In view of their DNA intercalation activities as anticancer agents, 17 novel [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized and evaluated against HepG2, HCT-116 and MCF-7 cells. Molecular docking studies were performed to investigate the binding modes of the proposed compounds with the DNA active site. The data obtained from biological testing highly correlated with those obtained from the molecular modeling studies. MCF-7 was found to be the most sensitive cell line to the influence of the new derivatives. In particular, compound 12_d was found to be the most potent derivative of all the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines, with IC₅₀ = 22.08 ± 2.1, 27.13 ± 2.2 and 17.12 ± 1.5 μM, respectively. Although this compound displayed nearly one third of the activity of doxorubicin (IC₅₀ = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 μM, respectively), it may be useful as a template for future design, optimization, and investigation to produce more potent anticancer analogs. Compounds 12_a, 10_c and 10_d displayed very good anticancer activities against the three HepG2, HCT116 and MCF-7 cancer cell lines, with IC₅₀ = 31.40 ± 2.8, 28.81 ± 2.4 and 19.72 ± 1.5 μM for 12_a, 33.41 ± 2.9, 29.96 ± 2.5 and 24.78 ± 1.9 μM for 10_c, and 37.55 ± 3.3, 30.22 ± 2.6 and 25.53 ± 2.0 μM for 10_d. The most active derivatives, 10_c, 10_d, 10_h, 12_a, 12_b and 12_d, were evaluated for their DNA binding activities. Compound 12_d displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC₅₀ value (35.33 ± 1.8 μM), which is nearly equipotent to that of doxorubicin (31.27 ± 1.8 μM). Compounds 12_a and 10_c exhibited good DNA-binding affinities, with IC₅₀ values of 39.35 ± 3.9 and 42.35 ± 3.9 μM, respectively. Finally, compounds 10_d, 10_h and 12_b showed moderate DNA-binding affinities, with IC₅₀ values of 50.35 ± 3.9, 57.08 ± 3.3 and 59.35 ± 3.2 μM, respectively.

中文翻译：

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[1,2,4]三唑并[4,3-a]喹喔啉和[1,2,4]三唑并[4,3-a]喹喔啉-1-硫醇衍生的DNA嵌入剂：设计，合成，分子对接silico ADMET曲线和抗增殖评估

考虑到它们作为抗癌剂的DNA嵌入活性，已经针对HepG2，HCT-116和MCF-7细胞设计，合成和评估了17种新颖的[1,2,4]三唑并[4,3- a ]喹喔啉衍生物。进行了分子对接研究以研究所提出的化合物与DNA活性位点的结合模式。从生物学测试获得的数据与从分子建模研究获得的数据高度相关。发现MCF-7是对新衍生物影响最敏感的细胞系。特别是，化合物12 _d被认为是对三名HepG2细胞，HCT116和MCF-7癌细胞系的所有测试化合物的最有效的衍生物，具有IC ₅₀分别为22.08±2.1、27.13±2.2和17.12±1.5μM。尽管该化合物显示出了阿霉素活性的近三分之一（IC _50分别为7.94±0.6、8.07±0.8和6.75±0.4μM），但它可能用作将来设计，优化和研究的模板以产生更多有效的抗癌类似物。化合物12_一个，10 _Ç和10 _d显示很好的抗肿瘤活性对三名HepG2细胞，HCT116和MCF-7癌细胞系，具有IC ₅₀ = 31.40±2.8，28.81±2.4和19.72±1.5μM为12_一个，33.41± 10 _c时为2.9、29.96±2.5和24.78±1.9μM，持续10 _d时为37.55±3.3、30.22±2.6和25.53±2.0μM 。最活跃的衍生物，10 _Ç，10 _d，10 _ħ，12_一，12 _b和12 _d，测试它们的DNA结合活性进行评价。化合物12 _d中显示的最高结合亲和力。该化合物可有效降低DNA的IC ₅₀值（35.33±1.8μM）插入DNA ，这几乎与阿霉素（31.27±1.8μM）等效。化合物12_一和10 _Ç具有良好的DNA结合亲和力，IC ₅₀值分别为39.35±3.9和42.35±3.9μM。最后，化合物10 _d，10 _ħ和12 _b表现出中等的DNA结合亲和力，与IC _50倍分别为50.35±3.9的值，57.08±3.3和59.35±3.2微米。