Discovery Of New Antifungal Chemical Entities Based On Isocryptolepine And Luotonin A

As an important natural product,the alkaloids mainly found in plants have potential biological activities such as anti-malarial,anti-tumor,and antibacterial activities.Some alkaloids have long been used as excellent pilot models for the development of a variety of drugs.Both isocryptolepine and luotonin A are alkaloids of natural origin isolated from plants.isocryptolepine,like cryptolepine and neocryptolepine,are derived from the African traditional medicinal plant,Cryptolepis sanguinolenta,the latter two have been reported to have excellent anti-phytopathogenic fungal activity by our group,so we believe that isocryptolepine also has corresponding potential activity.Luotonin A is derived from the Chinese medicinal plant,Peganum nigellastrum Bunge,and studies on its biological activity have focused on anti-tumor.We have reported its anti-fungal and insecticidal activity,however,the activity was average.In this study,we selected isocryptolepine and luotonin A as the lead compound,applied the dominant skeleton collocation strategy and bioelectronic isochronous replacement strategy to optimize the core skeleton,designed several novel compounds,and attempted simple derivatization to explore the effect of core skeleton changes on antifungal activity.Their main contents are subdivided as follows:1.Design of novel chemical entities based on luotonin A and the evaluation study of its antifungal and antibacterial activityBased on the previous research of the group,the dominant group splicing strategy was applied to splice the antifungal active groups benzimidazole and indole substituted quinazolinone to the core skeleton of luotonin A.To further discuss the effect of the alteration of the core skeleton and the substitution of different groups on the bactericidal activity,we introduced F,Cl,CF₃,OCH₃,NO₂ and other substituents on the A and E rings of the newly synthesized two classes of compounds.Among them,the W series compounds showed strong fungicidal activity against Botrytis cinerea.The EC₅₀values of compounds W-7,W-8,W-12 and W-15 were all less than0.05μg/m L against B.cinerea,and further studies on the mechanism of action of compound W-7 will be conducted subsequently.2.Design of novel chemical entities based on isocryptolepine and the evaluation of their antifungal activityPrevious studies of the group found that the novel compounds constructed by introducing nitrogen atoms on the isocryptolepine structure have enhanced antifungal activity and reduced cytotoxicity.In this chapter,we will continue to try to introduce nitrogen atoms at different sites on the core skeleton of isocryptolepine by applying the bioelectronic isomer replacement strategy and briefly perform derivatization to discuss the changes in antifungal activity of several classes of compounds.After antifungal activity tests,we found that the WA series of compounds substituted with fluorine atoms were more effective in fungicidal activity against a variety of plant pathogenic fungi,with compound WA-8 showing the strongest fungicidal activity.3.Preliminary exploration of the mechanism of action of the highly active luotonin A analogue W-7After the screening of antifungal activity in the above two chapters,W-7 showed excellent antifungal activity against Botrytis cinerea,so this chapter will conduct a preliminary exploration of the fungicidal mechanism of action of the highly active compound W-7.The study found that compound W-7 may affect the normal physiological function of mycelium cells by disrupting the cell wall of the mycelium.