Target compounds 5a-t were synthesized as shown in using previously reported methods , and compounds 5u-w were synthesized as shown in . Substituted methyl benzoates 1 were produced when substituted benzoic acid was heated with absolute methanol in the presence of 98% H2SO4. Then substituted methyl benzoates 1 was treated with hydrazine hydrate in methanol under reflux condition to form substituted benzoyl hydrazines 2, 2-mercapto-5-substituted-1,3,4-oxadiazoles 3 was easily prepared by the reaction of substituted benzoyl hydrazines 2, potassium hydroxide, and carbon disulfide in ethanol under reflux conditions, then, 2-mercapto-5-substituted-1,3,4-oxadiazoles 3 was converted to thioether derivatives 4 by a thioetherification reaction with dimethyl(diethyl) sulfate or halide (RX). Treatment of thioether derivatives 4 by KMnO4 afforded the target compounds 5. The compounds were synthesized from substituted benzoic acid by five steps following esterification, hydrazidation, cyclization, thioetherification and oxidation. The structures of the target compounds were confirmed by 1H and 13C nuclear magnetic resonance, infrared spectroscopy and elemental analysis.
The general synthetic route of target compounds 5a-w is shown in and . Target compounds were obtained from disubstituted benzoic acid, 4-(trifluoromethyl)-benzoic acid and 4-fluorophenoxyacetic acid by previously reported methods [, ]. Substituted methyl benzoates 1 were produced when substituted benzoic acid was heated with absolute methanol in the presence of an acid catalyst. Then substituted methyl benzoates 1 was treated with hydrazine hydrate to form substituted benzoyl hydrazines 2, 2-mercapto-5-substituted-1,3,4-oxadiazoles 3 was easily prepared by cyclization, then, 2-mercapto-5-substituted-1,3,4-oxadiazoles 3 was converted to thioether derivatives 4 by a thioetherification reaction with dimethyl(diethyl) sulfate or halide (RX). Treatment of thioether derivatives 4 by KMnO4 afforded the target compounds 5. It is generally known that there are lots of studies of oxidation of sulfides to sulfone by different oxidant, such as, H2O2-ammonium molybdate, H2O2-sodium tungstate and AcOH-KMnO4. In our research, sulfone was prepared by the oxidation of sulfide with AcOH-KMnO4 at room temperament. Through the research of different experimental conditions during oxidation of sulfides to sulfone, we found out that the yield and rate of reaction were closely related to the proportion of V(AcOH) to V(H2O). The key point of oxidation reaction is the volume ratio of V(AcOH) and V(H2O), hence, any improper volume of V(AcOH) or V(H2O) can lead to incomplete reaction or no reaction. It was demonstrated that the best proportion of volume of V(AcOH) and V(H2O) is 1.5:1.
In summary, a series of sulfone derivatives containing 1,3,4-oxadiazole moiety were synthesized from substituted benzoic acid. The target compounds 5a, 5b and 5u exhibited excellent activity against six fungi as well as two phytopathogenic bacteria compared to the commercial fungicides bactericides epoxiconazole, Kocide 3000 and bismerthiazol, respectively. The antibacterial tests showed that when 4-F substituted benzene combined with 2-substitued electron withdrawing group (Br, Cl), the corresponding compounds had presented good antibacterial activities. Moreover, introduction of –OCH2-, compounds resulted in excellent to good activities against and two phytopathogenic bacteria, but not increase against five other fungi. In addition, the antifungal and antibacterial assays demonstrated that the inhibition activity of compounds 5u was the best among all target compounds and even superior to the commercial agents, Kocide 3000 and bismerthiazol. To our knowledge, this is the first report of sulfone derivatives containing 1,3,4-oxadiazole moieties containing disubstituted benzene and phenoxymethyl with potent controlling effect against and . Further evaluation of their biological efficacy, crop safety, and toxicity is conducted before them as bactericide candidates adopted for widespread use.
The SAR of early synthesized compounds suggested that 2-(methylsulfonyl)-1,3,4-oxadiazole or 2-(ethylsulfonyl)-1,3,4-oxadiazole affords antifungal activities higher than 2-(phenylsulfonyl) -1,3,4-oxadiazole or 2-(yl)-1,3,4-thiadiazole [, ]. The further research for novel sulfone derivatives, with illustration of SAR, a series of novel sulfone derivatives containing 1,3,4-oxadiazole moiety were synthesized from disubstituted and trifluoromethyl-substituted benzoic acid () and 4-fluorophenoxyacetic acid () via reactivity-selectivity principle. Their antibacterial and antifungal activities on selected target phytopathogenic fungi and bacteria were investigated, and their SAR was also discussed. To our knowledge, the antibacterial and antifungal activities of all the synthetic derivatives including known compounds were reported for the first time.
A series of novel sulfone derivatives containing 1,3,4-oxadiazole moiety were synthesized. All the target com-pounds were characterized by 1H and 13C nuclear magnetic resonance, infrared spectroscopy and elemental analysis. Their antifungal activities were tested with six important phytopathogenic fungi, namely, and using the mycelium growth inhibition method. Their antibacterial activities were tested with two important phytopathogenic bacteria, namely, and from tobacco bacterial by the turbid meter test. Remarkably, compounds 5h, 5j, 5u and 5v exhibited the most potent inhibition against and with 50% inhibition concentration (EC50) from 1.97 to 7.75 μg/mL and 0.45 to 0.52 μg/mL, respectively. Their antifungal tests indicated that among target compounds exhibited good antifungal activities against six kinds of fungi, especially against with EC from 3.71 to 17.44 μg/mL. antibacterial activities tests demonstrated that the controlling effect of compounds 5u (81.9%) against rice bacterial leaf blight were better than that of bismerthiazol (50.8%) and thiodiazole-copper (44.7%). Our results also demonstrated that com-pounds 5h, 5u and 5v have a better antifungal and antibacterial activity, with good characteristics of broad spectrum. The structure−activity relationship (SAR) was also discussed.
5-(7-bromo-5-chloro-3-methylbenzofuran-2-yl)-1-phenyl-1H-pyrazole-3-carbohydrazide 1 underwent a series of hetero-cyclization reactions with different chemical reagents such as triethylorthoformate, acetic acid in phosphorous oxychloride, benzoic acid in phosphorous oxychloride, N,N’carbonyldiimidazole in dioxane, carbon disulphide in pyridine to afford substituted 1,3,4-oxadiazoles 2, 3, 4, 5 and 6 respectively. Extending the reaction of 6 with 4-(2-chloroethyl) morpholine hydrochloride afforded 7. The structures of the newly synthesized compounds were established on the basis of spectral analysis such as IR, 1H NMR, 13C NMR and Mass spectral data. The synthesized compounds were screened for their antimicrobial activity against two gram positive and gram negative bacteria and a fungus and found to possess good activity against selected strains.