among postmenopausal women. This highlights the need for improved aromatase inhibitors with fewer side effects than those currently available. This study focuses on designing and evaluating potential aromatase inhibitors containing the 1,2,4-triazole/indole hybrid, given their proven impact in this respect. Accordingly, by exploiting the thiol and amine groups in 5-((1H-indole-3-yl)methyl)-4-amino-4H-1,2,4-triazole-3-thiol (2) to react with some reagents, new hybrid 1,2,4-triazole-indole compounds were obtained. A cytotoxicity (MTT) test was conducted to assess the anticancer activity of the newly synthesized compounds on the breast cancer cell line MCF-7. The results of the MTT assay indicated that compounds 4d and 5 exhibited significant cytotoxic activity against the MCF-7 cancer cell lines with IC values of 17.67 ± 0.34 and 17.01 ± 0.53 μM (respectively) compared with Cisplatin, which showed an IC value of 18.03 ± 0.71 μM. Molecular dynamics simulations were conducted to investigate the crystal structure of human placental aromatase cytochrome (AR) P450 for compounds 4d and 5. The results revealed that compound 5 exhibited significant interactions with key residues in the binding site, leading to a stable complex throughout the entire simulation. Depending on molecular dynamics data, compound 5 was selected for an in vitro aromatase inhibition study. Compound 5 inhibited aromatase with an IC value of 0.026 μM, which is approximately equivalent to the reference compound letrozole (IC 0.024 μM).