摘要：

Isocoumarins are secondary metabolites with wide biological sources and multiple significant pharmacological activities.The3,4-dihydroisocoumarin is one of the subclasses of isocoumarins with remarkable antimicrobial,anticancer,protein-inhibiting activity,etc ~([1-2]).Few studies about the impact of the chiral center and substitutes of the coumarin skeleton on the antifungal activities were reported ~([3]).Herein,a series of novel and chiral 3-substituted-3,4-dihydroisocoumarin derivatives were systematically and designed synthesized stereospecifically from 2-methylbenzoic acid in good yields.The structures of 60 kinds of products were elucidated by specific rotation,HRMS,~1 H NMR,~(13)C NMR and X-ray analysis and 37 of them were reported at the first time.The in vivo antifungal activities of them against 13 types of common phytopathogenic fungi were evaluated by the mycelium linear growth rate method.Most compounds showed different degree of inhibitory activity against each tested fungi at 50 μg/mL,it proved that they showed a broad spectrum of activity.Halogenated compounds Ⅱ16,Ⅱ17 and V4 which displayed optimal activity were further investigated their toxicity regression equation against tested fungi.Concentration-effect relationship of them were obtained,and the minimal inhibitory concentrations(MICs) were 7.29-68.34μg/mL and most of MICs were equal to or less than 30 μg/mL.The EC_(50) of Ⅱ17 against Alternaria alternate,Curvularia lunata and Pyricularia oryza were 7.29,8.6 and 9.10μg/mL,respectively,much lower than the positive control kresoxim-methyl(69.38,239.55 and 54.69μg/mL,respectively).The structure-activity relationship indicated the skeleton of isocoumarin,8-methoxy group on ring A and 3-aryl on ring B were the key structural moieties for their antifungal activities.Furthermore,the halogen group on ring C enhanced the activity.Generally,m-F substituted and p-F substituted isomers were more active than o-F substituted isomer with S-configuration.Furthermore,m-F substituted isomers had a higher activity than p-F substituted isomer with R configuration.In conclusion,the chiral isocoumarins were readily synthesized ~([4-7]),and both R and S types were achieved via optimization.The compounds containing halogen showed better antifungal activity than the positive control,and worth to be further systematically explored as lead compounds.

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