Study On The Design And Synthesis Of Cryptolepine Derivatives,Structure-Activity Relationship And Its Mechanism

Cryptolepine is one of the natural alkaloids?Neurocryptolepine and Isocryptolepine?isolated from the Cryptolepis sanguinolenta and has been found to have a wide range of biological properties after first synthesis and isolation,including significant antimalarial activity,antitumor activity,antibacterial activity,and antihyperglycemia activity.Our research group in the previous research on neurocryptolepine and isocryptolepine found that they have good inhibitory potential against a variety of phytopathogenic fungi.This research have therefore explored whether Cryptolepine has good antifungal activity against a variety of phytopathogenic fungi,and improved antifungal activity through chemical synthesis modification.It is expected to screen out target compounds with high activity for further research on their mode of action.The research content of this thesis consists of the following three parts:Chapter 1:A comprehensive summary and review of cryptolepineThis chapter mainly summarizes the four aspects of total synthesis and structural modification of cryptolepine,biological activity of cryptolepine,simplification of natural product structure,as well as the infection process of gray mold and current fungicides for controlling gray mold.Chapter 2:Structural Modifications of cryptolepine A and D Rings and their antifungal Structure-Activity Relationshipssynthesize the parent compound of cryptolepine with substitution with A and D rings and introduce different groups,mainly including electron-donating groups?methoxy,methyl,tertiary Butyl?,an electron withdrawing group?fluorine,chlorine,bromine?,inhibiting the activity of the synthesized compound against four plant pathogenic fungi.Studies have found that cryptolepine has a better antifungal activity against Botrytis cinerea,and its EC₅₀ reaches 0.050?g/mL.Further modification and screening of 2-methoxycryptolepine has a better antifungal activity activity,its EC₅₀reached 0.027?g/mL.Chapter 3:Structural modification of C-ring atom of cryptolepine and synthesis of ring-opened simplified derivativesOn the basis of the above studies,we further applied the bioisosterism principle to replace the C ring nitrogen atoms of cryptolepine with oxygen,sulfur,and carbon atoms,and analyzed the effects of the C ring changes on antifungal activity.At the same time,the transformation of the rigid structure of cryptolepine into a flexible structure may be a better target binding,which is beneficial to the reduction of molecular toxicity.Tests have shown that in the presence of N-5 methyl group,the antifungal ability of four plant pathogenic bacteria will be completely lost after ring opening,but the absence of N-5methyl group has better antifungal activity against four plant pathogenic fungal,Especially the inhibition rate of compound L-38 against Sclerotinia sclerotiorum?Botrytis cinereal?FusaHum graminearum Sehw?Rhizoctonia solani at a concentration of 50?g/mL is:93%,100%,70.35%,89.74%.Therefore,it is very successful to open-loop and simplify the structural framework of cryptolepine.Chapter 4:Diversity-oriented synthesis of 11th position of cryptolepine derivatives and their antifungal activity and mechanism of compound L-3On the basis of the above research,we introduced the structure of bishydrazide,ester,and amide at the 11th position of cryptolepine.In vitro there are different levels of reduction of antifungal activity against four plant pathogenic fungal for most compounds.The inhibition rate of compound L-72 were 96%,90%,100%,and 87%against Sclerotinia sclerotiorum?Botrytis cinereal?FusaHum graminearum Sehw?Rhizoctonia solani at 50?g/mL concentration.Furthermore,the compound L-3 with the highest antifungal activity against Botrytis cinerea was selected to study the mechanism of action.Research results:In the first part,the A-and D-rings of cryptolepine were first modified with different substitutions,and L-3 compounds with excellent antifungal effect on Botrytis cinerea were found.Simplified and found that the L-38 compound that is simple to synthesize and has good activity against 4 pathogenic fungi,and then conducted a diversified targeted synthesis of the B ring,L-72 has good activity against4 pathogenic fungi,and finally selected L-3 with the highest antifungal activity against Botrytis cinerea was studied of the mechanism.