NEW JOURNAL OF CHEMISTRY, vol.46, no.16, pp.7442-7451, 2022 (SCI-Expanded)
In this study, we developed a series of new aromatase MAO-B dual inhibitors against breast cancer. Aromatase inhibitors are the most comma* used drugs clinically for breast cancer. In this dual hybridization entity, the azale group acts as an aromatase inhibitor by binding to the HEM group of the enzyme and the thiazolyhydrazone group acts as an MAO-B inhibitor. The basic idea behind the development of this combination was to prevent the effect of aromatase inhibitor on dopaminergic neurons and to reduce its side effects due to decreasing estrogen level in patients with breast cancer. For this purpose, new hybrid derivatives containing the imidazole ring with known aromatase inhibitory activity and the thiazolyhydrazone structure with known MAO-B inhibitory activity were synthesized. From the obtained derivatives, compound 2e showed activity with an IC50 value of 0.079 +/- 0.002 mu M against the MCF-7 cell Line. The aromatase inhibitory activity of compound 2e had an IC50 value of 0.020 +/- 0.002 mu M, while letrazole inhibited the aromatase enzyme with an IC50 value of 0.021 +/- 0.002 mu M. In addition, 2e was also found to inhibit the DNA synthesis in the S phase of the cell cycle. In the flow cytometric study, the apoptotic potentials of the compounds were determined. On the side, compound 2e showed an inhibitory effect on the enzyme MAO-B with an IC50 value of 0.045 +/- 0.002 mu M. Molecular docking studies were performed using aromatase, hMAO-B, and caspase-3 crystals to elucidate the interactions of the compounds with the active sites of the enzymes.