Design, Synthesis, and Mechanistic Study of Novel Ciprofloxacin/Thiazole Chalcone Hybrids as Potential Anticancer Agents

A novel series of thiazole chalcone/ciprofloxacin hybrids were synthesized and screened for their anticancer activity against NCI-60 cancer cell lines, USA. Interestingly, compounds <b>4b</b> and <b>4d</b> exhibited potent antiproliferative activities, particularly against leukemia HL-60, RPMI-8226, and colon HCT-116 cells, with IC₅₀ values of 0.3-3.70 µM. Importantly, compounds <b>4b</b> and <b>4d</b> exhibited enhanced selectivity for cancer cells relative to doxorubicin with IC₅₀ values of 26.80, 41.20, and 19.80 µM, respectively. Mechanistic investigations revealed that compounds <b>4b</b> and <b>4d</b> inhibited topoisomerases (Topo) I/IIβ activity, being fourfold and twofold more effective than untreated controls, respectively. Furthermore, these compounds induced G1 phase cell cycle arrest and promoted apoptosis, which likely explain their potent anticancer properties. In depth, compound <b>4d</b> increased the relative gene expression of pro-apoptotic Bax (5.58-fold) and caspase-3 (10.86-fold) as well as the initiator caspase-9 (4.2-fold), and reduced the relative gene expression of <i>Bcl-2</i>. Therefore, ciprofloxacin/thiazole chalcone derivatives, particularly <b>4b</b> and <b>4d</b>, may serve as promising candidates for the development of antitumor agents.