New dimension of ciprofloxacin hybrids: Synthesis, characterization and anticancer evaluation of newly C3-modified ciprofloxacin derivatives

The strategic application of drug repurposing and repositioning in the design of hybrid molecules represents a promising alternative in contemporary drug discovery. Recent studies have highlighted the anticancer activity of ciprofloxacin derivatives, attributing this effect primary to their capacity to inhibit DNA topoisomerase II. In silico ADME profiling of C3-modyfied ciprofloxacin analogues, have further identified their role as potential P-glycoprotein inhibitors. Building upon these findings, we proposed the synthesis of a series of ciprofloxacin-peptidomimetic hybrid compounds to explore the synergistic antitumor activity arising from the combined fluoroquinolone and peptidomimetic pharmacophores. To achieve this goal, a novel chemoselective synthetic protocol was developed, employing the Passerini multicomponent reaction, which revealed an unexpected yet versatile role of acetic acid as a reaction medium but not as a substrate. The cytotoxic effects and the potential to overcome multidrug resistance were evaluated using various cancer cell lines. In parallel, molecular docking simulations with the multidrug resistant transporter P-glycoprotein provided mechanistic insights into the mode of action of these hybrids. Importantly, the studied compounds demonstrated reduced cytotoxicity towards erythrocytes and non-cancerous cells derived from vascular, hepatic, and connective tissues compared to cancer cells. Overall, our findings indicate that these ciprofloxacin-peptidomimetic hybrids exhibit significantly enhanced cytotoxic and chemosensitizing activity against cancer cells while maintaining a favorable toxic profile in normal cells. This novel class of hybrid molecules represents a promising source of lead compounds for the development of anticancer agents with improved therapeutic efficiency and safety.