Synthesis And Structure-Activity Relationship Study Of Dehydroabietic-Based Antifungal Derivatives

The design and synthesis of rosin-based derivatives with high added value by chemical structure modification of natural forestry resources rosin is one of the research hotspots of natural products.In this paper,rosin was used as raw material to introduce thiophene ring through chemical modification of its carboxyl group.Based on the principle ofactive substructure splice,four kinds of rosin-based derivatives were designed and synthesized by introducing acyl thiourea,amide,acyl hydrazone,thiadiazole and other active groups into the rosin framework.Then the antifungal activities of the synthesized compounds were investigated,and the structure-activity relationships of antifungal activities were preliminarily established.Thus it provided theoretical guidance for the synthesis of highly effective rosin-based antifungal agents,the conclusions were as follows:（1）80 compounds with four characteristics were synthesized from rosin.Dehydroabietic-based acyl thiourea,dehydroabietic-based amide,dehydroabietic-based acyl hydrazine and dehydroabietic-based thiadiazole were synthesized by acyl chlorination,acyl thioureification,amidation,nucleophilic substitution,nucleophilic addition and other reactions.At the same time,their structures of the synthesized compound were characterized by FTIR、¹H NMR、¹³C NMR、ESI-MS and elemental analysis.（2）The antifungal activity of the synthesized dehydroabietic-based derivatives was investigated by mycelial growth rate method,and the results showed that the synthesized dehydroabietic-based derivatives showed different degree of inhibition against the six kinds of fungi.Dehydroabietic-based acyl thioureas had better inhibitory activityagainst Valsa mali,compound 2B showed 90.90%inhibition rate against V.mali at 50.0μg/m L.And the EC₅₀value of compound 2B was 2.574μg/m L,which was better than the positive control carbendazim（2.585μg/m L）.Dehydroabietic-based amide had the best inhibitory activity against Fusarium oxysporum f.sp.cucumerinum.The inhibitory rate of compound 3E against F.oxysporum reached 100.0%at 50.0μg/m L,and the EC₅₀ value of compound 3E was 0.974μg/m L,which was better than carbendazim（0.992μg/m L）.Dehydroabietic-based acyl hydrazine had certtain inhibitory activity against V.mali.The inhibition ratesof compound 4C and 4F were more than 70.0%at 50.0μg/m L,and their EC₅₀ values（15.897μg/m L and 14.717μg/m L）were higher than carbendazim（2.585μg/m L）.Dehydroabietic-based thiadiazole compounds had certain inhibitory activity against Botrytis cinerea.The inhibition rates of compound 5B and 5I were more than 70.0%at 50.0μg/m L,and their EC₅₀ values were 5.502μg/m L and 8.086μg/m L,respectively,which were close to carbendazim（1.358μg/m L）.In conclusion,the preliminary analysis of structure-activity relationship indicated that the introduction of electron-withdrawing substituents such as fluorine and nitro on the thiophene ring could significantly improve the antifungal activity of the derivatives.（3）In this paper,the efficacy of compound 3E against F.oxysporum was further determined by pot culture method.The results showed that compound 3E had better protective and therapeutic effects.The protective and therapeutic effects of compound 3E on F.oxysporum were 74.36%and 68.51%at 400.0μg/m L,respectively,which were better than carbendazim.At the same time,the effects of compound 3E on some physiological and biochemical indexes of F.oxysporum were studied.Combined with the results of scanning electron microscope and transmission electron microscope,we found that compound 3E could significantly affect the ultrastructure of hyphae and increase the permeability of cell membrane.Therefore,we preliminarily explored the antifungal mechanism of compound 3E against F.oxysporum,and speculated that the agent molecules could destroy the cell intima tissue structure,resulting in cell fluid exosmosis,affecting the intracellular osmotic pressure,and finally leading to the rupture and extinction of mycelia.