| Natural halogenated compounds play an important role in the discovery and development of drugs,with antibacterial,antioxidant,anti-tumor and antiviral pharmacological activities,and have been widely used in the field of medicine.At the same time,thiazole ring is an important five-membered aromatic heterocyclic ring in the field of medicine.Due to its unique structural advantages,thiazole ring significantly enhances its ability to form non-covalent interactions.It is widely found in marketed drugs,such as the antibiotic cefixime and the anticancer drug dasatinib.Cancer is one of the major public health problems in the world,which seriously threatens human life and health.Eukaryotic translation initiation factor eIF4E is a key rate-limiting protein in eukaryotic translation functions and plays an important role in the regulation of translation initiation in human cells.Studies have shown that eIF4E is over-expressed in a variety of cancers,including lung cancer,colorectal cancer,and cervical cancer,and is closely related to the occurrence and development of diseases,and is a potential anti-cancer target.Therefore,the discovery and modification of eIF4E inhibitors can achieve the proliferation inhibition of a variety of tumor cells,which is an important approach for anticancer drug research and development.Taking EGPI-1 previously discovered by our research group as the lead compound,we optimized the structure of the drug molecule based on structure,and introduced halogen elements into the optimization process,75 thiazolylhydrazones were designed and synthesized.The results of SRB assay showed that 20 μM b8,b10 and d9 have the highest inhibitory activity against HCT116(human colon cancer cells),with the inhibitory rate of 93.09%.b14 and d7 have the highest inhibitory activity against A549(human lung cancer cells),with the inhibitory rate of 76.87%.d9 and d14 have the highest inhibitory activity against Hela(human cervical cancer cells),with the inhibitory rate of 90.94%.d9 have the highest inhibitory activity against siha(human cervical squamous cell cells),with the inhibitory rate of 91.90%.d7 and d9 have the highest inhibitory activity on SKOV-3(human ovarian cancer cells),with the inhibitory rate of 85.38%.In addition,d9 exhibits high inhibitory activity on HCT116,A549,siha and SKOV-3 cell lines,with IC50 values of 3.5 μM,7.9 μM,4.6 μM and 5.4 μM,respectively.bll also exhibits high proliferation inhibitory activity on HCT116,A549 and SKOV-3 cell lines,with IC50 values of 7.3 μM,4.2 μM and 3.6 μM,respectively.The IC50 values of d9 and b11 against the above cell lines were better than that of the positive control 4EGI-1 and the lead compound EGPI-1.The results of protein level experiment showed that d9 can significantly reduce the p-4EBP protein level and up-regulate the expressions of pro-apoptotic proteins Bax and c-PARP in HCT116 cells.b11 down-regulates the expression of apoptosis suppressor protein survivin in A549 cells.At the same time,b11 showed good tumor growth inhibition in Hela xenograft tumor models.Mpro plays an important biological function in RNA replication,transcription and translation of structural proteins of coronavirus,and its deletion is fatal to coronavirus.And the active regions of Mpro from different coronaviruses are highly conserved,which makes it possible to develop broad spectrum anti-coronavirus drugs.Therefore,developing small molecule Mpor inhibitors is currently a cutting-edge research strategy for anti-coronavirus drugs.During the epidemic period,all compounds were screened for their activity against SARS-CoV-2 Mpro.The screening results showed that chalcone and pyrazoline compounds showed certain inhibitory effects on Mpro.In order to obtain compounds with better inhibition effect on enzyme activity,87 chalketone and pyrazoline compounds were designed and synthesized by taking the laboratory active compounds as the leader and introducing halogen elements into the compound design,combined with the characteristics of non-peptide Mpro inhibitors.At the concentration of 50 μM,28 compounds exhibits an inhibition rate of more than 50%on TGEV Mpro,and 42 compounds exhibits an inhibition rate of more than 50%on SARS-Cov-2 Mpro.Among the 87 compounds,j3,k2,and k11 all achieves 100%inhibition rate on TGEV Mpro and SARS-Cov-2 Mpro,and exhibits outstanding enzyme inhibition effects.k11 exhibits high inhibitory activity against both TGEV Mpro and SARS-COV-2 Mpro,with IC50 values of 2.78 μM and 1.25 μM,respectively.The inhibitory activity levels of j3 and k2 against SARS-COV-2 Mpro both enters the nM level,which are 810 nM and 630 nM,respectively,superior to the reported non-peptide Mpro inhibitors Z222979552 and xanthohumol.In addition,the structure-activity relationship analysis showed that the introduction of 2-Br groups into the structure of chalcone or pyrazoline compounds can further improve their inhibitory activity against Mpro.Based on the above data analysis,compounds bll and d9 can significantly inhibit the proliferation of various tumor cells,and are promising inhibitors of eIF4E/eIF4G interaction,which are expected to become potential lead compounds for the development of anticancer drugs.At the same time,compounds j3,k2 and k11 showed good enzyme inhibition effect on Mpro and the structure-activity relationship results may provide some feasible suggestions for the subsequent development of Mpro inhibitors. |
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