Synthesis and docking study of benzimidazole–triazolothiadiazine hybrids as aromatase inhibitors

Aromatase is involved in the biosynthesis of estrogen and thus is a critical target for breast cancer. In this study, to identify new aromatase enzyme inhibitors, seven 3‐[4‐(5‐methyl‐1 H ‐benzo[ d ]imidazol‐2‐yl)phenyl]‐6‐(substituted phenyl)‐7 H ‐[1,2,4]triazolo[3,4‐ b ][1,3,4]thiadiazine derivatives were synthesized. First, a 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay was performed to determine the inhibitory activity of the synthesized compounds on the MCF‐7 cell line. The aromatase inhibitory activity was determined for the active compounds 5b , 5c , 5e , and 5g on the MCF‐7 cell line. Compound 5g showed significant aromatase inhibitory activity (IC 50 = 0.037 ± 0.001 µM). Interestingly, this compound, which bears a difluoro substituent at positions 2 and 4 of the phenyl ring, displayed the most potent aromatase inhibitory activity without significant cytotoxicity to a normal healthy cell line (NIH3T3). Furthermore, the interactions between the best active compounds and the active site of the enzyme were analyzed through a docking study. The results of this study determined that benzimidazole–triazolothiadiazine derivatives are promising compounds that should be further developed as a novel class of aromatase inhibitors.