| Summary: | In the last step of estrogen biosynthesis, aromatase enzyme catalyzes the conversion of androgens to estrogens. Aromatase inhibition is an important way to control estrogen-related diseases and estrogen levels. In this study, sixteen of benzimidazole-triazolothiadiazine derivatives have been synthesized and studied as potent aromatase inhibitors. First, these compounds were tested for their anti-cancer properties against human breast cancer cell line (MCF-7). The most active compounds <b>5c</b>, <b>5e</b>, <b>5k</b>, and <b>5m</b> on MCF-7 cell line were subject to further in vitro aromatase enzyme inhibition assays to determine the possible mechanisms of action underlying their activity. Compound <b>5e</b> showed slight less potent aromatase inhibitory activity than that of letrozole with IC<sub>50</sub> = 0.032 ± 0.042 µM, compared to IC<sub>50</sub> = 0.024 ± 0.001 µM for letrozole. Furthermore, compound <b>5e</b> and reference drug letrozole were docked into human placental aromatase enzyme to predict their possible binding modes with the enzyme. Finally, ADME parameters (absorption, distribution, metabolism, and excretion) of synthesized compounds (<b>5a</b>–<b>5p</b>) were calculated by QikProp 4.8 software.
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