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.