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.