Synthesis And Fungicidal Activities Of 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one Oxime Ethers And Hydrazone Derivatives

Based on the mode of action and structure-activity relationship of triazole fungicides, we selected Triadimefon as a lead compound, kept the 1,2,4-triazole and tertiary butyl as the active groups, modified the carbonyl group by introducing the fungicidal groups of oxime ether,hydrazone,1,3,4-oxadiazole and thiazole into the side chain and designed and synthesized four series of novel triazoles: oxime ethers, oxime ether N-acylarylhydrazones, oxime ether 1,3,4-oxadiazoles and thiazolylhydrazone derivatives. According with the pharmacophore features, efforts were conducted to alter the length, width and flexibility of the side chain and the polarity and hydrophobicity of the substituents in order to find new inhibitors, which could match the active site of 14α-demethylase(CYP51) better.Four series with 92 kinds of new triazoles were derived from 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one:(1) Twenty-four kinds of(Z)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one oxime ethers A1~A24 were synthesized from 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one via oximation and Williamson etherification reaction;(2) Based on the key intermediate(Z)-3,3-dimethyl-1-(1H-1,2,4- triazol-1-yl)butan-2-one oxime, N-acylarylhydrazone groups were introduced into the side chain by etherification, hydrazinolysis and condensation with various of substituted benzaldehyde to obtain thirty-one kinds of oxime ether N-acylarylhydrazones B1~B31;(3) Compounds B were further oxidative cyclized by iodobenzene diacetate(IBD) to afford twenty-two kinds of(Z)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one O-((5-aryl-1,3,4-oxadiazol-2-yl)methyl) oxime C1~C22;(4) Fifteen kinds of(E)-4-(tert-butyl)-2-(2-(2-benzylidene)hydrazinyl)-5-(1H-1,2,4-triazol-1-yl)thiazole D1~D15 were synthesized from 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one via bromination and cyclization with 2-benzylidenehydrazinecarbothioamide. The processes for preparation of the four series target compounds were studied and the key processes were optimized. The chemical structures of all the new compounds were elucidated by 1H NMR、13C NMR and MS spectral data, and the crystal structures of three compounds were determined by single crystal X-ray diffraction.Fungicidal activity was tested against various plant pathogens in vitro or in vivo for all the new compounds. The structure-activity relationship was analyzed and the ligand-based pharmacophore model was constructed. The structure of the triazoles was optimized gradually according to the pharmacophore model in order to discover novel fungicides with higher efficiency and broader spectrum. The results showed that:(1) Oxime ethers A exhibited low fungicidal activities with narrow spectrum in general, while introducing benzene ring or halogen into the side chain and extending the carbon chain properly could increase their inhibition rates. Oxime ether N-acylarylhydrazones B showed excellent activity against Rhizoctonia solani. It was favored for activity to introduce bulkier hydrophobic group into the para-position of the phenyl, hydrophilic hydroxyl group or strong electrophilic nitro group into the ortho-position of the phenyl or bulkier hydrophobic group into 3,5-position of the phenyl. Oxime ether 1,3,4-oxadiazoles C showed a broader spectrum of activity compared to that of compound A, and their fungicidal activity were between that of compound A and B. At the same time, the activity was influenced by the nature of the substitutions as well as their position on the phenyl. The most active compounds are A7 with 98% protective rate against Blumeria graminis(500 mg/L), B3 with 90.9% inhibition rate against Phytophythora capsici(25 mg/L), and B1、B3、B4、B13、B14 and B26 with 80% protective rate against Rhizoctonia solani(500 mg/L), respectively.(2) Compound B was optimized in structure and compounds B29、B30、B31 and D were designed and synthesized. The new compounds were tested in vitro or in vivo against seven common pathogens. In vitro, B30 has good activities on Phytophthora infestans and Pyricularia oryzae with ED50 values of 0.71 mg/L and 1.15 mg/L, respectively. B31 exhibit potent inhibition activity against Phytophthora infestans, Pyricularia oryzae and Septoria tritici, with ED50 values of 1.19 mg/L, 0.339 mg/L and 0.458 mg/L, respectively. In vivo assay, B30 and B31 show very good protective activity and could be the candidates for further optimization. Some of compound D showed fairly good activity against Pyricularia oryzae, especially D5、D13、D14 and D15, which have ED50 values of 1.66 mg/L、0.129 mg/L、0.14 mg/L and 0.216 mg/L, respectively. D13、D14 and D15 also showed significant activity against Septoria tritici, with ED50 values of 0.0481 mg/L、0.202 mg/L and 1.04 mg/L, respectively. As a result, compound D13、D14and D15 have excellent fungicidal activity with a broad antifungal spectrum, which makes the(E)-4-(tert-butyl)-2-(2-(2-benzylidene) hydrazinyl)-5-(1H-1,2,4-triazol-1-yl)thiazole to be an ideal skeleton for further study.Two ligand-based pharmacophore models were developed for CYP51 in Rhizoctonia solani and Pyricularia oryzae using Discovery studio 2.5. The pharmacophore models have good prediction for the four series of compounds and can be used to guide the structure optimization. Some novel potential fungicides with high fit values were identified for further investigation via screening a virtual compound database.