Synthesis And Bioactivity Study Of Almazole Alkaloids And Their Derivatives

Plant diseases seriously affect the growth of crops and the quality and yield of agricultural products.More and more antiviral agents and fungicides have been successfully applied in agricultural production to protect crops.However,with the enhancement of human awareness of environmental protection and food safety,chemical pesticides with high toxicity and refractory biodegradation are gradually eliminated;In addition,the long-term use of pesticides will often lead to resistance problems,resulting in reduced control effects;highly toxic pesticides will gradually fade out of the market,green pesticides will become the new favourite,and the development of efficient green pesticides have become the main way to create new pesticides.After thousands of years of evolutionary selection in nature,natural products have the characteristics of novelty and diversity of chemical structures,biological relevance,and drug-like properties and have become one of the effective ways to create new green pesticides.In this thesis,four almazole alkaloid derivatives were designed and synthesized by using the natural product almazole alkaloids as the lead compounds through the structural modification,and structural modification of different sites of the core skeleton and their inhibitory activities against tobacco mosaic virus(TMV)and eight plant pathogens were investigated to broaden the spectrum of biological activities of almazole alkaloids and their derivatives.The specific work of this paper mainly includes the following two parts:Part 1: Mainly carry out the design,synthesis,biological activity and mechanism of action of almazole D alkaloids and their derivatives.(1)Structural diversity derivation of almazole D alkaloids: Taking almazole D alkaloids as the lead compounds,through the structural modification of the 2-position and 4-position of the oxazole ring and the amino-N atom in the molecular structure of almazole D,two series of almazole D derivatives were designed and synthesized.To investigate the effects of different structural sites and different substituents on the biological activities of compounds against TMV and plant pathogens.(2)Anti-TMV activity study: Through a systematic anti-TMV activity study on almazole D and its derivatives,it was found that most of these compounds have certain anti-TMV activity,among which compounds II-6a,II-6b,II-6g,Ⅱ-6l,Ⅱ-6n,Ⅱ-11 a,Ⅱ-11 d,Ⅱ-11 i,Ⅱ-11 n anti-TMV activity was significantly better than the commercial antiviral agent of ribavirin.(3)The structure-activity relationship study of anti-TMV activity found that the type,position and number of substituents on the benzene ring had an impact on the anti-TMV activity of the compound.Different substituent positions have different anti-TMV activities,but the more the number of substituents,the more its activity is lower.(4)Research on the mechanism of anti-TMV action showed that compound II-6b could induce the polymerization of 20 S CP,thereby affecting the assembly of TMV virus particles;molecular docking revealed that there were obvious hydrogen bonds between compounds II-5,II-6b and II-11 n and amino acid residues.(5)The results of fungicidal activity showed that: By testing the fungicidal activity of all compounds,it was found that most of the compounds at the tested concentration of 50 μg/L against eight common plant pathogens exhibited broad-spectrum fungicidal activity.Among them,the inhibition rate of compounds II-11 b,II-11 f,and II-11 g on Cercospora arachidicola Hori was more than70%,and the inhibition rate of 5 compounds(Ⅱ-11c～Ⅱ-11g)on Rhizoctonia cerealis reached 90%,and the inhibition rate of 11 compounds on Alternaria solani was better than that of commercial fungicides chlorothalonil and carbendazim,reaching more than 50%.Part 2: Design,synthesis and biological activity of chiral primary amine compounds.(1)Design and synthesis of chiral primary amine compounds: Based on the synthesis of almazole C alkaloids,combined with the previous work,taking prealmazole C and chiral primary amine thiourea compounds as lead compounds,a series of chiral amides and thioureas were designed and synthesized.(2)Research on anti-TMV activity: It was found that most of the compounds have good anti-TMV activity,and their activity is better than that of commercial ribavirin,especially compounds III-15 c and III-15 i are comparable to the best commercial antiviral agent ningnamycin at present.(3)Anti-TMV structure-activity relationship and mechanism of action: the type,position and number of substituents on the benzene ring have an impact on the anti-TMV activity of the compounds;through the molecular docking simulation of compounds III-8,III-13 c,III-15 i with TMV protein molecules,it was found that the compounds can form intermolecular hydrogen bonds with the amino acid residues in the protein molecules,and then interact.(4)The results of fungicidal activity showed that all compounds have a certain fungicidal effect through the fungicidal activity test and showed broad-spectrum anti-phytopathogenic activity,especially the fungicidal activity of 4 compounds on Alternaria solani was better than that of commercial fungicides chlorothalonil and carbendazim.