Discovery of Novel 1,3,5‐trisubstituted‐2‐thioxo‐imidazole Derivatives as Potential Aromatase Inhibitors: Design, Synthesis, In Vitro Anti‐Breast Cancer Screening and Molecular Docking Studies

ABSTRACT Imidazole derivatives have a multi‐targeted ability that indicates their ability to act as anticancer agents in respect to breast cancer. This study aimed to evaluate the anticancer response of a new series of 1, 3, 5‐trisubstituted‐2‐thioxo‐imidazoles derivatives ( 5–8 ) in vitro. The structural elucidation was performed with the usage of IR, ¹H‐NMR and ¹³C‐NMR. Compounds 6b and 8b had significant anti‐cytotoxic activity in the MCF‐7 cell line and had IC 50 values of 5.316 µg/mL and 2.805 µg/mL where they had minimal toxicity on normal cells (MCF‐10A). The mechanistic studies have shown that compound 6b and 8b were very effective in stopping the cell cycle at the G1 stage and also the induction of apoptosis. Moreover, the compounds 6b and 8b depicted in the paper displayed an inhibitory action concerning the aromatase enzyme. The results of qRT‐PCR implied that both compounds 6b and 8b exerted a considerable apoptotic impact in the manner in which they up‐regulated caspase‐9 and p53 and down‐regulated Bcl‐2. The binding interaction mechanisms between the docked compounds and aromatase enzyme and Bcl‐2 receptors were better understood in terms of a molecular docking analysis. Altogether, the results of the present study suggest that the 1, 3, 5‐trisubstituted‐2‐thioxo‐imidazole backbone can be used as a promising new scaffold in future development of multi‐action anti‐cancer drugs in breast cancer.