Synthesis And Biological Activity Of 1,3-Diarylpyrazole Derivatives

Pyrazole is a heterocyclic fragment with multiple biological activities,such as anti-inflammatory,anti-tumor,anti-oxidant,anti-tuberculosis and antibacterial activities.It has a wide range of applications in the field of medicinal chemistry.It is usually combined with other active fragments.Highly active small molecules such as thiohydantoin,?,?-unsaturated compounds,benzimidazole,etc.can be obtained.This thesis focuses on pyrazole-benzimidazole small molecules with low anti-bacterial activity and pyrazole ester fragments with anti-cancer activity,and molecular hybridization is carried out to obtain small molecules with anti-cancer activity or better antibacterial activity..The research content includes:1.A total of 77 1,3-diarylpyrazole-N-substituted benzimidazoles and 1,3-diarylpyrazole ester derivatives were synthesized,and compounds were characterized by mass spectrometry,proton nuclear magnetic resonance spectroscopy and carbon spectroscopy.The structure of the compound was characterized,and the anti-cancer activity of a variety of cancer cell lines was determined by the SRB method in vitro.The results showed that the pyrazole-benzimidazole series can selectively inhibit the human colon cancer cell line HCT116 in vitro.There is no obvious inhibitory effect on human liver cancer cell line Huh-7.The IC₅₀ values of most of the compounds for HCT116 cells are lower than the positive control etoposide(IC₅₀=15.6?M),and through preliminary activity analysis,the preferred compound of the framework is obtained with 4-trifluoromethyl substituted benzyl compound 17 and select compound17 for the study of the activity mechanism.2.Flow cytometry experiments showed that compound 17 can block the G0/G1phase of the HCT116 cell cycle,and it showed a dose-dependent manner.The fluorescence staining experiment verified that compound 17 can obviously induce the apoptosis of cancer cell HCT116.Finally,simulation calculations exhibited that it has good oral bioavailability,and the oral absorption percentage values(93.5%-96.7%)are significantly higher than the positive control etoposide(53.51%).3.The in vitro antibacterial activity shows that compound C15 had a certain inhibitory ability against B.cereus,with an MIC value of 32?g/m L,other compounds showed poor activities against other bacteria such as methicillin-resistant Staphylococcus aureus(MRSA),Escherichia coli(E.Coli),Bacillus subtilis(B.subtilis),konjac soft rot(B.subtilis),Salmonella.In summary,the above experimental results verified that pyrazole-benzimidazole compounds had good selective anti-human colon cancer cell line HCT116 potential,which provided an important reference for subsequent structural modification and enriched the types of anti-cancer candidate lead compounds,it also provided more options for the development of molecules based on the pyrazole-benzimidazole skeletons.