Containing 1,3,4 - Thiadiazole (evil) Yl Sulfone Derivatives, Synthesis And Biological Activity Study

Most of sulfone (sulfoxide) compounds possess a broad spectrum of bioactivity, such as insecticidal, antifungal, herbicidal, antitumor, anticancer, anti-HIV-1 and antitubercular activities et al. In recent years, sulfone (sulfoxide) compounds displayed good bioactivities in pesticide. For example, Aventis company developed new insecticide named as Fipronil which possessed a broad spectrum of bioactivity against Myzus persicae, Empoasca, larvae of Lepidoptera, Musca domestica and Hymenoptera pests. SDC biotechnology company opened up herbicide Benzobicyclon containing sulfone structure which was a kind of HPPD (4-hydroxyphenyl pyruvate dioxygenase) inhibition. Aventis company exploited Isoxaflutole with sulfone structure which was a good herbicide against weeds of maize and sugar beet fields. Therefore, sulfone (sulfoxide) compounds have been one of the focuses of chemical and biological research fields.In order to create high-effcient and environment friendly pesticide, this paper hoped to use gallic acid as the lead compound which was screened from natural products and synthesized a series of sulfone derivatives containing 1,3,4-thiadiazole (oxadiazole) moiety (see figure), then bioactivities of the compounds would be tested for the high-bioactivity compound.The synthesis of title compounds, characterization of the compounds, synthetic methods, bioactivity were entirely studied and the good results were obtained. The results provided a valuable reference for further development of the compounds.1. The synthesis of title compounds (A-E)Starting from gallic acid, 14 new 2-substitutedthio-5-(3,4,5-trimethoxyphenyl)-l,3,4-thiadi-azole compounds (No. A) and 17 new 2-substitutedthio-5-(3,4,5-trimethoxy-phenyl)-l,3,4-oxadi-azole compounds (No. B) were synthesized in six steps including etherification, esterification, hydrazidation, salt formation, cyclization, and thioetherification. 13 New 2-substitutedsulfon-yl-5-(3,4,5-trimethoxyphenyl)-l,3,4-thiadiazole compounds (No. C) and 17 new 2-substituted-sulfonyl-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazole compounds (No. D) were synthesized from sulfides by oxidation with H₂O₂. 9 New 2-substitutedsulfinyl-5-(3,4,5-trimethoxyphenyI)-1,3,4-thiadiazole (oxadiazole) compounds (No. E) were synthesized from sulfides by oxidation with mCPBA. 70 New title compounds containing heterocyclic sulfides, sulfones and sulfoxides have been obtained and their structures were characterized by IR, ¹H NMR, ¹³C NMR and element analysis.2. The single-crystal structure of the compounds(A₁, B₁ and D₁₃)The single-crystal structure of A₁, B₁ and D₁₃ were confirmed by X-ray crystallography. In compound A₁, it belongs to the monoclinic system with space group C2/c and cell dimensions of a = 1.5730(6) nm, b=0.5477 nm, c=4.2244 (14) nm, R₁=0.0783, wR₂=0.1832. Compound B₁ belongs to the triclinic system with space group P - 1, R₁=0.0592, wR₂=0.1268. Compound D₁₃ belongs to the monoclinic system with space group P21/c, R₁ = 0.1785, wR₂=0.2011. An intramolecular hydrogen bond was found in the compounds by single-crystal X-ray diffraction of D₁₃ compound.3. The synthetic methods of A-DThe synthetic methods and the synthetic conditions of 2-substitutedthio-5-(3,4,5-trimethoxy-phenyl)-1,3,4-thiadiazole (oxadiazole) derivatives were optimized, a kind of new green synthetic method was adopted which catalyzed by indium in aqueous media for reaction 4 h. Compared with typical synthesis method, the advantages of the reaction procedure were short reaction period, high yield and simple working up. To our knowledge, this is the first report on synthetic method of sulfide derivatives containing 1,3,4-thiadiazole (oxadiazole) moiety.Moreover, the synthetic methods and the synthetic conditions of 2-substitutedsulfonyl-5-(3,4,5-trimethoxy phenyl)-1,3,4-thiadiazole (oxadiazole) were analysed carefully in this reaction which oxidation of sulfides to sulfones. The optimial condition were as follows: In the synthetic reaction of sulfone, H₂O₂ was oxidant, ionic liquid [bmim]PF₆ and (NH₄)₆Mo₇O₂4 were catalyst, the molar ratio of [H₂O₂ : substrate] wes 5:1, the molar ratio of [(NH₄)₆Mo₇O₂₄: substrate] wes 0.01:1, the molar ratio of [ionic liquid : substrate] was 13:1, the reaction temperature was 40°C and the reaction time was 3 h. Compared with traditional synthesis method, the results showed the present new method of synthesis some title compounds in the ionic liquid [bmim]PF6 offers several advantages: faster reaction time, better selectivity (such as olefinic link, carbonyl and heterocycle groups are tolerable), higher yields and the ionic liquid [bmim]PF₆ can be recycled and reused. There is no report on the new synthetic method in current literature.4.The antifungal and antitumor activities of A-DThe antifungal activities of some title compounds to Gibberella zeae, Botrytis cinerea and Sclerotinia sclerotiorum were tested by the mycelial growth rate method. The results showed some of them exhibited good antifungal activities such as compound D₈ and D₉, respectively. At the concentration 50μg/mL, title compounds D₈ and D₉ inhibited growth of Gibberella zeae at 67.5%, 55.8%, Botrytis cinerea at 100%, 100%, Sclerotinia sclerotiorum at 100%, 100%, respectively, which were slightly better than that of Hymexazol (52.9% against Gibberella zeae, 75.4% against Botrytis cinerea and 77.5% against Sclerotinia sclerotiorum at 50μg/mL). The EC₅₀ of compounds D₈ and D₉ against nine plant pathogen(G. zeae, P. grisea, C. gloeosporioides, B. cinerea, S. sclerotiorum, R. solani, P. infestans, C. mandshurica, F. oxysporum) were tested, respectively. EC₅₀ was 2.9-93.3μg/mL. Compounds D₈ and D₉ were found firstly that they possessed good antifungal activities.In vitro antitumor activities of some title compounds to PC3 and BGC-823 were tested. The results showed some of them exhibited good antitumor activities such as compound A₂ and A₅, respectively. At the concentration 5μmol/L, the test of MTT method indicated that inhibitory rate of the compound A₅ to PC3 was 55.71% and the compound A₂ to BGC-823 was 61.21%. At the concentration 1μmol/L, that inhibitory rate of the compound A₅ to PC3 wass 54.90% and the compound A₂ to BGC-823 was 50.51%.