Synthesis And Antifungal Activity Of 3-(Fluoro-Substitued Phenyl)-3,4-Dihydroisocounmarins

Isocoumarin is a common structural unit in active natural products and best-selling drugs.The compounds are widely distributed with a wide variety of structures and diverse structure.They have a lot of biological activities such as antibacterial,anti-cancer,and anti-oxidation activities,these compounds have always been aimed to study.3,4-Dihydroisocoumarin is a kind of less studied groups relatively.Our previous studies proved that it generally possess excellent antibacterial activity.In order to select active higher antimicrobial drug molecules,a series of 3-（fluoro-substituted phenyl）-3,4-dihydroisocoumarin compounds were designed and synthesized on the basis of previous studies.The antifungal activity of the compounds was explored and their structure-activity relationship was discussed as well.The main contents and specific results of this study are as follows:（1）A series of dihydroisocoumarin derivatives were designed and synthesized with the model of nature dihydroisocoumarin YLZ-1.The commercially available derivatives of methyl benzoic acid were used as starting materials.Via otho-lithiation,Micheal addition and cyclization under acid condition,24 classes of 3,4-dihydro-isocoumarin derivatives were synthesized.The structures of all synthesized compounds including the intermediates were confirmed by ¹H NMR,¹³C NMR,and MS analyses.23 of them were reported at the first time.（2）In vitro antifungal activities of all products against 13 different plant pathogenic fungi were tested by mycelia growth rate assay at 50μg/m L.The antifungal activities of seriesⅠis higher than that of the others.All the compounds possessed less inhibition against some plant pathogenic fungi.Most of seriesⅠshowed higher activity than azoxystrobin.Half of them showed higher average inhibition rates of 50%–87%for all the fungi.However,onlyⅡ0,Ⅱ1,Ⅲ0,andⅢ1 have reached 60%in the seriesⅡandⅢ.（3）The ten compounds with higher initial activities were further subjected to median effective concentrations(EC₅₀)assay.All compounds’EC₅₀ less than azoxystrobin.CompoundⅠ4 showed the highest activity against Alternario solani and Alternaria alternate with EC₅₀ of 11.4,9.9μg/m L.In conclusion,the isocoumarins studied in this dissertation were easy to be synthesized.Compounds I0,I1 and I4 have great advantages compared with azoxystrobin.The results in this study indicated that it possess great potential to develop new antifungal drugs.