Design,Synthesis,Structure-Activity Relationship Of Novel Inhibitors Against Cy-FBP/SBPase

In recent years,"cyanobacteria bloom" broke out frequently.Human' s life suffered great harm about that.In order to find efficient and selective green algicides,our group considered fructose-1,6-bisphosphatase/sedoheptulose-1,7-diphosphatase(Cy-FBP/SBPase)as the target enzyme which is an important regulating enzyme in the photo-sythetic system of cyanobacteria.The compound G3 was successfully screened out by using computer-aided drug design and showed a good inhibitory effect on Cy-FBP/SBPase and cyanobacteria Synechocystis PCC6803.The following works were done in this paper:1?We synthesised 20 molecules of G series by modification of the substituents on the benzene ring on both sides of compound G3 and five compounds were new.The in-hibitor activity of the corresponding compounds(G2-G5,G6,G8)is generally better against Cy-FBP/SBPase when the substituents are halogen,N02 and CF3 which are on the para position of benzene ring..The IC50 values of these compounds were between 0.7?M and 2.3 The G2 fluorine atom was in the para position of benzene ring and showed the best inhibitory activity aganist Cy-FBP/SBPase with IC50 values of 0.7 ?M and Cyanobacteria 6803 with EC50 values of 0.46?M.2?We synthesised 9 molecules of H series by removing the both sides of the amide bond of G3 and two compounds were new.The inhibitory activity of H series were ob-viously decreased.Almost all of their IC50 values were more than 50 ?M.3?We synthesised 16 molecules of Y series by replacing the thiadiazole of G3 with methylene and fourteen compounds were new.The corresponding compounds(Y3-Y5,Y7)were still maintain good inhibitory activity aganist Cy-FBP/SBPase when the sub?stituents are halogen(Cl,Br,I),CF3 which are on the para position of benzene ring.The IC50 values of these compounds were between 5.86?M and 22.8?M.However,the in-hibitory activity of most other compounds was significantly reduced.Almost all of their IC50 values were more than 50 p.M.4?We synthesised 18 molecules of Q series by taking only half the structure of G3 and removing the symmetry of G3.The Q series almost lost the inhibitory activity on Cy-FBP/SBPase and all of their IC50 values were more than 100 However,part of the Q series compound remain showed a good inhibition on cyanobacteria.The Q3 chlo-rine atom was in the para position of benzene ring and its EC50 values was reached 0.13?M aganist Cyanobacteria 6803.We found that different parts of the G3 structure had different contributions to inhi-bition by analyzing the relationship between the structure and activity of these four series of compounds.The order of importance as follows:Symmetry(?)>On both sides of amide bond moiety(?)>Thiadiazole moiety(?)>On both sides of benzene ring moi-ety(?).