Aim: Development of 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)- thione hybrids as potential dual-acting mechanism anticancer agent to overcome the drug resistance.

Background: Chemotherapy is an essential tool for the treatment of lung and female breast cancers, and numerous anticancer agents have been launched for this purpose. However, the clinical outcomes of chemotherapy are usually far from satisfactory due to the side effects and resistance to chemotherapeutic drugs. Thus, it is urgent to develop novel anti-lung and anti-breast cancer agents.

Objective: The primary objective of this study was to evaluate the potential of bis-isatin scaffolds with alkyl/ether linkers between the two isatin moieties against different human breast cancer cell lines including A549, MCF-7 and their drug-resistant counterparts A549/CDDP, MCF-7/ADM cells.

Methods: The 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-(4-methyl/phenyl/benzyl-3-aryl)-1,2,4- triazole-5(4H)-thione hybrids were screened for their in vitro activity against drug-sensitive lung (A549), breast (MCF-7) and their drug-resistant counterparts A549/CDDP (cisplatin-resistant), MCF- 7/ADM (doxorubicin-resistant) cancer cell lines by MTT assay. The inhibitory activity of these hybrids against topoisomerase II and EGFR was also evaluated to investigate the potential mechanism of action of these hybrids.

Results: The most prominent hybrid 7k (IC50: 37.28-49.05 µM) was comparable to Vorinostat against A549 and A549/CDDP lung cancer cells, and was 2.79-2.94 times more active than Vorinostat against MCF-7 and MCF-7/ADM breast cancer cell lines. Moreover, hybrid 7k (IC50: 8.6 and 16.4 µM) also demonstrated dual inhibition against topoisomerase II and EGFR.

Conclusion: The 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)-thione hybrids possess equally activity against both drug-sensitive cancer cells and their drug-resistant counterparts, and the majority of them were no inferior to the reference Vorinostat. The mechanistic study revealed that these hybrids could inhibit both topoisomerase II and EGFR, so these hybrids can be developed as dual-acting mechanism anticancer agents.

目的：开发1-[（1R，2S）-2-氟环丙基]环丙沙星-1,2,4-三唑-5（4H）-硫酮杂化物作为潜在的双重作用机制抗癌药，以克服耐药性。

背景：化学疗法是治疗肺癌和女性乳腺癌的必不可少的工具，为此目的已经推出了许多抗癌药。然而，由于副作用和对化学治疗药物的抗性，化学疗法的临床结果通常不能令人满意。因此，迫切需要开发新型的抗肺癌和抗乳腺癌药物。

目的：这项研究的主要目的是评估两个isatin部分之间具有烷基/醚连接基的双isatin支架对不同的人类乳腺癌细胞系（包括A549，MCF-7及其耐药性A549 / CDDP）的潜力，MCF-7 / ADM电池。

方法：筛选1-[（（1R，2S）-2-氟环丙基]环丙沙星-（4-甲基/苯基/苄基-3-芳基）-1,2,4-三唑-5（4H）-硫酮杂化物MTT法检测其对药物敏感性肺（A549），乳腺癌（MCF-7）及其耐药同种药物A549 / CDDP（顺铂耐药），MCF-7 / ADM（对阿霉素）癌细胞的体外活性。还评估了这些杂种对拓扑异构酶II和EGFR的抑制活性，以研究这些杂种的潜在作用机理。

结果：最突出的杂种7k（IC50：37.28-49.05 µM）与伏立诺他抗A549和A549 / CDDP肺癌细胞相当，比伏立诺他抗MCF-7和MCF-7 / ADM乳腺癌的活性高2.79-2.94倍癌细胞系。此外，杂种7k（IC50：8.6和16.4 µM）也显示出对拓扑异构酶II和EGFR的双重抑制作用。

结论：1-[（（1R，2S）-2-氟环丙基]环丙沙星-1,2,4-三唑-5（4H）-硫酮杂种对药敏癌细胞及其耐药同行具有相同的活性，并且其中大多数不低于参考伏立诺他。机理研究表明，这些杂种可以同时抑制拓扑异构酶II和EGFR，因此这些杂种可以被开发为双重作用机制的抗癌药。