Design, Synthesis And Biological Activity Of Novel Benzimidazoles And Quinazolines Derivatives

Benzimidazoles and quinazolines have various biological activities such as antitumor,antibacterial and so on.In recent years,benzimidazole and quinazoline have been used as the core structure,and other active fragments were introduced by the principle of splitting.Many compounds with antitumor activity were synthesized,which laid the foundation for the study of antitumor compounds.In this thesis,two large series of compounds,novel benzimidazoles derivatives and quinazolines derivatives,were synthesized by the principle of splitting,and their biological activities were evaluated.The specific research is as follows:1.Overview of benzimidazoles and quinazolines.2.Inthispaper,31novelbenzimidazolesderivativescontaining3,4,5-trimethoxyphenyl fragments and 32 novel quinazolines derivatives containing3,4,5-trimethoxyphenyl fragments were synthesized by the principle of splitting.The derivatives were subjected to NMR and HR-MS structural characterization,and a total of 63 compounds were not reported.3.In vitro anti-tumor activity of two large series of compounds synthesized against MGC-803 cells,PC-3 cells and MCF-7 cells by MTT assay.From the MTT results,the IC₅₀0 values of compound A-5 in the novel benzimidazoles derivatives series for MGC-803,PC-3 and MCF-7 were 3.56±0.49??,3.34±0.09??,5.40±0.51??,respectively,which is better than the positive control drug fluorouracil?5-Fu?;the IC₅₀0 values of compound C-9 in the novel quinazolines derivatives series for MGC-803,PC-3 and MCF-7 were 2.24±0.19??,1.24±0.13??,1.34±0.24??,respectively,which is better than the positive control drug fluorouracil?5-Fu?.4.Compounds A-5 and C-9 have stronger inhibitory effects on PC-3 cells.The related biological activities of PC-3 cells were further studied by using compounds A-5 and C-9 as representatives of two large series.Growth curves and cloning experiments showed that both compounds inhibited the proliferation of PC-3 cells in a concentration-time dependent manner.The cycle and apoptosis of PC-3 cells by compounds A-5 and C-9 showed that PC-3 cells were significantly blocked in G2/M phase when the concentration of compound A-5 was 2?mol/L.when the concentration of compound A-5 was 4?mol/L significantly induced apoptosis of PC-3 cells;compound C-9 concentration of 2?mol/L significantly blocked PC-3 cells in the G2/M phase and significantly induced apoptosis in PC-3 cells.In summary,a total of 31 novel benzimidazole target compounds,32 novel quinazoline target compounds,and a total of 63 compounds were synthesized.Two large series of synthesized anti-tumor activities were evaluated in vitro,and compounds A-5 and C-9 were screened for broad-spectrum antitumor activity,and they were found to have a good inhibitory effect on PC-3 cell proliferation in further mechanistic studies.