Synthesis And Antitumor Activity Of Fluoroquinolone Thiazole Amino Derivatives

Cancer is devouring human health every minute,posing a great threat to people’s life safety.Unfortunately,the current methods for treating cancer are still unsatisfactory,especially the anticancer drugs used in clinical practice,which generally have significant toxic side effects and cause significant harm to patients during the treatment process,resulting in a lower treatment index.Therefore,there is still a need for continuous exploration and innovation in the search for efficient and low toxicity cancer treatment drugs.Quinolones are widely used antibacterial drugs in clinic.Their mechanism is to play an antibacterial role by inhibiting the activity of bacterial topoisomerase,which is also an important target of anti-tumor drugs,and the topoisomerase of prokaryotic cells is highly similar to the topoisomerase of eukaryotic cells.Therefore,based on the principles of drug design,reasonable chemical modifications of the structure of quinolone antibiotics can enhance their anti-tumor activity,which is conducive to the discovery of new antitumor precursors.2-Aminothiazole,as an advantageous backbone,has a thiazole ring in its structure that can increase the solubility and salt forming ability of the entire molecule,thereby improving pharmacokinetic properties,facilitating oral absorption and bioavailability,and enhancing the stability of drug molecules,the constructed thiazole amino derivatives have various pharmacological activities,particularly in the design and synthesis of anti-tumor drug molecules.However,there have been no reports on the construction of quinolone thiazole amino derivatives by hybridization of quinolone mother nuclei with 2-aminothiazole.In this paper,based on the design strategy of bioelectronic isotonic drugs,we designed and synthesized target compounds containing quinolone thiazole amino groups,using the five membered thiazole heterocycles as the isotopes of the C-3 carboxyl group of quinolone drug molecules,and the amino group as the modified group.Through the substitution of the thiazole amino group for the C-3 carboxyl group,we increased the antitumor activity of its quinolone.Using quinolone drugs such as ofloxacin and N-methylciprofloxacin as raw materials,active quinolone imidazole amide is generated by reacting with carbonyl diimidazole(CDI),and then reacting with monomethyl potassium malonate to generate quinolone β-Ketone ester,hydrolyzed and deacidified to obtain quinolone C-3 methyl ketone,followed by bromination reaction to obtain quinolone α-Bromo C-3 methyl ketone,then cyclized with substituted phenyl thiourea to obtain the target product fluoroquinolone thiazole amino derivatives.Mass spectrometry,nuclear magnetic resonance hydrogen spectroscopy,and carbon spectroscopy were used to confirm the synthesis of 26 novel fluoroquinolone thiazole amino target compounds.MTT assay was used to determine the half growth inhibitory concentration(IC50)on human nonsmall cell lung cancer A549,human liver cancer SMMC-7721 and colon cancer CT-26 cells to evaluate the antitumor activity in vitro.The results showed that the anti-proliferative activity of the 26 target compounds against the three types of tumor cells mentioned above was higher than that of the parent fluoroquinolones,and the anti-tumor activity against A549 and SMMC-7721 was higher than that of CT-26,showing differences in tumor cell activity;The structure-activity relationship indicates that the activity of compounds containing electron withdrawing groups on the benzene ring is higher than that of electron donating groups.At the same time,the IC50 values of compound 12 h for A549 and SMMC-7721 were less than 5 μ mol/L,compounds 6h,6j,and 12 j have IC50 values below 10 μ mol/L for A549 and SMMC-7721,in the same order of magnitude as the positive anti-tumor drug control doxorubicin,showed good anti-tumor activity.In addition,molecular docking analysis of compound 12 h shows that it can interact with human topoisomerase II α(PDB ID: 1ZXM)is closely combined and consistent with the activity test results,further demonstrating the rationality of the target compound design.In summary,based on the antibacterial mechanism of fluoroquinolone,this article synthesized 26 new fluoroquinolone thiazolyl amino target compounds using thiazole as its C-3 carboxyl isosteric group and amino group as modifying group.The anti-tumor activity test results on three experimental cancer cell lines showed that the target compound had significantly higher activity than the parent compound,and some compounds had an IC50 of micro moles,which was comparable to the control doxorubicin,indicating that thiazole amino as an isosteric C-3 carboxyl group is beneficial for enhancing anti-tumor activity and providing guidance for further structural modification.