Design, Synthesis And Biological Activity Study Of Novel Pyrimidine And Quinoxaline Derivative

As important nitrogen-containing heterocyclic compounds,pyrimidines and quinoxalines were key chemical intermediates and play an important role in the design and synthesis of new heterocyclic compounds.On the other hand,pyrimidine compounds have antiviral,antibacterial,insecticidal,anti-inflammatory,anti-cancer and other wide biological activities,it has the characteristics of high efficiency and low toxicity,quinoxaline compounds can be used as antiviral agents,fungicides,herbicides,insecticides and plant growth regulators agents,etc.,and quinoxaline compounds are used in many fields.Both of them have attracted much attention because of their special structures and broad biological activities,they are of great significance for drug discovery.In this paper,pyrimidine derivatives（M1-M22）and quinoxaline derivatives（T1-T20）were designed and synthesized by synthesizing pyrimidine and quinoxaline structures after structural modification.All compounds characterized by ¹H NMR,¹³C NMR,¹⁹F NMR and HRMS.The structures of compounds M4 and M6 were determined by single crystal X-ray diffraction,and the biological activities of the target compounds were tested.The main research contents of this paper are summarized as follows:1.Twenty-two pyrimidine derivatives were designed and synthesized,the anti-tobacco mosaic virus（TMV）activity of the series of compounds was tested by the half leaf spot method.The results showed that the target compounds had better resistance to TMV.Compounds M10,M13 and M17 had good inhibitory activity,the EC₅₀ values of the curative activities of compounds M10,M13 and M17 were 126.4,169.1 and 139.3μg/m L,respectively,which were better than ningnamycin（362.7μg/m L）;compounds M6,M11 and M13 had significant protective activities,the EC₅₀values were 122.1,111.6 and 103.4μg/m L,respectively,which were better than ningnanmycin（255.1μg/m L）.The antibacterial activity of these compounds was tested by turbidity method.The results showed that the series of target compounds had certain inhibitory activities against the tested bacteria.The EC₅₀ value of compound M20 against Pectobacterium carotovorum subsp.brasiliense was 23.9μg/m L,which was better than thiodiazole-copper（242.2μg/m L）and bismerthiazol（151.8μg/m L）.The antifungal activity of these compounds was determined by the mycelial growth rate method.The results showed that the EC₅₀ value of compound M21（26.0μg/m L）against Rhizoctonia solani was comparable to the azoxystrobin（26.7μg/m L）,while the The EC₅₀ values of compounds M19（6.9μg/m L）and M20（10.1μg/m L）against Phytophthora litchi were better than azoxystrobin（10.8μg/m L）.2.Twenty quinoxaline derivatives were designed and synthesized,and their biological activities were tested.The results showed that the EC₅₀ value of compound T11 against Acidovorax citrulli was 35.1μg/m L,which was much better than thiodiazole-copper（198.5μg/m L）and bismerthiazol（295.1μg/m L）;the inhibitory activities of compounds T10 and T20 against Rhizoctonia solani were 89.5 and 95.1%,respectively,which were better than azoxystrobin（76.4%）.The EC₅₀ values of compounds T10 and T20 against Rhizoctonia solani were 8.5 and 12.0μg/m L,respectively,which were better than azoxystrobin（26.1μg/m L）.3.The possible mechanism of pyrimidine compounds against TMV was studied by microcalorimetry and molecular docking experiments.The results showed that the dissociation constant of the interaction between M13 and tobacco mosaic coat protein（TMV-CP）was 0.008μmol/L,better than ningnamycin（2.338μmol/L）,the affinity of compound M13 was better than that of ningnamycin;four hydrogen bonds were formed between compound M13 and TMV-CP,indicating that there was a good interaction between them.In vitro and in vivo experiments on rice indicated that compounds M21 and T10 had certain control effects on rice sheath blight.The antifungal effects of compounds M21 and T10 were observed by scanning electron microscope,which made the hyphae of Rhizoctonia solani to produce a lot of folds,and the epidermis was severely shrunken and shriveled.