N-Acylated Ciprofloxacin Derivatives: Synthesis and In Vitro Biological Evaluation as Antibacterial and Anticancer Agents

A novel series of N-acylated ciprofloxacin (CP) conjugates 1-21 were synthesized and screened as potential antimicrobial agents. Conjugates 1 and 2 were 1.25-10-fold more potent than CP toward all Staphylococci (minimal inhibitory concentration 0.05-0.4 μg/mL). Most of the chloro- (3-7), bromo- (8-11), and CF₃-alkanoyl (14-16) derivatives expressed higher or comparable activity to CP against selected Gram-positive strains. A few CP analogues (5, 10, and 11) were also more effective toward the chosen clinical Gram-negative rods. Conjugates 5, 10, and 11 considerably influenced the phases of the bacterial growth cycle over 18 h. Additionally, compounds 2, 4-7, 9-12, and 21 exerted stronger tuberculostatic action against three Mycobacterium tuberculosis isolates than the first-line antitubercular drugs. Amides 1, 2, 5, 6, 10, and 11 targeted gyrase and topoisomerase IV at 2.7-10.0 μg/mL, which suggests a mechanism of antibacterial action related to CP. These findings were confirmed by molecular docking studies. In addition, compounds 3 and 15 showed high antiproliferative activities against prostate PC3 cells (IC₅₀ 2.02-4.8 μM), up to 6.5-2.75 stronger than cisplatin. They almost completely reduced the growth and proliferation rates in these cells, without a cytotoxic action against normal HaCaT cell lines. Furthermore, derivatives 3 and 21 induced apoptosis/necrosis in PC3 cells, probably by increasing the intracellular ROS amount, as well as they diminished the IL-6 level in tumor cells.