Design,Synthesis,and Biological Activity Of Asymmetric Persulfur Molecules

Pesticides play an irreplaceable role in increasing crop yield and quality.However,due to the long-term irrational use of existing pesticides,the resistance of field agricultural pests has sharply increased.Therefore,the development of new,efficient,and low-toxicity pesticide varieties is always an important issue for pesticide scientists.Persulfur groups have rich pharmacological properties,and molecules containing disulfide group exhibit excellent pesticide activity,such as ricin,allicin,ajoene,and insecticidal monomers.However,research on this type of molecule has mainly focused on symmetrical disulfide molecule,and there has been little progress in the study of asymmetric disulfide molecule in recent decades.The key scientific problem in this regard is the difficulty in synthesizing asymmetric disulfide molecules.Currently,the coupling reaction between thiol molecules is the main method for preparing disulfide compounds.However,when preparing onemolecule asymmetric disulfide compounds using this method,inevitably,there will be a by-product of two-molecule symmetric disulfides.To improve the yield of asymmetric disulfide molecules,it is often necessary to add one of the thiols in excess of 10 equiv.,which poses significant challenges in laboratory and production operations.This thesis first presents the design of a novel disulfide transfer reagent that enables the precise synthesis of asymmetric disulfide molecules.By solving the problem of difficult synthesis of asymmetric disulfide molecules,we designed and synthesized isoxazole asymmetric disulfide molecules with good bactericidal activity and oxazoline asymmetric disulfide molecules with good acaricidal activity.The specific content is as follows:This thesis presents the design and synthesis of a novel,odorless,easily synthesized,and air-stable disulfide transfer reagent based on the β-elimination principle.By optimizing the reaction conditions,24 different types of asymmetric disulfide molecules(referred to as II)were synthesized under mild reaction conditions.Through controlled experiments and DFT calculations,a reasonable reaction mechanism for the bis-disulfide reagent was proposed.Finally,the antibacterial activity of the asymmetric disulfide molecules II against Dickeya zeae(D.zeae)and Xanthomonas campestrispv.campestris(Xcc)was tested using the turbidity method.The research results showed that the series of asymmetric disulfide molecules exhibited inhibitory activity against D.zeae,with the II-5n containing the isoxazole group(EC50 = 24.3 mg/L)outperforming the positive control agent thiodiazole copper(EC50 = 30.2 mg/L).These results indicate that the presence of different substituents on theisoxazole asymmetric disulfide molecules significantly influences their antibacterial activity.Additionally,the activity experiment demonstrated that the II-5a also exhibited excellent ovicidal activity against Tetranychus cinnabarinus(T.cinnabarinus),with an LC50 of 0.1352 mg/L,surpassing the positive control agent etoxazole(LC50 = 0.2990 mg/L).Building on the lead compound II-5n containing the isoxazole ring discovered in Part 1,this section further designs and synthesizes 31 structurally novel asymmetric disulfide molecules containing the isoxazole ring for antibacterial activity evaluation.The structures of these compounds were characterized using 1H NMR and 13 C NMR,and their antibacterial activity against D.zeae and Xcc was assessed using the turbidity method.The research results showed that at a concentration of 100 mg/L,compounds Ⅲ-2g,Ⅲ-2h,and Ⅲ-2o exhibited antibacterial rates against D.zeae exceeding 90%,with Ⅲ-2o surpassing the positive control thiodiazole copper(95.3%).Additionally,compounds Ⅲ-2a,Ⅲ-2b,Ⅲ-2h,Ⅲ-2i,and Ⅲ-2o exhibited antibacterial rates against Xcc of 95.2%,96.3%,97.3%,95.5%,and 94.9% respectively at 100 mg/L,all higher than the positive control thiodiazole copper(93.2%).To further validate the antibacterial activity of the asymmetric disulfide molecules containing the isoxazole ring,the EC50 values of highly active compounds Ⅲ-2h,Ⅲ-2i,Ⅲ-2o,and Ⅲ-2ae were determined and ranged from 13.1 to 30.9 mg/L.Furthermore,compounds Ⅲ-2a,Ⅲ-2b,Ⅲ-2h,Ⅲ-2i,and Ⅲ-2o exhibited good activity against Xcc with EC50 values ranging from 8.4 to 23.4 mg/L,surpassing thiodiazole copper(30.2 mg/L).Building on the lead compound II-5a containing the oxazoline ring discovered in Part 1,this section further designs and synthesizes 29 structurally novel asymmetric disulfide molecules containing the oxazoline ring for acaricidal activity evaluation.The structures of these compounds were characterized using 1H NMR,13 C NMR,and 19 F NMR.The synthesized target compounds were evaluated for their ovicidal activity against the phytophagous T.cinnabarinus eggs and acaricidal activity against the juvenile mites.The research results showed that all synthesized target compounds exhibited excellent ovicidal activity against T.cinnabarinus.At a concentration of 1.0 mg/L,all target compounds achieved 100% inhibition of egg hatching,particularly compound Ⅳ-7l(LC50 = 0.0035 mg/L),which outperformed the control agent etoxazole(LC50 = 0.2990 mg/L).Furthermore,for the evaluation of acaricidal activity against T.cinnabarinus juveniles and adults,compounds Ⅳ-5 and Ⅳ-7j exhibited a mortality rate exceeding 90% at a concentration of 0.1 mg/L,surpassing etoxazole(58.9%).However,these target compounds showed poor activity against adult mites,possibly due to the mechanism of their acaricidal activity.In con-clusion,the synthesized asymmetric disulfide molecules containing the oxazoline ring have potential applications in acaricidal activity.In summary,this thesis aims to explore green and efficient novel pesticides.Firstly,the challenging issue of precise synthesis of asymmetric disulfide molecules was addressed by designing a novel disulfide reagent,enabling the precise construction of asymmetric disulfide molecules.In Part 1(corresponding to chapter 2 of this thesis).A total of 24 different types of asymmetric disulfide molecules were synthesized,and their antibacterial and acaricidal activities were preliminarily evaluated.Lead compounds II-5n with good antibacterial activity and II-5a with good acaricidal activity were discovered.In Part 2(corresponding to chapter 3 of this thesis),31 asymmetric disulfide molecules containing the isoxazole ring were designed and synthesized based on II-5a,and their antibacterial activity against the phytopathogenic bacteria D.zeae and Xcc was evaluated.It was found that the EC50 of III-2ae for D.zeae was 11.8 mg/L,better than that of thiodiazole copper(EC50 = 24.3 mg/L),and III-2i for Xcc was 6.9 mg/L,better than thiodiazole copper(EC50 = 30.2 mg/L).In Part 3(corresponding to chapter 4 of this thesis),using II-5a as the lead compound,29 oxazoline asymmetric disulfide molecules with excellent acaricidal activity were designed and synthesized.Compound Ⅳ-7l,which exhibited excellent ovicidal activity against T.cinnabarinus eggs,outperformed the positive control agent etoxazole.It was found that the asymmetric disulfide molecule IV-7l containing oxazoline ring had an LC50 of 0.0035 mg/L for the eggs of T.cinnabarinus,which was better than the etoxazole(LC50 = 0.2990 mg/L).These research results provide lead compounds and theoretical basis for the development of asymmetric disulfide molecules pesticides.