Synthesis Of A Series Of Maleimide Derivatives And Comparion Of Their Antimicrobial Activities

Plant diseases caused by plant pathogenic fungi have resulted in large harm to the agriculture in every country, Sclerotinia sclerotiorum and Botrytis cinerea, as two representatives of plant pathogenic fungi with a wide host range, complex origins, latent infection and strong saprophytism, are high-risk plant pathogen. Unfortunately, as the extensive use of these fungicides, pathogens exert resistance in some degree. Furthermore, developing novel, highly effective and structurally concise antifungal agents with low toxic ities is an urgently challenging and especially significant task to control crop diseases.In the previous study, it has been reported that natural products with maleic anhydride structure or maleimide structure have high biological activities, but they are few species and uneasy to isolate. Therefore,63 maleimides, including five novel compounds (Ⅱ-16,Ⅱ-17,Ⅱ-19, Ⅲ-17 and Ⅲ-19), were synthesized and characterized by azeotropic method and acetic acid method in the paper. Their in vitro antifungal activities and structure-activity relationship studies against Sclerotinia sclerotiorum and B. cinerea were preliminary investigated by the mycelium growth rate method. The results showed that 25 of 63 compounds had interesting inhibitory potency with EC50< 10 μg/mL against S. sclerotiorum. Among them, EC50s of N-3,5-dichlorophenyl)-3-methylmaleimide (Ⅱ-18) and N-octyl-3,4-dichloromaleimide (Ⅳ-4) were 1.11 μg/mL and 1.01 μg/mL, respectively, more effective than that of dicloran (EC50= 1.72 μg/mL), and slightly less than that of procymidone (EC50= 0.44 μg/mL) against S. sclerotiorum in vitro.10 of 63 compounds (Ⅰ-13,Ⅰ-14,Ⅰ-18,Ⅰ-20,Ⅱ-18, Ⅱ-19, Ⅲ-1, Ⅲ-16, Ⅲ-19 and Ⅲ-21) had stronger inhibitory potency than that of dicloran (EC50= 15.90 μg/mL) and that of pyrimethanil (EC50 =19.27 μg/mL) against B. cinerea in vitro, besides, N-(2,6-diethylphenyl)-maleimide (1-14) and N-hexyl-3,4-dichloromaleimide (Ⅲ-3) were also more effective than that of pyrimethanil. Particularly, N-(3,5-dichlorophe-nyl)-3-methylmaleimide (Ⅱ-18) was the most effective in all 63 compounds with EC50=2.39 μg/mL against B. cinerea in vitro, only less than that of procymidone (EC50= 0.51 μg/mL). As for five novel compounds (Ⅱ-16,Ⅱ-17,Ⅱ-19, Ⅲ-17 and Ⅲ-19), they also possessed good antifungal activities against S. sclerotiorum and B. cinerea in vitro. The structure-activity relationship studies demonstrated that the introduction of substituents on positions 3 and 4 dissimilarly affected the antifungal activity against S. sclerotiorum and B. cinerea in vitro, 3,4-nonsubstiuents maleimides (Ⅰ-1-Ⅰ-21) displayed stronger antifungal activities than most of 3-methylmaleimide and 3,4-dichloromaleimide compounds as a whole. The variation of.N-alkyl and N-phenylalkyl chain length and different substituents on the benzene ring also influenced the antifungal activity, but did not have a clear influence on the activity.Moreover, antimicrobial activities of 63 compounds to another 8 kinds of fungus and 3 kinds of bacterium were preliminary screened through cylinder-plate method. The result showed that maleimide derivatives owned high activities against microorganism except Mucor and Rhizopus. What’s more, most of 3,4-nonsubstiuents maleimides (Ⅰ-1-Ⅰ-21) had wider antimicrobial spectrum as a whole than 3-methylmaleimides and 3,4-dichloromaleimides. Particularly, compounds with double substituents on the phenyl ring had wide antimicrobial spectrum, such as N-(2,6-dimethylphenyl), N-(2,6-diethylphenyl), N-(2-methyl-5-chlorolphenyl) and N-(3,4,5-trifluorophenyl)-maleimide. However, N-(2,6-dimethylphenyl)-3-methylmaleimide (Ⅱ-13) had the widest antimicrobial spectrum and had good inhibition activity against all the 11 microorganism. So, some maleimide derivatives can be used as potential lead compounds for developing novel antifungal agents and are high value of developing utilization.