The Development Of New Quinoline Fungicidal Chemical Entities Inspired From Natural Quinine Alkaloids-Ⅲ

Quinine,commonly known as cinchona,is a natural alkaloid compound.It was first extracted from the bark of the Rubiaceae Cinchona tree and its genus.Studies have shown that the bark of cinchona tree has the highest alkaloid content,and the content of quinine in the dry bark is about 70%.Such alkaloids also include quinidine,cinchonine,and cinchonine.In the early stage of our research group,we simplified the structure with quinine as the lead compound and evaluated the antifungal activity of 53quinoline compounds This study continued to use the quinoline compounds with better activity for anti-agricultural fungal research.The research content of this paper includes the following three aspects:1.Research on the design,synthesis and structure optimization of a new antifungal chemical entity oriented by piperazine functional groupsBased on the previous experimental research,this chapter applies the splicing strategy of dominant functional groups to introduce differently substituted piperazine groups on the 4-position hydroxyl of the two dominant quinoline nuclei.Synthetic diversity is mainly based on the electron-withdrawing characteristics of substituents on arylpiperazine,the length of alkyl piperazine alkyl chain and the substitution site of quinoline nucleus.A total of 19 compounds have been synthesized.The in vitro growth rate method was used to determine the antifungal activity of four common agricultural fungi（Sclerotium,Rhizoctonia solani,Botrytis cinerea,Fusarium graminearum）.The activity test results showed that after introducing the acyl piperazine group at the 4-position,the antibacterial activity of 1a-10 and 2a-3 was relatively good.The EC₅₀ of1a-10 against Botrytis cinerea was 13.70μg/m L.at 50μg/m L,the inhibition rate was89.04%.2.Research on the design,synthesis and structural optimization of a new antifungal chemical entity oriented by alkanolamine as its active functional groupIn this chapter,we still use the splicing strategy of functional groups,using alkanolamine with good spatial rotation flexibility as the chain bridge,and discussing the structure-activity relationship among the length of the alkanolamine chain bridge,different amines,and different electron-donating groups.A total of 32 compounds were synthesized.The in vitro growth rate method was used to determine the antifungal activity of four common agricultural fungi（Sclerotium,Rhizoctonia solani,Botrytis cinerea,Fusarium graminearum）.The results show that the 4-position ether bond coupled with isopropanol benzylamine has the best activity,and the dominant structure M1b-10 has an EC50 of less than 15μg/m L for the four fungi,especially for Botrytis cinerea,the EC₅₀ is 4.53μg/m L.3.Preliminary study on the mechanism of the highly active compound M1b-10 against Botrytis cinereaBased on the above research and analysis,the compound M1b-10 has the best antibacterial activity against Botrytis cinerea in vitro.Therefore,this chapter further explores its mechanism of action against Botrytis cinerea.Through spore germination inhibition test,cell membrane permeability test,in vivo test,scanning electron microscope and transmission electron microscope observation,it can be preliminarily concluded that compound M1b-10 may damage the cell wall and vacuoles of Botrytis cinerea,thereby affecting Its normal growth and development.The above research shows that the use of alkanolamine as a chain bridge to connect quinoline and benzylamine to synthesize new antibacterial compounds is a relatively successful experiment.In the future,we can use this as a design idea and expand the antibacterial spectrum for activity testing,in order to obtain better superior antibacterial compounds.