Molecular Design,Synthesis And Activities Study Based On Piperonyl Pharmacophore

Taking the structure of natural products as leading compounds has been an effective strategy to find new bioactive molecules.In this paper,the structure of?-lactam and stilbene was selected as the mother nucleus.By means of superposition principle of biological activity and molecular hybridization,piperonyl moiety which had a wide of bioactivity was introduced,structural derivatization and lead optimization based on this structure.The specific research contents are as follows:1.Synthesis and antifungal activity of lactam compounds based on piperonyl pharmacophoreWith natural?-lactam as the backbone,by introducing a piperonyl moiety,modifying the hydroxyl position of?-lactam,a totle of 15 compounds which no literature reported were prepared.At the same time,for the purpose of activity comparison,four bioisostere furanone compounds were synthesized.We selected Rhizoctonia solani,Gloeosporium theae-sinensis,Alternaria tenuis Nees,Fusarium graminearum as testing strains,natural products piperine and commercial fungicide carbendazim as positive control,and systematic antifungal activity of these 19compounds were tested.The results showed that the inhibition activity of compounds7a(IC₅₀:121.75 mg/L),7b(IC₅₀:159.64 mg/L)and 7i(IC₅₀:115.09 mg/L)against Alternaria tenuis Nees higher than the positive control(IC₅₀:182.47 mg/L).The inhibitory activity of compounds 7b(IC₅₀:113.47 mg/L),7c(IC₅₀:148.67 mg/L),7i(IC₅₀:156.69 mg/L)and 10q(IC₅₀:140.15 mg/L)against Fusarium graminearum higher than the control piperine(IC₅₀:262.91 mg/L).2.Synthesis and bioactivity of stilbene compounds based on piperonyl pharmacophoreUsing natural stilbene as a skeleton,by introducing a piperonyl moiety,carboxylic acid containing piperonyl moiety and stilbene moiety,then the structure of the carboxyl position is modified by the amide bond construction,a total of 20 new compounds were synthesized,the antifungal,insecticidal and cytotoxicity of these 20compounds were tested?1?The antifungal test used the same four fungi strains as the first system.The test results showed that the overall antifungal activity of the compounds was poor,the inhibition rate of compounds less than 40%.?2?Insecticide activity test selected common pest targets in agriculture?aphids and cotton bollworms?,testing the insecticidal of twenty compounds under three concentration gradients of 1000 mg/L,667 mg/L and 444 mg/L.The results showed that only compound 4o?>70%?and 4r?>90%?had good inhibition activity on cotton bollworm at a concentration of 1000 mg/L,others had little activity.?3?Cytotoxicity test selected melanoma cells?A875?,hepatocellular carcinoma?Hep G-2?and monkey kidney cell?MARC145?as tested cell lines,the MARC145are normal cells and serves as a blank control,the 5-Fluorouracil was used as a positive control.The test results show that compounds 4d(IC₅₀:16.53 mg/L),4f(IC₅₀:22.57 mg/L)and 4n(IC₅₀:25.65 mg/L)had good activity on hepatocellular carcinoma Hep G-2,other compounds have poor activity on the three kinds of cancer cells(IC₅₀:>40 mg/L)...