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

Abstract

A novel series of N-acylated ciprofloxacin (CP) conjugates <b>1-21</b> were synthesized and screened as potential antimicrobial agents. Conjugates <b>1</b> and <b>2</b> were 1.25-10-fold more potent than CP toward all <i>Staphylococci</i> (minimal inhibitory concentration 0.05-0.4 μg/mL). Most of the chloro- (<b>3-7</b>), bromo- (<b>8-11</b>), and CF₃-alkanoyl (<b>14-16</b>) derivatives expressed higher or comparable activity to CP against selected Gram-positive strains. A few CP analogues (<b>5</b>, <b>10</b>, and <b>11</b>) were also more effective toward the chosen clinical Gram-negative rods. Conjugates <b>5</b>, <b>10</b>, and <b>11</b> considerably influenced the phases of the bacterial growth cycle over 18 h. Additionally, compounds <b>2</b>, <b>4-7</b>, <b>9-12</b>, and <b>21</b> exerted stronger tuberculostatic action against three <i>Mycobacterium tuberculosis</i> isolates than the first-line antitubercular drugs. Amides <b>1</b>, <b>2</b>, <b>5</b>, <b>6</b>, <b>10</b>, and <b>11</b> 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 <b>3</b> and <b>15</b> 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 <b>3</b> and <b>21</b> 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.