Synthesis And Biological Activity Of Chalcone Derivatives Containing Indole Or Pyrazole Oxime Ether

Chalcone is an extremely important natural product of flavonoids,which has a wide range of biological activities such as antiviral,antibacterial,antioxidant,anticancer,anti-insect,anti-inflammatory and so on.It has a broad application prospect in the development of modern pesticides;As an important member of nitrogen-containing heterocyclic compounds,indole and pyrazoxime ether derivatives also have many biological activities,such as antibacterial,antiviral,anti-insect,anticancer,etc.They play a crucial role in the research and synthesis of heterocyclic drugs and are used in many fields.In this paper,according to the principle of active splicing in drug synthesis,many bioactive derivatives of indole and pyrazoxime ether were introduced into the chalcone structure,and chalcone derivatives containing indole or pyrazoxime ether were synthesized.The target compounds were characterized by NMR and HRMS.The structure of compound H5 was further confirmed by single-crystal X-ray diffraction.The inhibitory activities of the target compounds against tobacco mosaic virus（TMV）,Xanthomonas oryzae pv.oryzae（Xoo）,Pseudomonas syringae pv.actinidiae（Psa）and Xanthomonas axonopodis pv.citri（Xac）were tested and screened.The relevant research contents are summarized as follows:1.Twenty-four chalcone derivatives containing indole（D1-D24）were designed and synthesized.The anti-TMV activity of a series compounds was tested by the half leaf spot method.The results showed that some of the compounds showed significant antiviral and antibacterial effects.The test results of EC₅₀value against tobacco mosaic virus showed that the curative activity EC₅₀value of compound D11 was107.4μg/mL,which was superior to ningnanmycin（NNM）311.5μg/mL,the protective activity EC₅₀value of compound D16 was 106.6μg/mL,which was lower than EC₅₀（205.4μg/mL）of ningnanmycin.The inhibition rate of inactivated activity of D11 was 86.1%,which was equivalent to that of NNM;The antibacterial activity of these compounds was tested by turbidity method.The results showed that the EC₅₀value of compound D23 against Xoo was 50.3μg/mL,which was superior to the commercial drugs thiodiazole copper（79.8μg/mL）and bismerthiazol（106.2μg/mL）.For compound D11 with good anti-TMV activity,the preliminary mechanism of action was explored,such as molecular docking,MST（microscale thermophoresis）,malondialdehyde（MDA）content and defense enzyme activity,the results showed that D11 had significant inhibitory activity against tobacco mosaic virus,which was consistent with the preliminary screening results;The effect of D23 on Xoo cells was observed by scanning electron microscopy（SEM）,the results showed that D23 had a higher inhibitory effect on Xanthomonas oryzae pv.oryzae.2.Twenty-six chalcone derivatives containing pyrazoxime ether（H1-H26）were designed and synthesized.The results of anti-TMV activity test showed that compound H9 had the best curative and protective effect on tobacco mosaic virus,and its curative activity EC₅₀value was 166.9μg/mL,which was greater than the ningnanmycin 280.4μg/mL,protective activity EC₅₀value was 126.5μg/mL,better than ningnanmycin 227.7μg/mL;The results of antibacterial activity showed that compound H17 had a higher inhibitory effect against Xoo,and its EC₅₀value was33.0μg/mL,which was superior to the commercial drugs thiodiazole copper（68.1μg/mL）and bismerthiazol（81.6μg/mL）,and the antibacterial activity of H17 was verified by SEM.MST test proved that compound H9（K_d=0.0096±0.0045μmol/L）has strong binding ability with TMV-CP,which was much higher than that of ningnanmycin（K_d=1.2987±0.4577μmol/L）.In addition,molecular docking results showed that the affinity of compound H9 with TMV protein was significantly higher than that of ningnanmycin.In summary,chalcone derivatives containing indole or pyrazole oxime ethers have the potential to become green pesticides,which has certain reference value for the development of new pesticides.