Design, synthesis, bioevaluation, DFT, docking, and molecular dynamic simulation for selected novel 1,3,4-Oxadiazole - indole derivatives hybrid against estrogen receptor alpha

Abstract

Breast tumors overexpress ER alpha and it initiates, as well as the progression of breast cancer. Studies have proven that anti-estrogen therapy (tamoxifen) is used to treat breast cancer. For the first time, in vitro bioevaluation, molecular docking, and DFT simulations were used to investigate the essential interactions of the estrogen receptor (ER) alpha with selected novel 1,3,4-Oxadiazole - indole derivatives hybrid against Triple Negative Breast Cancer (TNBC) cell lines. The key step of this synthesis is the oxidative cyclization of N-acylhydrazones, 2(a-j), in 20 min using reagent BTI [bis(trilfuoroacetoxy)iodobenzene]. Synthesized compounds, 3(a-j), were screened against a series of cancer cell lines, and among these compounds, the compound, 3d ((5′-Bromo-1H-indol-1-yl) methyl)-5′’-(3-bromo-4-methylphenyl)-1,3,4-Oxadiazole), as a potent molecule which displayed IC50 values of 10.56 and 22.61 µM against MDA MB 468, and MDA MB 231 cell lines respectively. In vitro antibody specific for Human Estrogen Receptor alpha assay showed an IC50 value of 5.27 µM for compound 3d. The structures were optimized to their molecular geometry (3d) by the DFT method with B3LYP hybrid functional and 6–311++g(d,p) basis set. The electrostatic potential map was plotted to understand the energy distribution and chemical reactive regions of the molecule. The optimized structures were used to perform in silico studies. Molecular docking followed by molecular dynamics trajectories is essential to investigate the stable binding of 3d to estrogen receptor alpha. Overall, results show that 3d has the potential to be further explored for the treatment of metastatic breast cancer.