Synthesis And Biological Activity Of Novel Fraxinellone Analogues Containing N-phenylpyrazole

Fraxinellone,which exists in many plants and can be isolated mainly from the root bark of Cortex Dictamni has a wide range of biological activities.In this paper,the structural modification of fraxinellone was carried out by active sub-structure combination.Two series of novel fraxinellone derivatives were designed and synthesized by introducing pyrazole rings at C-2?/5?and C-4/10 position of fraxinellone.The structures of all target compounds were determined by ¹H NMR,¹³C NMR,IR,HRMS,optical rotation and melting point.The biological activities of all target compounds were also evaluated.The results are as follows:1.2?/5?-pyrazolyl-fraxinellone derivatives were synthesized and the structural configurations of compounds 7g and 8k were determined by X-single crystal diffraction.The growth inhibitory activity of all target compounds against the pre-third-instar larvae of Mythimna separata Walker was determined by the leaf-dipping method at a concentration of 1 mg/mL.Meanwhile,the larvicidal activity of all target compounds against Plutella xylostella Linnaeus were evaluated according to the leaf disc assay at a concentration of 250?g/ml.In addition,the cytotoxic activity of compound 7g and 8h was mensurated by Cell Counting Kit-8?CCK-8?.Among all the target compounds,the compounds 7g–i and 8g–j exhibited more potent insecticidal activity than toosendanin,a commercial botanical pesticide.Furthermore,the compound 8g displayed more promising larvicidal activity with the LC₅₀ value of 0.31 mol/mL than the toosendanin against P.xylostella.Meanwhile,compounds 7g and 8h exhibited low cytotoxicity to noncancerous mammalian cells.The structure–activity relationship?SAR?revealed that introduction of polyhalogenated phenylpyrazole ring on furyl-ring of fraxinellone could lead more potent compounds against both M.separata and P.xylostella than that of monohalogenated phenylpyrazole ring or electron-donating groups substituted phenylpyrazole ring.2.A series of 20 novel N-phenylpyrazole fraxinellone hybrid compounds were prepared by structural modification of A ring of fraxinellone.Two keysteric configurations of compounds 11g and 11h were unambiguously determined by X-ray crystallography.The growth inhibitory activity of these N-phenylpyrazole fraxinellone hybrids against the pre-third-instar larvae of M.separata was determined by the leaf-dipping method;All target compounds were screened for antibacterial activity against six kind of Gram-positive bacteria and Gram-negative bacteria according to 2-fold serial dilution method in Mueller-Hinton?MH?broth.The biological activity showed that only compound 11g showed better antibacterial activity against Bacillus subtilis with MIC value of 4 g/mL,but for insecticidal activity,compounds 11n,11o and 11t exhibited more promising insecticidal activity with final mortality rates?FMRs?of>60%,when compared with their precursor fraxinellone and the positive control toosendanin.This suggested that introduction of polyhalogenated phenylpyrazole at C-4 and C-5 positions of fraxinellone could lead to more promising insecticidal derivatives than monohalogenated phenylpyrazole,especially introduction of N-?2-chloro-4-fluoro-phenyl?pyrazole.