Synthesis And Antifungal Activities Of 2-arylquinoxalines

Quinoxalines are a very important class of benzopyrazine compounds,which have important applications in the fields of drug design and synthesis.Many of these compounds with quinoxaline framework as the core of pharmacodynamic activity and anti-bacterial,anticancer and enzyme inhibition activities have been reported extensively,but there are few reports on antifungal activity.Our previous research found that 2-arylisoquinoline alkaloids has excellent antifungal activity and potential for further design as a lead compound.This research belongs to the extended research of the preliminary work.On the basis of retaining the molecular planar structure and conjugated system similar to the lead compound,designing a series of2-arylquinoxaline compounds and evaluating their antifungal activity against 13 pathogenic fungi,hoping to find compounds with better antifungal activity and understand structure-activity relationships.The main research results are as follows:（1）The existing synthesis method was improved,and 41 target compounds（three series of A,B,C）were synthesized using o-phenylenediamine,acetophenone,and benzaldehyde as starting materials.the A series are 26 2-arylquinoxaline compounds,the B series are 7 iodide4-methyl-2-aryl quinoxaline salts,the C series are 8 bromide 4-substituted benzyl-2-aryl quinoxaline salts,and none of the C series compounds have been reported.The structure of the compound was characterized by ¹H NMR and ¹³C NMR.（2）Using the mycelium growth rate method,determination of Fusarium oxysporium f.sp.vasinfectum,Fusarium oxysporium f.sp,Niveum.Fusarium solani,Alternaria alternate,Curvularia lunata,Valsa mali,Fusarium graminearum,Arysalospora piricola,Colletotrichum gloeosporioides,Pyricularia grisea,Alternaria brassicae,Botrytis cinerea,Mycos Araerella melonis,a total of 13 kinds of pathogenic fungi in vitro antifungal activity,the results showed that all the target compounds exhibited inhibitory effects at the concentration of 50μg/m L.According to the results of preliminary screening of antifungal activity,compounds with higher activity（Fungus inhibition rate>70%）were selected to determine antifungal virulence against 8 sensitive fungi.It is found that compounds A1,B33,C34,and C36 have obvious advantages in the strength of antifungal activity.A1 has the strongest antifungal activity against Colletotrichum gloeosporioides(EC₅₀=26.99μM),which is higher than the positive drug Kresoxim-methyl(EC₅₀=49.5μM);B33 has the strongest antifungal ability against Curvularia lunata(EC₅₀=10.33μM),which is much higher than the positive drug Kresoxim-methyl;C34 has the highest antifungal activity against Botrytis cinerea(EC₅₀=7.03μM),which is much higher than that of Kresoxim-methyl(EC₅₀=23.30μM);C36(EC₅₀=7.03μM)has the strongest antifungal activity against Fusarium solani,even stronger than the excellent positive drug Thiabendazole(EC₅₀=11.57μM).In summary,these four compounds have the potential to be developed as new agricultural fungicides.（3）By comparing the antifungal inhibition rate and/or EC₅₀ value of the target compound,we analyzed the structure-activity relationship of such compounds.For the A series of compounds,compared to the template compound,the introduction of substituents at different positions on the C ring will lead to a decrease in antifungal activity,and the decreasing trend is para position>meta position>ortho position.For the substitution at the same site,the difference in the electrical properties of the substituents has little effect on the antifungal activity.It can be judged that this series of compounds cannot be substituted by the C ring to increase the antifungal activity;For the B series compounds,the introduction of methyl groups on the C ring will reduce the antifungal activity,while the trifluoromethyl group will only increase the antifungal activity in the meta and para positions,and it will also cause the antifungal activity to decrease when the ortho position is substituted.For C series compounds,the introduction of methyl on the D ring has little effect on the activity,while the introduction of fluorine atoms will lead to a decrease in the antifungal activity of the compound as a whole,but it has a synergistic effect on individual strains.On the whole,after N₄ methylation,the antifungal activity of A series compounds against most fungi was decreased,but the antifungal activity against four fungi including Fusarium oxysporum was improved to a certain extent.N₄ benzyl substituted compound C36surpassed compound A1 in antifungal activity.The results show that the N₄ position of compound A1 is a sensitive site,and introducing a suitable hydrocarbon group here is a successful strategy to enhance antifungal activity.In summary,this research designed and synthesized a series of 2-arylquinoxaline compounds,which enriched the molecular library of these compounds,revealed its in vitro antifungal activity and investigated the structure-activity relationship of the compound,discovered several compounds with excellent antibacterial activity,expanded the biological activity research of quinoxaline compounds,provided a theoretical basis and candidate compounds for the development of new agricultural fungicides.