Anti-breast cancer potential of new indole derivatives: Synthesis, in-silico study, and cytotoxicity evaluation on MCF-7 cells

• Published in: Journal of molecular structure 2025-04, Vol.1326, p.141176, Article 141176
• Main Authors: Abood, Rehab G., Abdulhussein, Heider A., Abbas, Sabah, Majed, Ahmed A., Al-Khafagi, Ahmed Adnan, Adil, Ayat, Alsalim, Tahseen A.
• Format: Article
• Language: English
• Subjects: breast cancer; Indole; MCF-7; Molecular docking; MTT; Triazole
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.141176

•Synthesis and evaluation of indole derivatives with triazole or oxadiazole rings for anti-tumor activity and were characterized using IR spectroscopy, 1H NMR, 13C NMR, and mass spectrometry.•The anticancer activity was tested on MCF-7 breast carcinoma cells using the MTT assay showing anti-tumor activity with IC50 values between 44.1 and 93.2 µg/ml.•Compounds 4a and 4d exhibited strong binding with the CDK4 receptor, with binding scores of -8.36 and -8.18 kcal/mol, respectively. Compound 4a showed the highest binding affinity in dynamic simulations.•All compounds demonstrated high safety for biological use.•According to the BOILED-Egg model, compounds 4a, 4b, 4c, and 4d cannot cross the blood-brain barrier, suggesting limited central nervous system impact but effective biological membrane permeability. Breast cancer remains the leading cause of death among women globally, with an increasing incidence. Although numerous FDA-approved treatments are available, issues such as drug resistance and selectivity necessitate the development of more effective agents with fewer side effects. In this study, we synthesized a series of indole derivatives containing triazole or oxadiazole rings with anti-tumor activity. The structures of all synthesized compounds were confirmed through infrared (IR) spectroscopy, proton nuclear magnetic resonance (1HNMR), carbon-13 nuclear magnetic resonance (13CNMR), and mass spectrometry. These compounds were assessed for their potential anticancer activity against MCF-7 breast carcinoma cells using the MTT assay. The results indicated that the indole derivatives exhibited antitumor activity, with IC50 values ranging from 44.1 to 93.2 µg/ml. Five compounds, specifically 2, 3, 4a, 4c, and 4d, were further evaluated through in-silico studies. Their interactions with the receptor protein CDK4 (PDB ID: 2W96) were analyzed to determine their potential as anti-breast cancer agents. Effective binding was observed between these compounds and the receptor. Molecular docking studies revealed that compounds 4a and 4d showed the highest activity, with binding scores of -8.36 and -8.18 kcal/mol, respectively. Notably, compound 4a demonstrated a stronger binding affinity than compound 4d during dynamic simulations. The ADMET study indicated that all compounds are highly safe for biological use. According to the BOILED-Egg model, compounds 4a, 4b, 4c, and 4d are unable to cross the blood-brain barrier, suggesting minimal impact on the central nervous