Design,Synthesis And Biological Evaluation Of Multi-substituted Lactam Derivatives

Leading optimization based on active natural products is an effective way and hot field for novel pesticides discovery.Lactam,a kind of natural product fragments,is widely found in terrestrial and marine organisms.It was reported that many lactam derivatives exhibited a wide range of biological activities,including insecticidal,acaricidal,herbicidal,anti-virus,antitumor,anti-ulcer activities etc.With the aim to develop novel green heterocyclic pesticides,two series of multi-substituted lactam derivatives were designed and synthesized based on the active lactams'structure.The highly efficient synthetic methods of target compounds were explored,and their potential antifungal activities in vitro were systematically investigated,which may provide basic data reference for the new lactam fungicides.The detailed research contents of this thesis are as follows:1.In this research,we applied the cyclic keto-enol of the natural source antibiotic thiolactomycin as the pilot skeleton.54 novel multi-substituted lactam derivatives were constructed by the strategies of bioisosterism,active substructure splicing and pharmacophore hybridization,and were made up of esterification,acylation and intramolecular cyclization by using the simple and easily available amino acid as the starting synthon,including 40 amino acid-oriented lactam derivatives and 14 lactam derivatives containing piperonyl moiety.The structures of all target compounds were confirmed by analytical methods,including ¹H NMR,¹³C NMR and ESI-MS.2.The above two types of target compounds and representative intermediates were evaluated for their antifungal activities in vitro against 12 series of common plant pathogenic fungi through the petri plate test,and commercial fungicide hymexazol was used as positive control.?1?For the amino acid-oriented lactam derivatives,the systematically activity screening results indicated that most of tested compounds presented significantly better antifungal activities than the intermediate M-1-5,especially for the inhibition of Phomopsis adianticola.Among them,the target compounds I-12(IC₅₀=47.51?g/mL),I-20(IC₅₀=34.86?g/mL),I-22(IC₅₀=28.15?g/mL),I-25(IC₅₀=33.04?g/mL)and I-35(IC₅₀=47.20?g/mL)displayed obvious inhibitory activities against Phomopsis adianticola,compared with the positive control hymexazol.According to the preliminary structure activity relationships,it could be seen that the target compounds exhibited better antifungal activities with these substituents,including isopropylphenyl,the electron-withdrawing substituted phenyl,2,2-dimethylbutyryl and saturated six-membered ring.?2?For the lactam derivatives containing piperonyl moiety,two kinds of compounds with ether and ester bond were designed and synthesized.The bio-assay indicated that II-5?ether compound?and II-12?ester compound?displayed the broad-spectrum inhibitory effects against the tested fungus.What's more,the IC₅₀0 values of compounds II-5?7.22?g/mL?and II-12?3.57?g/mL?against Phytophthora capsici were significantly better than hymexazol.For the further analysis of structure-activity relationships,we could draw a conclusion that the compounds with ether bond represented better activities than the compounds containing ester bond,and compounds with six-membered ring had better antifungal activities than the five-membered ring compounds.In addition,phenyl-substituted compounds with electron-withdrawing group displayed more notable activities than those with electron-donating group.