Study On The Syntheses And Bioactivities Of Analogues Of Marine Nature Product Essramycin

1,2,4-triazole derivatives which possess variety biological activities such as anti-tumor,anti-bacterial,analgesic,weeding;have already been widely utilized in the fields of medicine and pesticides.The marine natural product Essramycin is the novel structure containing 1,2,4-triazolopyrimidone with antibacterial and anti-tumor activity.In this paper,analogs of Essramycin containing 1,2,4-triazolopyrimidine were designed and synthesized,and their anti-tumor and antiepileptic activities were screened.Based on the skeleton of Essramycin,two kinds of compounds which are 1,2,4-triazolidine pyrimidone and 1,2,4-triazolidine pyrimidine compounds were designed and prepared.The compounds of 1,2,4-triazolidine pyrimidone were prepared by the reaction of amidation,cyclization,condensation and cyclization by using aryl acid and aminoguanidine as the starting materials.The general procedure for this kind of compounds was obtained.1,2,4-triazolopyrimidine compounds were prepared by chlorination and ammonolysis reaction with 1,2,4-triazolidine pyrimidine as starting materials.All the structures of the compounds were confirmed by NMR,MS and IR.The anti-tumor activitis of the 42 compounds were tested on the four tumor cell lines(Hep G2?MCF-7?SKOV3 and H1299)by SRB.The compound ?g shows good inhibitory effect on Hep G2,MCF-7 and SKOV3,the value of IC50 is 14.8?M,16.3?M and 5.9?M,respectively;the compound ?a and?c have moderate inhibitory effects on Hep G2 and SKOV3 cell lines,the values of IC50 are 21.7?M,33.1?M and 15.5?M,23.1?M,respectively;The compound Ip and Io have moderate inhibitory effect on H1299 cell lines,the values of IC50 are 12.2?M and 25.4?M respectively.The preliminary structure-activity relationship shows that the compounds with R1,R2 as electron-donating groups,R3 as H in sructure A,have better anti-tumor activities.In structure B,the compounds with R4 as strong electron-donating groups and R6 as substituted benzene with electron-donating groups,have better anti-tumor activities.The antiepileptic activities of the 42 compounds were screened on the intracellular Ca2+ shock model of neurons in primary cerebral cortex and 4-AP induced epilepsy model.1,2,4-triazolidine pyrimidine compounds show no inhibitory effect on the two models.the five compounds(? c,? f,? d,? e,? g)with the structure of 1,2,4-triazolidine pyrimidone show excellent inhibitory activities with the values of IC50 2.35?M,3.21?M,12.35?M,15.40?M,11.03?M,respectively.The preliminary structure-activity relationship indicates that the pyrimidone structure is a necessary fragment of antiepileptic activity.The results of antiepileptic activities provide important guidance for further research and development of 1,2,4-triazolopyrimidone compounds.