N-Acylated Ciprofloxacin Derivatives: Synthesis and In Vitro Biological Evaluation as Antibacterial and Anticancer Agents.
Marta StrugaPiotr RoszkowskiAnna BielenicaDagmara Otto-ŚlusarczykKarolina StępieńJoanna StefańskaAnna ZabostEwa Augustynowicz-KopećMichał KolińskiSebastian KmiecikAlina MyslovskaMałgorzata WrzosekPublished in: ACS omega (2023)
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 CF 3 -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 (IC 50 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.
Keyphrases
- induced apoptosis
- molecular docking
- gram negative
- signaling pathway
- endoplasmic reticulum stress
- mycobacterium tuberculosis
- multidrug resistant
- cancer therapy
- oxidative stress
- structure activity relationship
- pseudomonas aeruginosa
- prostate cancer
- cystic fibrosis
- reactive oxygen species
- molecular dynamics simulations
- cell death
- staphylococcus aureus
- silver nanoparticles
- escherichia coli
- drug delivery
- risk assessment
- cell proliferation
- essential oil
- antimicrobial resistance