Synthesis And Biological Activity Research Of Several Types Of Chromone Heterocyclic Derivatives

Cyanobacterial fructose-1,6-biphosphatase/sedoheptulose-1,7-bisphosphatase (Cy-F/SBPase; herein FBPase, EC:3.1.3.11; SBPase, EC:3.1.3.37) is a very significant catalytic hydrolysis bifunctional enzyme for Calvin cycle of photosynthesis of Cyanobacterial cell. Cyanobacterial fructose-1,6-bisphosphate aldolase (Cy-FBAase, EC4.1.2.13) is a key enzyme for Calvin cycle too. Cyanobacterial growth can be inhibited by disturbing the two enzymes’function.The Cy-F/SBPase’s crystal structure is determined by our group. Based on the Cy-F/SBPase’s structural features, two skeletons were designed previously by our group through computer-aided drug design. The two skeletons were:chromone-connecting benzhydrazone and benzimidazole-connecting furazan. Both of the two skeletons were directely synthesized and appropriately structurally modified based on the principle of active sub-structure stitching strategy.1. We mainly synthesized four categories, seven structural types of252compounds,231of which were new. There were131new compounds among145final molecules of F-series; all new compounds among14final molecules of G-series;18new compounds among19final molecules of H-series;19new compounds among20final molecules of I-series;14new compounds among15final molecules of J-series; all new compounds among11final molecules of N-series;24new compounds among28final molecules of Q-series.2. The target compounds were screened in the proteasome level inhibitory activity of Cy-F/SBPase and Cy-FBAase, they were also screened in vivo level suppression activity on the Microcystis aeruginosa FACHB912and Synechocystis sp. PCC6803. Some of these compounds were also screened in the proteasome level inhibitory activity of THNR, while some were screened in vivo level suppression activity on the rice blast fungus. The results were as follows:(1) F-series compounds were tested in the proteasome level and in vivo, we found:34compounds of F-series have small IC50value less than30μM on Cy-F/SBPase, in which the best active compound F162has the minimum ICso value2.41μM.32compounds of F-series have small IC50value less than40.30μM on Cy-FBAase, in which the best active compound F158has the minimum IC50value0.87μM.19compounds of F-series showed good activities on the Microcystis aeruginosa FACHB912, of which the EC50were between0.17μM and33.37μM. The19compounds can be used as the potential Microcystis aeruginosa FACHB912algal inhibition agent. Another19compounds of F-series (F120～F127, F129, F150～F159) showed good activities on the Synechocystis sp. PCC6803, of which the EC50were between0.80μM and29.80μM. The19compounds can be used as the potential Synechocystis sp. PCC6803algal inhibition agent. In addition, these19compounds were likely to inhibit the growth of Synechocystis sp. PCC6803by inhibiting Cy-FBAase.(2) G-series compounds were tested in the proteasome level, we found:The enzyme activities on Cy-F/SBPase of G-series phenylacetylhydrazone compounds were much inferior to the corresponding benzoylhydrazone compounds.(3) H-series and I-series compounds were tested in the proteasome level, we found:The enzyme activities on Cy-F/SBPase of H-series and I-series compounds were worse than the corresponding benzoylhydrazone compounds. Only H15and120showed good activities on Cy-F/SBPase. The IC50of H15was26.71μM, and IC50of120was27.40μM.(4) J-series compounds were tested in the proteasome level and in vivo, we found:In J-series, only J16showed>90%screening inhibition rate at100μM on Cy-F/SBPase, and only J6showed the same rate level on THNR. None of them showed good activities on rice blast fungus, because all screening inhibition rates were less than53.00%.(5) N-series compounds were tested in the proteasome level, we found:Among N-series compounds, N1～N10had screening inhibition rates more than80%at100μM on Cy-F/SBPase. The IC50values of N4、N8、N9were5.36～20.16μM, in which N9had the minimum IC505.36μM.(6) Q-series compounds were tested in the proteasome level and in vivo, we found:Q-series compounds generally showed low screening inhibition rates less than55.00%at100μM on Cy-F/SBPase, so they showed bad activities. Four compounds involving Q8、Q9、Q22and Q25had good screening inhibition rates between80%and90%at100μM on THNR. Q-series compounds had screening inhibition rates less than35%at100μM on rice blast fungus, so they showed bad activities.3. We found some new chemical synthesis methods:(1) A new synthesis way to6-hydroxy-3-formyl chromone and6-carboxy-3-formyl chromone by solid phase Fries rearrangement was found.(2)3-(5’-aryl-1’,3’,4’-oxadiazole-2’-) chromone could be conveniently and rapidly synthesized by oxidant [Bis(trifluoacetoxy)iodo]benzene(BTI) or Iodobenzene diacetate(IBD) in dichloromethane.(3) Benzimidazole-connecting chromone could be conveniently and rapidly synthesized by oxidant Iodobenzene diacetate (IBD) in ethanol.(4) A series of strong fluorescence compounds which were characterized by a four heterocyclic structure of benzo[4,5]imidazo [1,2-c][1,2,5]oxadiazolo[3,4-e]pyrimidine were synthesized.