Synthesis And Activity Of 7-Hydrazonyl Fluoroquinolone Compound

Fluoroquinolones are broad-spectrum, high-efficiency and low-toxicity anti-infective chemotherapeutic agents characterized by 1-substituted-6-fluoro-quinoline-4(1H)-one-3- carboxylic acid scaffold. On the basis of the structural homologies and functional similarities between the prokaryotic type II topoisomerases(DNA gyrase andtopoisomerase IV) and the eukaryotic II topoisomerases represented the cellular targets for antibacterial fluoquinolones and many anticancer drugs, it is possible to transform an antibacterial activity of fluoroquinolones into an antitumor activity by a rationally mechanism-based drug design. Currently, many contributions to modifying the C-7 position with a piperazine heterocyclic ring have resulted in a large number of excellent antibacterial fluoroquinolone drugs, but it less knows about the anticancer activity for the corresponding C-7 modifications. Considering the importance of acylhydrazone pharmacophore in drug research and development, and its many derivatives exhibit a variety of pharmacological activities, especially some of the compounds has become clinical antitumor drugs. Therefore, based on the principles of pharmacophore hybridization and scaffold hopping, a series of novel title compounds, 6-fluoro-7-acylhydrazone-quinoline-4(1H)-one-3-carboxy acids, were designed and synthesized with an acylhydrazone group as a substituent attached to the C-7 position of fluoroquinolone scaffold. Finally, a new idea will be created from rationality of the such modification by the evaluation for the in vitro antitumor activity of the title compounds for further research.Synthesis for the title compoundsOxyfluoride acid precursor to fluoroquinolones ofloxacin as initial raw material, nucleophilic substitution reaction with hydrazine hydrate to give the corresponding 6-fluoro-7-hydrazino-1,8(3,1 oxopropyl)- quinoline-4(1H)-one-3-carboxylic acid intermediates, electronics, and other drugs and use of biological design principles row and pharmacodynamics active groups superposition, with an aromatic aldehyde condensation fluoro-hydrazone-1,8-7-(3,1-oxopropyl)-quinolin-4-(1H)-one-3-carboxylic acid the title compound. Fluoroquinolones target compound obtained by 1H-NMR, MS spectral data were structural characterization analysis to detect the correctness of the target compound.In vitro antitumor activityWhen evaluated hydrazonyl 7- fluoroquinolone target compound in a concentration of 1mg / ml against Staphylococcus aureus ATCC25923, Escherichia coli ATCC25922, Pseudomonas aeruginosa ATCC27853, Staphylococcus gold 186, Staphylococcus aureus 241 using Kirby-Bauer method, 200 E. coli 339, 141 Pseudomonas aeruginosa, Pseudomonas aeruginosa 146 has a certain extent, while the performance in sensitivity Shique is hypoallergenic, but lower than the reference ofloxacin.The in vitro antitumor activity of the title compounds was evaluated against human hepatoma HepG2 cell lines by the MTT assay. The results revealed that the target compounds showed more potent than that of the control A1 at the concentration of 30 μΜ. In particular, p-nitrobenzaldehyde hydrazone compound F6 and vanillin acylhydrazone compound F7 exhibited better anti-proliferative activity with the respective inhibitor rate to 60% and 40% and corresponding half-inhibitory concentration(IC50) at 3.6 μM and 5.1μM, respectively.3 Results and conclusionStrategy of pharmacophore hybridization and scaffold hopping-based in drug design, ten novel title compounds of 7-acylhydrazone fluoroquinolone carboxylic acid F1?F10 were synthesized with an acylhydrazone group as a substituent attached to the C-7 position of fluoroquinolone scaffold, and the structures were characterized by 1H NMR and MS spectral data. 7- fluoroquinolone acids hydrazonyl target compound against Staphylococcus aureus ATCC25923, Escherichia coli ATCC25922, Pseudomonas aeruginosa ATCC27853, Staphylococcus gold 186, gold aureus 241, E. coli 200, E. coli 339, Pseudomonas aeruginosa false Aeromonas 141, 146 Pseudomonas aeruginosa antibacterial activity was significantly lower than that of ofloxacin.The in vitro antitumor results of the target compounds against human hepatoma HepG2 cell lines showed that compounds F6 and F7 had better anti-proliferative activity with an IC50 value reached to micromolar concentration range, respectively. It suggests that it is reasonably practicable for the C-7 position-based modification to discover and develop a promising antitumor fluoroquinolone lead compound.