Design, synthesis, molecular modeling, DFT, ADME and biological evaluation studies of some new 1,3,4-oxadiazole linked benzimidazoles as anticancer agents and aromatase inhibitors

Abstract

Breast cancer is the most frequent female cancer and second cause of cancer-related deaths among women around the world. Two thirds of breast cancer patients have hormone-dependent tumors, which is very likely be treated with hormonal therapy. Aromatase is involved in the biosynthesis of estrogen thus a critical target for breast cancer. In this study, in order to identify new aromatase enzyme inhibitors, a series of benzimidazole-1,3,4-oxadiazole derivatives were synthesized and characterized by ¹H NMR, ¹³C NMR, and MS spectra analyses. In the in vitro anticancer assay, all the compounds tested anticancer activities using MTT-based assay against five cancer cell lines (MCF-7, A549, HeLa, C6, and HepG2). Among them, compound 5a exhibited the most potent activity with IC₅₀ values of 5.165 ± 0.211 μM and 5.995 ± 0.264 μM against MCF-7 and HepG2 cell lines. Compound 5a was included in the BrdU test to determine the DNA synthesis inhibition effects for both cell types. Furthermore, compound 5c was also found to be more effective than doxorubicin on the HeLa cell line. The selectivity of anticancer activity was evaluated in NIH3T3 cell line. In vitro, enzymatic inhibition assays of aromatase enzyme were performed for compound 5a acting on the MCF-7 cell line. For compound 5a, in silico molecular docking and dynamics simulations against aromatase enzyme was performed to determine possible protein-ligand interactions and stability. DFT study was performed to evaluate the quantum mechanical and electronic properties of compound 5a. Finally, the theoretical ADME properties of the potential aromatase inhibitor compound 5a were analyzed by calculations.

Communicated by Ramaswamy H. Sarma

Keywords:

• Benzimidazole
• aromatase
• docking
• dynamics
• DFT
• ADME

Disclosure statement

The authors declared no conflict of interest.

Authors’ contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Ulviye Acar Çevik], [Ismail Celik], [Ayşen Işık], [Iqrar Ahmad] and [Harun Patel]. The first draft of the manuscript was written by [Yusuf Özkay] and [Zafer Asım Kaplancıklı1] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Additional information

Funding

This study was financially supported by Anadolu University Scientific Projects Fund, Project No: 1706S381. We are grateful to the Doping and Narcotic Compounds Analysis Laboratory for the anticancer activity screening.