LAUSR

AIMS To develop novel anticancer candidates which are sensitive to both drug-sensitive and drug-resistant cancers, a series of 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-(4-methyl/phenyl/benzyl-3-aryl)-1,2,4-triazole-5(4H)-thione hybrids were designed, synthesized and evaluated for their anticancer activity. BACKGROUND Chemotherapy is an essential tool for the treatment of 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 anticancer agents. OBJECTIVE To enrich the anticancer SAR of 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-(4-methyl/phenyl/benzyl-3-aryl)-1,2,4-triazole-5(4H)-thione hybrids and develop these hybrids as dual-acting mechanism anticancer agents. METHOD 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)-thione hybrids were designed, synthesized, and evaluated for in vitro anticancer activity against drug-sensitive lung (A549), breast (MCF-7) cancer cell lines and their drug-resistant counterparts A549/CDDP (cisplatin-resistant), MCF-7/ADM (doxorubicin-resistant) cells. The most active hybrid 7k was selected for further evaluation of its inhibitory activity against topoisomerase II and EGFR. RESULT These 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. CONCLUSION These hybrids could serve as dual-acting mechanism anticancer candidates to fight against both drug-sensitive and drug-resistant cancers. Other: These hybrids could act as lead compounds for further investigations.