Hybrid molecules are used as anticancer agents to improve effectiveness and diminish drug resistance. So, the current study aimed to introduce twenty novel phenothiazine sulfonamide hybrids 5–22, 24 and 25 of promising anticancer activity. Compounds 11 and 13 revealed more potent anticancer properties (IC₅₀ 8.1 and 8.8 μM) than that of the reference drug (doxorubicin, IC_{50 =} 9.8 μM) against human breast cancer cell line (T47D). To determine the mechanism of their anticancer activity, compounds 5, 6, 7, 11, 13, 14, 16, 17, 19 and 22 that showed promising activity on T47D, were evaluated for their aromatase inhibitory effect. The study results disclose that the most potent aromatase inhibitors 11 and 13 showed the lowest IC₅₀ (5.67 μM and 6.7 μM), respectively on the target enzyme. Accordingly, the apoptotic effect of the most potent compound 11 was extensively investigated and showed a marked increase in Bax level up to 55,000 folds, and down-regulation in Bcl2 to 5.24*10⁻⁴ folds, in comparison to the control. Furthermore, the effect of compound 11 on caspases 3, 8 and 9 was evaluated and was found to increase their levels by 20, 34, and 8.9 folds, respectively, which indicates the activation of both intrinsic and extrinsic pathways. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking and computer aided ADMET studies were adopted to confirm their mechanism of action.

中文翻译：

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芳香酶抑制剂和细胞凋亡诱导剂：以磺酰胺部分为杂化分子的新型吩噻嗪衍生物的设计，合成，抗癌活性和分子建模研究

杂合分子用作抗癌剂，以提高效力并降低耐药性。因此，当前的研究旨在引入二十种新颖的吩噻嗪磺酰胺杂种5-22、24和25，它们具有良好的抗癌活性。与参考药物（阿霉素，IC _{50 =} 9.8μM）相比，化合物11和13显示出更强的抗癌特性（IC ₅₀ 8.1和8.8μM）对人乳腺癌细胞系（T47D）。为了确定其抗癌活性的机制，评估了对T47D表现出有希望的活性的化合物5、6、7、11、13、14、16、17、19和22的芳香酶抑制作用。研究结果表明，最有效的芳香酶抑制剂11和13的最低IC _50值（5.67μM和6.7μM）分别位于目标酶上。因此，与对照相比，最有效的化合物11的凋亡作用被广泛研究并且显示出Bax水平显着增加直至55,000倍，并且Bcl2下调至5.24×10 ^-4倍。此外，评估了化合物11对胱天蛋白酶3、8和9的作用，发现其水平分别增加了20、34和8.9倍，这表明内在和外在途径均被激活。另外，检查了化合物11对细胞周期的作用及其细胞毒性作用。此外，通过分子对接和计算机辅助ADMET研究来确认其作用机理。