Synthesis And Antitumor Activity Of Fluoroquinolone Aminothiazole Derivatives

Cancer is a complex disease marked by abnormal cell growth.Although significant progress has been made in cancer treatment,the chemotherapy index is still low due to the emergence of current clinical anti-cancer drug resistance and serious side effects.The search and development of new anticancer drugs remains a hot topic in drug research.Although quinolones are widely used as antibacterial drugs in clinic,their structural modification shows that these compounds show high activity to eukaryotic topoisomerase and toxicity to tumor cells,which also highlights the potential to be developed as new anti-cancer drugs.2-Aminothiazole derivatives have extensive pharmacological activities.The presence of the C-2 amino group not only facilitates the splicing of thiazole with other active fragments to synthesize structurally diverse compounds,but also increases the hydrophilicity of the compound,improves its water solubility and bioavailability and enhances its ability to form hydrogen bonds with the target.This structure is considered to be the skeleton of the dominant pharmacophore,which is widely used in the construction of anti-tumor drug molecules,such as clinical anticancer drugs dasatinib,ebomycin and bleomycin.Based on research on the structural modification of quinolone,it was found that the carboxylic acid at the C-3 position of its mother nucleus is not a necessary anti-tumor group and can be replaced by heterocyclic isosteres.However,there have been no reports of quinolone heterocyclic amines constructed by connecting the quinolone mother nucleus with heterocyclic rings through amino groups.Therefore,this paper is based on structural and mechanistic drug design strategies,this article synthesized 30 fluoroquinolone C-3 aminothiazole derivatives by combining the C-3 position of fluoroquinolone mother nucleus with 2-aminothiazole derivatives,and characterized their structures using spectral data.The in vitro antiproliferative activity of 30 target compounds against human gastric cancer cells（SGC-7901）,human liver cancer cells（SMMC-7721）and human pancreatic cancer cells（Capan-1）was evaluated by MTT method.The experimental results showed that the in vitro anti proliferative activity of 30 target compounds against three types of tumor cells was stronger than that of the parent fluoroquinolone drug and their inhibitory effects on SMMC-7721 and Capan-1 were stronger than those of SGC-7901,showing a certain degree of selectivity.The structure-activity relationship indicates that compounds containing fluorine and nitro electron withdrawing substituents have stronger activity than electron donating compounds,while ortho substituted nitro groups have stronger activity than meta and para groups.Among them,The IC₅₀ values of compound1i,2h,3h and 3i against Capan-1 cell line were all less than 5μM,showing excellent in vitro anti-tumor activity,and the IC₅₀ of compound 3h against SMMC-7721 and Capan-1 cell lines was also less than 5μM,which was similar to the antitumor drug doxorubicin.Through molecular docking,it was found that the compound 3h with the best activity could closely combine with topoisomerase IIα（PDB ID:1ZXM）through multiple forces,which further confirmed the rationality of the design.In summary,the fluoroquinolone 3-aminothiazole target compound constructed by combining the quinolone mother nucleus with the 2-aminothiazole structure exhibits good anti-tumor activity,providing a new approach for further research on anti-tumor fluoroquinolone drugs.