Design,Synthesis,and Activity Of Novel Inhibitors Against Magnaporthe Grisea

As an important food corp,rice has been suggering from the invasion of diseases.Rice blast is the first of three major rice diseases.In China,It caused a big loss of rice in an area of millions hectares.All the methods,including chemical control,breeding of disease resistant varieties,and field cultivation management,aim to prevent disease and reduce losses.Chemical control with the characteristics of high efficiency and convenience,is the main and most effecite method in current prevention and control of rice blast.Sterol 14a-demethylase(CYP51)is an an enzyme in the process of the biosynthesis of sterols.As we know,sterols are the components of fungal biomass membrane.The lack of sterols will directly cause the disappearance of biological membrane structure and function.Base on the important role in fungi,CYP51 become the important target emzyme for drug design.Scytalone dehydratase(SD)and trihydroxynaphthalene reductase(3HNR)are two important emzyme in the process melanin biosynthesis.The major function of melanin in Magnaporthe grisea is the supporting effect in fungus invasion of host cells.Blocking the formation of melanin,also prevent the infringement of Magnaporthe grisea on crops.Sturcture-based drug design is surrounded with target emyze,to find out drug molecules with high affinity and selectivity for the target enzyme.As a complex system as life,single target drug can not control and prevent the disease of many factors thoroughly and effectively.From the multi angle for prevention and control,it can overcome the limitations of single drug targets in a certain extent.This dissertation is about drug molecular design and synthesis,which is base on active cavity structure characteristics of three target emyzes,CYP51,SD,and 3HNR.First,make a homology modeling for Magnaporthe grisea CYP51,whoes crystal structure data.has not been reported yet.A more reasonable three dimensional structure of Magnaporthe grisea CYP51 was obtained.By the analysis of the structural characteristics of CYP51,SD,and 3HNR,the basic situation of each active cavity is understood.Multi-target-directed inbibitors were screened by using the methods of computer aided drug design.With an analysis of hit compound one by one,four compounds were selected with a basic skeletons of heterocyclic amide,triazol-chalcone,benzothiazole/benzoxazole,nitrostyrene.Base on the hit compound of heterocyclic amide,a series of compounds,which have different heterocycles(pyridine,pyridine,triazole)on amide,or helogen in different position of benzene ring,or additional hydrophobic side chains in different size on amide were synthesized.Anti fungal activity of those compounds were evaluated.Base on the hit compound of triazol-chalcone,a series of compounds,which have different substituted group(helogen,cyano,hydroxyl,methoxy,alkyl)were synthesized.Anti fungal activity of those compounds were also evaluated.The reason of defferent actities were discussed by using molecular docking.Base on the hit compound of benzothiazole/benzoxazole,different substituent groups have been tried.Such as,benzene rings(triazol benzene,phenol and thiophenol),heterocycle(imidazole,pyrazole,substituted pyrazole,1,2,3-triazole,1,2,4-triazole,amino-1,2,4-triazole,pyridine)were synthesized.Anti fungal activity of those compounds were also evaluated.Base on the hit compound of nitrostyrene,various function groups were introduced to benzene ring,and carbon-carbon bond.All these compounds were synthesized and tested against 3HNR and in vivo.The structure-activity relationship of 3HNR and substitute nitrostyrene were discussed basing bioactivity data by using molecular docking.Fortunately,some compounds showed good results on 3HNR and in vivo were obtained,particularly 2-bromo-2-nitrostyrene derivatives.The best compound is close to the commercial inhibitor.