Synthesis And Optimization Of Novel Target Inhibitors Against Candida Albicans FBA Ⅱ And Magnaporthe Grisea

In recent years,with the improvement of medical standards,there have been more and more surgical treatments for bone marrow and organs.The use of clinical immunosuppressant has been increased,and the population’s immunity has also gradually decreased.On the other hand,the abuse of broad-spectrum antibiotics have caused the serious resistance of fungi,which in turn increased the chance of fungal infection.Therefore,the synthesis of new antifungal drugs has received extensive attention.The two most famous fungi for recent investigation are the medical pathogen Candida albicans and the agricultural pathogen Magnaporthe grisea.The infectious disease caused by Candida albicans as the main pathogenic fungus has been increasing.Therefore,one of the hot spots of current research about antifungal drugs is whether it a synthetic method could be found which effectively inhibits Candida albicans.The type Ⅱ fructose-1,6-bisphosphate aldolase(FBA-Ⅱ)is a key regulatory enzyme that plays a key role in glycolysis and gluconeogenesis.Inhibition of FBA-Ⅱ can control the metabolism of glucose in the body.According to reported literatures Candida albicans FBA-Ⅱ has been proved to be a potential target for fungicides.Rice blast caused by rice blast fungus is one of the most widely distributed and most harmful fungal diseases.It brings serious economic losses to rice production every year.More than 50%or 100%losses in serious cases.Therefore,the research and development of the fungicide of rice blast fungus has received extensive attention.Previously,our group has found that benzoquinone compounds had a good inhibitory activity against Candida albicans FBA-Ⅱ(CaFBA-Ⅱ),and also exhibit inhibitory effect on rice blast fungus.The compound with the best inhibitory activity is ZY12.In this paper,ZY12 was taken as the lead compound,by the rational structural modification.The DF series,glyoxal diphenyl or dibenzoyl hydrazide compounds.XZ series,substituted phenyl ketone compounds WF series,N-substituted phenyl-1,2,3-triazole acetamide compounds N series,were obtained by orientation synthesis.There are 18 strutures for DF series,9 strutures for XZ series,44 strutures for WF series and 20 strutures for N series.91 target products were synthesized in this paper,in which 40 products have not been reported.The biological activities of four novel compounds were further tested and some novel compounds with high inhibitory activity against Candida albicans FBA-II were found.For example,the IC50 of compound XZ10 was 1.47 μM,and the IC50 of N4 was 0.43 μM.Compounds that inhibit higher activity on rice blast fungus,such as compound WF16,have an EC50 of 5.41 μM.By the selection of representative compounds for molecular docking studies,the binding patterns of these four compounds to Candida albicans FBA-II and Pyricularia oryzae were analyzed in detail.Small molecules and Candida albican’s FBA-II were analyzed in detail,a deep understanding of the mechanism of interaction between small molecule and Candida albican’s FBA-II,which has provided new ideas for further design and transformation in the future.