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 antimicrobialagents. Conjugates 1 and 2 were 1.25-10-foldmore potent than CP toward all Staphylococci (minimal inhibitory concentration 0.05-0.4 mu g/mL).Most of the chloro- (3-7), bromo- (8-11), and CF3-alkanoyl (14-16) derivativesexpressed higher or comparable activity to CP against selected Gram-positivestrains. A few CP analogues (5, 10, and 11) were also more effective toward the chosen clinical Gram-negativerods. Conjugates 5, 10, and 11 considerably influenced the phases of the bacterial growth cycleover 18 h. Additionally, compounds 2, 4-7, 9-12, and 21 exerted strongertuberculostatic action against three Mycobacteriumtuberculosis isolates than the first-line antituberculardrugs. Amides 1, 2, 5, 6, 10, and 11 targeted gyrase andtopoisomerase IV at 2.7-10.0 mu g/mL, which suggests amechanism of antibacterial action related to CP. These findings wereconfirmed by molecular docking studies. In addition, compounds 3 and 15 showed high antiproliferative activitiesagainst prostate PC3 cells (IC50 2.02-4.8 mu M),up to 6.5-2.75 stronger than cisplatin. They almost completelyreduced the growth and proliferation rates in these cells, withouta 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 theydiminished the IL-6 level in tumor cells.

Automated summary

A novel series of N-acylated ciprofloxacin conjugates were synthesized and screened as potential antimicrobial agents. Some of the conjugates showed higher or comparable activity to ciprofloxacin against selected Gram-positive and Gram-negative strains. Additionally, these compounds exhibited strong inhibitory effects against Mycobacterium tuberculosis isolates and antiproliferative activities against prostate cancer cells.