Synthesis And Antitumor Activity Of Barbituric Acid Derivatives

Objective:In recent years,malignant tumours have become a serious health issue as their incidence has been increasing yearly.At present,drug therapy is still an effective and important method in the clinical treatment of cancer.One of the major obstacles to the druggability of compounds with effective antitumour activity is their toxicity to normal cells.Therefore,the development of novel anticancer agents with lower toxicity to normal cells is needed.Natural products play a leading role in drug discovery and structural modifications of active natural products is an effective way of discovering potentially active molecules,lead compounds,and new drugs.Method:Barbituric acid is also known as Malonylureaears,chemical name:2,4,6-trihydroxy-pyridine.As a key structure of malonylurea,barbituric acid has been actively used as an antiepileptic drug in the market.In recent,it has been found that the modified product of barbituric acid has obvious anticancer activity.Based on the research of others,the new barbituric acid-linked heterocyclic compound was synthesized by substituting indoles ring with phenyl-1,2,3-triazole,phenylpyrazole,and other heterocyclic rings.It is desirable to obtain novel derivatives with better antitumor activity and selectivity.Result and Discussion:In this paper,a total of 29 new series of derivatives were synthesized.(1)C-4 accesses aromatic pyrazole aldehyde via Knoevenagel reaction;(2)C-4 accesses aromatic phenyl triazole aldehyde via Knoevenagel reaction;(3)C-4 position is spliced by a Knoevenagel reaction with different nitrogen-containing heterocyclic substituted benzaldehydes.Compounds were structurally confirmed by 1H-NMR,13C-NMR,and high-resolution Mass Spectrometry,and test their anti-tumor activity in vitro by MTT and other methods.Compound 5-(1-(4-trifluoromethylphenyl)-1H-1,2,3-triazole)-4-vinyl-barbituric acid(i19)when substituted by the 4-CF3phenyl is the most obvious and has obvious selectivity.The IC50 values for BEL-7402,HCT-116,and MCF-7 cells:4.02 μM,21.53μM and 8.98 μM,respectively.The IC50 value in L02 cells(82.23 μM)was 20.45 times higher than that of BEL-7402 cells.Conclusion:The introduction of a heterocyclic ring at the C-4 position of barbituric acid gives derivatives,which has further research value.