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Journal of Chemistry

Volume 2014 (2014), Article ID 681364, 9 pages

http://dx.doi.org/10.1155/2014/681364
Research Article

Synthesis and Biological Activities of Some Novel (E)-Alpha-(methoxyimino)benzeneacetate Derivatives with Modified 1,2,4-Triazole Moiety

1College of Quality and Technical Supervision, Hebei University, Baoding 071002, China

2Institute of Plant Protection and Soil Fertilizer, Hubei Academy of Agricultural Science, Wuhan 430064, China

Received 6 June 2014; Revised 23 July 2014; Accepted 26 July 2014; Published 24 August 2014

Academic Editor: Gabriel Navarrete-Vazquez

Copyright © 2014 Xianyou Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

To find new strobilurin analogues with high activity against resistant pathogens, a series of (E)-α-(methoxyimino)benzeneacetate derivatives containing 1,2,4-triazole Schiff base side chain were designed and synthesized. Their structures were confirmed by IR, 1H NMR, and 13C NMR, ESI-HRMS, or elemental analyses. Bioassays indicated that most of the target compounds showed moderate to good fungicidal activities against Rhizoctonia solani, Botrytis cinerea Pers., Fusarium graminearum, Cotton rhizoctoniosis, and Blumeria graminis. For example, compounds 6g and 6j exhibited promising antifungal activity against Rhizoctonia solani, Botrytis cinerea Pers., and Fusarium graminearum. Compounds 6c, 6l, and 6m had higher fungicidal activities against Blumeria graminis at the concentration of 50 µg/mL; inhibitory rate is 91.41%, 92.13%, and 91.77%, respectively.

1. Introduction

The strobilurins, derived from fermentations of Strobilurus tenacellus by Anke and coworkers in 1977, are one of the most important classes of agricultural fungicides [1]. Their primary mechanism of action is the inhibition of mitochondrial respiration by blocking electron transfer at the ubiquinol oxidation center (Qo site) of the cytochrome complex (complex III) [2].

Strobilurin derivatives have attracted significant attention of the agricultural chemists owing to their outstanding characteristics and unique mode of action, broader antifungal spectrum, long-lasting effects, high antifungal activity, and low toxicity toward mammalian cells [36]. The strobilurins were first commercialized in 1996 with the launch of azoxystrobin and kresoxim-methyl (Figure 1) [7]. Till date, over ten strobilurin derivatives are commercially available [810]. However, following the use of strobilurin fungicides in a short period of field applications, significant increase in resistance to fungicide has been observed [11].

681364.fig.001
Figure 1: Structures of azoxystrobin, kresoxim-methyl, triadimefon, and triadimenol.

Recently, significant research efforts focusing on structural modification of strobilurins have been devoted to overcoming the above-mentioned problem. Moreover, according to the literature, the methoxyiminoacetate is an effective pharmacophore which is indispensable for antifungal activity of strobilurin fungicides. The aromatic bridge helps to stabilize the molecule and the molecule also exhibits photo stability. Therefore, numerous studies have reported that modification of the side chain is the most effective method to obtain novel strobilurin derivatives with higher biological activities [6, 1214].

In general, 1,2,4-triazole and similar Schiff bases exhibit diverse biological activities, such as pesticides, fungicides, herbicidal, anticancer, anti-inflammatory, antiviral, and antimicrobial properties [1522]. So far, over twenty triazole fungicides have been commercialized, like triadimefon and triadimenol (Figure 1). Therefore, based on the active substructure combination and bioisosteric replacement, the intermediate derivatization method was employed to synthesize a series of novel strobilurin derivatives containing 1,2,4-triazole moieties. Moreover, strobilurin pharmacophores were designed and synthesized with the objective of obtaining more active candidates against resistant fungal strains (Figure 2). The results of bioassays revealed that most of the (E)-α-(methoxyimino)benzeneacetate derivatives exhibited potential antifungal activities against Rhizoctonia solani, Botrytis cinerea Pers., Fusarium graminearum, Cotton rhizoctoniosis, and Blumeria graminis.

681364.fig.002
Figure 2: Design strategy of the title compounds.

2. Experimental

2.1. General Information

All melting points were determined on an XT-4A apparatus and are uncorrected. The IR spectra (KBr disks) were taken on a Bruker Equinox 55 spectrophotometer. The 1H NMR spectra were measured on a Bruker Advance 600 spectrometer for DMSO-d6 solutions using TMS as internal standard. Elemental analyses were determined on a Flash-1112 series elemental analyzer. All the reagents used were AR grade. Molecular weights of monomers were determined by high resolution mass spectroscopy (ESI-HRMS, Bruker daltonics apexultra 7.0 tesla Fourier transform ion cyclotron resonance mass spectrometer). The completion of reactions was monitored by TLC.

2.2. General Procedure for the Synthesis of Benzohydrazide (2) [23]

A mixture of ethyl benzoate 1 (0.1 mol) and hydrazine hydrate (0.1 mol) in ethanol (30 mL) was stirred vigorously for 6 h at room temperature. The mixture was filtered, and the solid was washed with cold water, dried, and recrystallized from ethanol to give intermediate 2, white crystal, yield: 90.6%, m.p.: 112–114°C.

2.3. General Method for the Synthesis of Potassium Dithiocarbazinate (3) [24]

Potassium hydroxide (0.15 mol) was dissolved in absolute ethanol (100 mL) followed by the addition of benzohydrazide 2 (0.1 mol). The resulting solution was cooled in ice. Subsequently, carbon disulfide (0.15 mol) was added dropwise, and the reaction mixture was stirred for 15 h at room temperature. The precipitated potassium dithiocarbazinate was collected by filtration. The precipitate was further washed with anhydrous ether (100 mL), dried, and used directly without purification for the subsequent reaction.

2.4. Synthesis of 4-Amino-3-phenyl-5-thiol-1,2,4-triazole (4) [25]

Potassium dithiocarbazinate 3 (0.5 mol) was added to hydrazine hydrate (0.15 mmol) and refluxed for 6 h with occasional shaking. The color of the reaction mixture changed to green with the evolution of hydrogen sulfide gas (lead acetate paper test and odor). The reaction mixture was cooled to room temperature and diluted with water. On acidification with concentrated hydrochloric acid, the corresponding triazole was precipitated. It was filtered, washed thoroughly with cold water, and recrystallized from ethanol to give 4-amino-3-phenyl-5-thiol-1,2,4-triazole 4. White crystal, yield: 63.1%, m.p.: 201-202°C; IR (KBr, cm−1): 3412, 3070, 2667, 1640. 1H NMR (600 MHz, DMSO-d6) δ: 13.90 (s, 1H, triazole–NH), 7.52–8.01 (m, 5H, Ar-H), 5.81 (s, 2H, NH2).

2.5. General Method for the Preparation of (E)-3-Thiol-4-arylideneamino-5-phenyl-4H-1,2,4-triazole (5a–5n)

Appropriate benzaldehyde (10 mmol) and 2 to 3 drops of glacial acetic acid were added to a solution of compound 4 (l0 mmol) dissolved in absolute alcohol (30 mL). The mixture was refluxed for 4 h with stirring. The solid that was obtained on cooling was filtered, washed with cold water, dried, and recrystallized from alcohol to give a series of Schiff bases 5a5n.

(E)-3-Thiol-4-benzylideneamino-5-phenyl-4H-1,2,4-triazole (5a). White powder, yield: 70.0%, m.p.: 180-181°C. IR (KBr, cm−1): 3102, 2974, 1610, 1554, 1530, 1482, 1269. 1H NMR (600 MHz, DMSO-d6) δ: 7.43–7.71 (m, 6H, Ar-H), 7.90 (d,  Hz, 4H, Ar-H), 9.71 (s, 1H, CH=N), 14.25 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 127.71, 128.22, 128.26, 128.33, 128.44, 129.47, 130.85, 134.39, 144.82, 154.73, 165.12. Anal. calcd for C15H12N4S: C, 64.26; H, 4.31; N, 19.98; found: C, 64.31; H, 4.29; N, 19.93.

(E)-3-Thiol-4-(4-methylbenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5b). Red solid, yield: 62.5%, m.p.: 239-240°C. IR (KBr, cm−1): 3110, 2979, 1618, 1516, 1512, 1484, and 1271. 1H NMR (600 MHz, DMSO-d6) δ: 2.41 (s, 3H, CH3), 7.46–7.58 (m, 3H, Ar-H), 7.66 (t,  Hz, 2H, Ar-H), 7.86 (dd, , 11.7 Hz, 2H, Ar-H), 7.92 (d,  Hz, 2H, Ar-H), 9.62 (s, 1H, CH=N), 14.21 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 21.16, 128.03, 128.22, 128.25, 128.42, 128.61, 130.82, 131.71, 137.95, 144.87, 154.73, 165.12. Anal. calcd for C16H14N4S: C, 65.28; H, 4.79; N, 19.03; found: C, 65.33; H, 4.77; N, 18.99.

(E)-3-Thiol-4-(4-dimethylaminobenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5c). White solid, yield: 75.1%, m.p.: 233-234°C. IR (KBr, cm−1): 3113, 2978, 1613 1552 1531, 1482, 1275. 1H NMR (600 MHz, DMSO-d6) δ: 3.34 (s, 6H, N-(CH3)2), 7.09 (t,  Hz, 1H, Ar-H), 7.22 (d,  Hz, 1H, Ar-H), 7.44–7.70 (m, 4H, Ar-H), 7.90–7.92 (m, 3H, Ar-H), 9.50 (s, 1H, CH=N), 14.28 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 41.92, 111.93, 120.04, 128.22, 128.24, 128.27, 128.42, 130.84, 144.84, 153.11, 154.72, 165.11. Anal. calcd for C17H17N5S: C, 63.13; H, 5.30; N, 21.65; found: C,63.20; H, 5.26; N, 21.59.

(E)-3-Thiol-4-(2-hydroxylbenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5d). White needle crystal, yield: 78.4%, m.p.: 195-196°C. IR (KBr, cm−1): 3122, 3102, 2977, 1620, 1550, 1531, 1486, 1269. 1H NMR (600 MHz, DMSO-d6) δ: 6.82–7.10 (m, 2H, Ar-H), 7.45 (t,  Hz, 1H, Ar-H), 7.54–7.56 (m, 3H, Ar-H), 7.73–7.93 (m, 3H, Ar-H), 9.65 (s, 1H, CH=N), 10.47 (s, 1H, Ar-OH), 14.21 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 116.25, 119.62, 121.01, 128.24, 128.24, 128.46, 129.65, 130.86, 131.03, 144.85, 146.81, 159.93, 165.12. Anal. calcd for C15H12N4OS: C, 60.79; H, 4.08; N, 18.91; found: C, 60.73; H, 4.10; N, 18.94.

(E)-3-Thiol-4-(3-hydroxylbenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5e). White needle crystal, yield: 65.8%, m.p.: 205-206°C. IR (KBr, cm−1): 3120, 3100, 2987, 1622, 1549, 1536, 1487, 1278. 1H NMR (600 MHz, DMSO-d6) δ: 7.02–7.20 (m, 2H, Ar-H), 7.49 (t,  Hz, 1H, Ar-H), 7.52–7.61 (m, 4H, Ar-H), 7.76–7.98 (m, 2H, Ar-H), 9.65 (s, 1H, CH=N), 10.42 (s, 1H, Ar-OH), 14.22 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 115.09, 117.22, 120.90, 128.21, 128.24, 128.42, 130.41, 130.87, 136.96, 144.85, 155.92, 157.36, 165.12. Anal. calcd for C15H12N4OS: C, 60.79; H, 4.08; N, 18.91; found: C, 60.71; H, 4.11; N, 18.89.

(E)-3-Thiol-4-(4-hydroxylbenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5f). White powder, yield: 68.8%, m.p.: 245-246°C. IR (KBr, cm−1): 3129, 3102, 2985, 1611, 1557, 1532, 1483, 1270. 1H NMR (600 MHz, DMSO-d6) δ: 7.17 (d,  Hz, 1H, Ar-H), 7.40–7.60 (m, 6H, Ar-H), 7.88–7.90 (m, 2H, Ar-H), 9.49 (s, 1H, CH=N), 10.41 (s, 1H, OH), 14.24 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 115.11, 126.48, 128.21, 128.24, 128.43, 128.85, 130.84, 144.85, 154.74, 159.05, 165.11. Anal. calcd for C15H12N4OS: C, 60.79; H, 4.08; N, 18.91; found: C, 60.73; H, 4.12; N, 19.00.

(E)-3-Thiol-4-(2-nitrobenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5g). Pale yellow needle crystal, yield: 82.1%, m.p.: 214-215°C. IR (KBr, cm−1): 3113, 2974, 1614 1554, 1530, 1482, 1270. 1H NMR (600 MHz, DMSO-d6) δ: 6.94 (d, .6 Hz, 2H, Ar-H), 7.49–7.58 (m, 3H, Ar-H), 7.75 (d, .6 Hz, 2H, Ar-H), 7.86–7.90 (m, 2H, Ar-H), 9.58 (s, 1H, CH=N), 14.32 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 126.45, 127.11, 127.83,. 128.22, 128.25, 128.42, 130.87, 131.67, 133.54, 140.25, 144.83, 146.91, 165.12. Anal. calcd for C15H11N5O2S: C, 55.38; H, 3.41; N, 21.53; found: C, 55.34; H, 3.46; N, 21.59.

(E)-3-Thiol-4-(3-nitrobenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5h). Pale yellow needle crystal, yield: 72.3%, m.p.: 214-215°C. IR (KBr, cm−1): 3108, 2972, 1620, 1557, 1538, 1487, 1269. 1H NMR (600 MHz, DMSO-d6) δ: 7.42 (t,  Hz, 2H, Ar-H), 7.47–7.61 (m, 3H, Ar-H), 7.88 (d,  Hz, 2H, Ar-H), 7.99–8.12 (m, 2H, Ar-H), 9.71 (s, 1H, CH=N), 14.32 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 125.88, 126.76, 128.22, 128.24, 128.44, 129.11, 130.83, 132.97, 135.83, 144.85, 146.87, 155.94, and 165.12. Anal. calcd for C15H11N5O2S: C, 55.38; H, 3.41; N, 21.53; found: C, 55.42; H, 3.39; N, 21.48.

(E)-3-Thiol-4-(4-nitrobenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5i). Red powder, Yield: 77.6%, m.p.: 238-239°C. IR (KBr, cm−1): 3111, 2971 1610, 1552 1537, 1487, 1269; 1H NMR (600 MHz, DMSO-d6) δ: 7.45–7.72 (m, 6H, Ar-H), 7.82−7.94 (m, 2H, Ar-H), 8.07 (d,  Hz, 1H, Ar-H), 9.55 (s, 1H, CH=N), 14.34 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 123.72, 127.87, 128.23, 128.25, 128.42, 130.86, 138.93, 144.82, 146.85, 154.73, 165.12. Anal. calcd for C15H11N5O2S: C, 55.38; H, 3.41; N, 21.53; found: C, 55.32; H, 3.45; N, 21.56

(E)-3-Thiol-4-(2-chlorobenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5j). Pale yellow needle crystal, yield: 73.1%, m.p.: 199-200°C. IR (KBr, cm−1): 3110, 2971, 1614, 1552, 1538, 1483, 1269. 1H NMR (600 MHz, DMSO-d6) δ: 7.45–7.63 (m, 3H, Ar-H), 7.80–7.93 (m, 2H, Ar-H), 8.15 (d,  Hz, 2H, Ar-H), 8.38 (d, .6 Hz, 2H, Ar-H), 9.78 (s, 1H, CH=N), 14.31 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 127.61, 128.21, 128.22, 128.43, 129.07, 129.18, 129.53, 130.43, 130.84, 133.24, 144.86, 150.17, and 165.12. Anal. calcd for C15H11ClN4S: C, 57.23; H, 3.52; N, 17.80; found: C, 57.28; H, 3.54; N, 17.75.

(E)-3-Thiol-4-(3-chlorobenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5k). Pale yellow needle crystal, Yield: 69.2%, m.p.: 210-211°C. IR (KBr, cm−1): 3106, 2969, 1618, 1553, 1542, 1488, 1279. 1H NMR (600 MHz, DMSO-d6) δ: 7.40–7.61 (m, 3H, Ar-H), 7.78–7.90 (m, 3H, Ar-H), 8.09 (d,  Hz, 1H, Ar-H), 8.38 (d,  Hz, 2H, Ar-H), 9.76 (s, 1H, CH=N), 14.29 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 126.45, 127.48, 128.22, 128.25, 128.42, 129.12, 129.51, 130.85, 134.33, 135.06, 144.84, 155.93, 165.12. Anal. calcd for C15H11ClN4S: C, 57.23; H, 3.52; N, 17.80; found: C, 57.20; H, 3.49; N, 17.76.

(E)-3-Thiol-4-(4-chlorobenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5l). Pale yellow needle crystal, yield: 68.2%, m.p.: 221-222°C. IR (KBr, cm−1): 3100, 2979, 1611, 1551, 1537, 1481, 1269. 1H NMR (600 MHz, DMSO-d6) δ; 7.46–7.68 (m, 5H, Ar-H), 7.85–7.87 (m, 3H, Ar-H), 8.04 (d,  Hz, 1H, Ar-H), 9.78 (s, 1H, CH=N), 14.26 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 128.21, 128.22, 128.41, 128.59, 128.63, 130.85, 134.16, 135.34, 144.85, 154.74, 165.12. Anal. calcd for C15H11ClN4S: C, 57.23; H, 3.52; N, 17.80; found: C, 57.21; H, 3.57; N, 17.77.

(E)-3-Thiol-4-(2,4-dichlorobenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5m). Pale yellow needle crystal, yield: 69.0%, m.p.: 222-223°C. IR (KBr, cm−1): 3107, 2985, 1620, 1563, 1523, 1481, 1274. 1H NMR (600 MHz, DMSO-d6) δ: 7.42 (t, .1 Hz, 1H, Ar-H), 7.48–7.60 (m, 4H, Ar-H), 7.64–7.67 (m, 1H, Ar-H), 7.92–8.13 (m, 2H, Ar-H), 9.75 (s, 1H, CH=N), 14.31 (s, 1H, triazole–NH). 13C NMR (600 MHz, DMSO-d6) δ: 128.21, 128.23, 128.10, 128.22, 128.23, 128.44, 130.86, 132.96, 133.54, 134.96, 144.82, 153.94, 165.13. Anal. calcd for C15H10Cl2N4S: C, 51.59; H, 2.89; N, 16.04; found: C, 51.53; H, 2.92; N, 16.08.

(E)-3-Thiol-4-(3,4-dichlorobenzylideneamino)-5-phenyl-4H-1,2,4-triazole (5n). White needle crystal, yield: 84.8%, m.p.: 205-206°C. IR (KBr, cm−1): 3112, 2971, 1612, 1554, 1537, 1481, 1275. 1H NMR (600 MHz, DMSO-d6) δ: 7.39 (d,  Hz, 2H, Ar-H), 7.52–754 (m, 2H, Ar-H), 7.79 (d,  Hz, 2H, Ar-H), 7.84–7.94 (m, 2H, Ar-H), 9.62 (s, 1H, CH=N), 14.29 (s, 1H, triazole–NH). 13C NMR (125 MHz, DMSO-d6) δ: 126.81, 128.04, 128.10, 128.22, 128.26, 128.43, 130.86, 132.95, 133.54, 134.97, 144.84, 155.94, 165.12. Anal. calcd for C15H10Cl2N4S: C, 51.59; H, 2.89; N, 16.04; found: C, 51.55; H, 2.85; N, 16.01.

2.6. General Procedure for the Synthesis of Target Compounds (6a–6n)

(E)-3-Thiol-4-arylideneamino-5-phenyl-4H-1,2,4-triazole 5 (1.75 mmol) was dissolved in DMF (15 mL), and anhydrous potassium carbonate (0.24 g, 1.75 mmol) was added to the solution. The solution was stirred for 0.5 h and (E)-methyl-2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate (0.50 g, 1.75 mmol) was then added. The reaction mixture was heated to 80°C and monitored by TLC. After 1 h, the mixture was cooled, diluted with water (30 mL), and extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with brine, dried (anhydrous magnesium sulfate), and filtered. The filtrate was evaporated, and the crude product was purified by silica gel column chromatography using a 1 : 3 (v/v) mixture of ethyl acetate and petroleum ether (boiling point range 60–90°C) as the eluting solution to obtain compound 6.

(E)-Methyl-2-(3-((4-((E)-benzylideneamino)-5-phenyl-4H-1,2,4-triazol-3-ylthio)methyl)phenyl)-2-(methoxyimino)acetate (6a). White solid, yield: 61.1%, m.p.: 94-95°C. IR (KBr, cm−1): 3103, 2964, 1655, 1611, 1554, 1514, 1478, 1274. 1H NMR (600 MHz, DMSO-d6) δ: 3.64 (s, 3H, COOCH3), 3.90 (s, 3H, =N-OCH3), 4.30 (s, 2H, CH2), 7.18 (t,  Hz, 1H, Ar-H), 7.31–7.36 (m, 2H, Ar-H), 7.45–7.71 (m, 7H, Ar-H), 7.85–8.14 (m, 4H, Ar-H), 8.74 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 33.68, 52.18, 60.41, 127.73, 128.16, 128.31, 128.31, 128.34, 128.66, 128.78, 129.47, 130.64, 130.79, 130.93, 131.14, 134.35, 140.63, 149.72, 152.49, 158.56, 159.58, 163.67. ESI-HRMS calcd. for C26H24N5O3S 486.15944; found: 486.15877.

(E)-Methyl-2-(2-(((4-((E)-(4-methylbenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6b). White solid, yield: 61.2%, m.p.: 119-120°C. IR (KBr, cm−1): 3113, 2963, 1653, 1602, 1567, 1525, 1486, 1285. 1H NMR (600 MHz, DMSO-d6) δ: 2.97 (s, 3H, Ar-CH3), 3.65 (s, 3H, COOCH3), 3.90 (s, 3H, =N-OCH3), 4.29 (s, 2H, CH2), 7.16 (d, .5 Hz, 1H, ArH), 7.32–7.41 (m, 4H, Ar-H), 7.46–7.52 (m, 3H, Ar-H), 7.54 (d,  Hz, 1H, Ar-H), 7.76 (d, .1 Hz, 2H, ArH), 7.81–7.85 (m, 2H, Ar-H), 8.68 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 21.25, 33.71, 52.04, 60.45, 128.04, 128.18, 128.32, 128.33, 128.61, 128.67, 128.74, 130.65, 130.77, 130.93, 131.11, 131.73, 137.93, 140.63, 149.74, 152.49, 158.56, 159.53, 163.50. ESI-HRMS calcd. for C27H26N5O3S 500.17509; found: 500.17536.

(E)-Methyl-2-(2-(((4-((E)-(4-(dimethylamino)benzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6c). White solid, yield: 73.2%, m.p.: 140-141°C. IR (KBr, cm−1): 3105, 2955, 1652, 1612, 1539, 1514, 1491, 1288. 1H NMR (600 MHz, DMSO-d6) δ: 3.11 (s, 6H, N-(CH3)2), 3.67 (s, 3H, COOCH3), 3.91 (s, 3H, =N-OCH3), 4.26 (s, 2H, CH2), 6.80 (d,  Hz, 2H, Ar-H), 7.16 (d,  Hz, 1H, Ar-H), 7.33–7.41 (m, 2H, Ar-H), 7.43–7.52 (m, 3H, Ar-H), 7.55 (d,  Hz, 1H, Ar-H), 7.67 (d,  Hz, 2H, Ar-H), 7.84 (d,  Hz, 2H, Ar-H), 8.43 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 33.71, 41.93, 52.06, 60.44, 111.93, 120.02, 128.15, 128.26, 128.33, 128.34, 128.66, 128.78, 130.61, 130.73, 130.97, 131.19, 140.69, 149.74, 152.46, 153.15, 158.56, 159.53, 163.57. ESI-HRMS calcd. for C28H29N6O3S 529.20164; found: 529.20172.

(E)-Methyl-2-(2-(((4-((E)-(2-hydroxybenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6d). White solid, yield: 70.2%, m.p.: 117-118°C. IR (KBr, cm−1): 3110, 2952, 1650, 1607, 1541, 1527, 1486, 1282. 1H NMR (600 MHz, DMSO-d6) δ: 3.68 (s, 3H, COOCH3), 3.92 (s, 3H, =N-OCH3), 4.31 (s, 2H, CH2), 6.96–7.10 (m, 2H, Ar-H), 7.17 (d,  Hz, 1H, Ar-H), 7.31–7.54 (m, 6H, Ar-H), 7.56 (d,  Hz, 2H, Ar-H), 7.83 (d,  Hz, 2H, Ar-H), 8.86 (s, 1H, CH=N), 10.52 (s, 1H, Ar-OH). 13C NMR (125 MHz, DMSO-d6) δ: 33.72, 42.16, 52.03, 60.42, 85.38, 116.27, 119.65, 121.04, 128.17, 128.37, 128.63, 128.71, 129.68, 130.63, 130.77, 130.94, 131.06, 131.13, 140.64, 149.75, 150.16, 152.47, 158.53, 159.94, 163.56. ESI-HRMS calcd. for C26H24N5O4S 502.15435: found: 502.15344.

(E)-Methyl-2-(2-(((4-((E)-(3-hydroxybenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6e). White solid, yield: 69.3%, m.p.:126-127°C. IR (KBr, cm−1): 3109, 2956, 1651, 1612, 1542, 1523, 1481, 1280. 1H NMR (600 MHz, DMSO-d6) δ: 3.68 (s, 3H, COOCH3), 3.92 (s, 3H, =N-OCH3), 4.31 (s, 2H, CH2), 6.99 (d,  Hz, 1H, Ar-H), 7.29–7.38 (m, 2H, Ar-H), 7.50–7.52 (m, 5H, Ar-H), 7.61–7.76 (m, 3H, ArH), 7.85 (d, .4 Hz, 2H, Ar-H), 8.73 (s, 1H, CH=N), 10.50 (s, 1H, Ar-OH). 13C NMR (125 MHz, DMSO-d6) δ: 33.74. 52.05, 60.43, 115.08, 117.21, 120.93, 128.19, 128.29, 128.34, 128.66, 128.78, 130.41, 130.63, 130.76, 130.97, 131.18, 136.93, 140.63, 149.74, 152.47, 157.35, 158.56, 160.02, 163.55. ESI-HRMS calcd. for C26H24N5O4S 502.15435: found: 502.15422.

(E)-Methyl-2-(2-(((4-((E)-(4-hydroxybenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6f). White solid, yield: 71.0%, m.p.: 143-144°C. IR (KBr, cm−1): 3113, 2953, 1658, 1600, 1546, 1513, 1480, 1278. 1H NMR (600 MHz, DMSO-d6) δ: 3.66 (s, 3H, COOCH3), 3.91 (s, 3H, =N-OCH3), 4.28 (s, 2H, CH2), 6.94 (d,  Hz, 2H, Ar-H), 7.17 (d,  Hz, 1H, Ar-H), 7.30–7.41 (m, 2H, Ar-H), 7.44–7.52 (m, 3H, Ar-H), 7.55 (d,  Hz, 1H, Ar-H), 7.73 (d, .7 Hz, 2H, Ar-H), 7.84 (d,  Hz, 2H, Ar-H), 8.55 (s, 1H, CH=N), 10.37 (s, 1H, Ar-OH). 13C NMR (125 MHz, DMSO-d6) δ: 33.72, 52.08, 60.42, 115.12, 126.43, 128.19, 128.35, 128.34, 128.65, 128.78, 128.84, 130.66, 130.77, 130.94, 131.13, 140.65, 149.76, 152.49, 158.56, 159.04, 159.57, 163.56. ESI-HRMS calcd. for C26H24N5O4S [M+H]+ 502.15435; found: 502.15425.

(E)-Methyl-2-(2-(((4-((E)-(2-nitrobenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6g). Pale yellow solid, yield: 77.2%, m.p.: 143-144°C. IR (KBr, cm−1): 3112, 2953, 1656, 1612, 1557, 1519, 1493, 1280. 1H NMR (600 MHz, DMSO-d6) δ: 3.69 (s, 3H, COOCH3), 3.93 (s, 3H, =N-OCH3), 4.33 (s, 2H, CH2), 7.18 (d,  Hz, 1H, Ar-H), 7.33–7.40 (m, 2H, Ar-H), 7.49–7.59 (m, 4H, Ar-H), 7.76–7.83 (m, 2H, Ar-H), 7.84–7.92 (m, 1H, Ar-H), 7.93 (t,  Hz, 1H, Ar-H), 8.04 (d,  Hz, 1H, Ar-H), 8.21 (d, .1 Hz, 1H, Ar-H), 9.05 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 33.73, 52.08, 60.40, 126.44, 127.13, 127.80, 128.19, 128.32, 128.33, 128.64, 128.73, 130.65, 130.72, 130.93, 131.13, 131.65, 133.55, 140.64, 146.90, 148.45, 149.75, 152.47, 158.56, 163.58. ESI-HRMS calcd. for C26H23N6O5S 531.14451; found: 531.14424.

(E)-Methyl-2-(2-(((4-((E)-(3-nitrobenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6h). Pale yellow solid, yield: 62.3%, m.p.: 112-113°C. IR (KBr, cm−1): 3105, 2959, 1652, 1609, 1557, 1523, 1482, 1275. 1H NMR (600 MHz, DMSO-d6) δ: 3.66 (s, 3H, COOCH3), 3.91 (s, 3H, =N-OCH3), 4.30 (s, 2H, CH2), 7.17 (d,  Hz, 1H, Ar-H), 7.30–7.41 (m, 2H, Ar-H), 7.47–7.55 (m, 4H, Ar-H), 7.81–7.92 (m, 3H, Ar-H), 8.31 (d,  Hz, 1H, Ar-H), 8.48 (d,  Hz, 1H, Ar-H), 8.65 (s, 1H, ArH), 8.92 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 33.71, 52.08, 60.41, 123.87, 124.67, 128.19, 128.35, 128.36, 128.65, 128.78, 129.10, 130.65, 130.74, 130.93, 131.13, 132.97, 135.86, 140.63, 146.85, 149.75, 152.46, 158.54, 160.05, 163.56. ESI-HRMS calcd. for C26H23N6O5S 531.14451; found: 531.14415.

(E)-Methyl-2-(2-(((4-((E)-(4-nitrobenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6i). Yellow solid, yield: 78.5%, m.p.: 140-141°C. IR (KBr, cm−1): 3103, 2957, 1648, 1614, 1567, 1528, 1491, 1273. 1H NMR (600 MHz, DMSO-d6) δ: 3.65 (s, 3H, COOCH3), 3.91 (s, 3H, =N-OCH3), 4.31 (s, 2H, CH2), 7.16 (d,  Hz, 1H, Ar-H), 7.31–7.40 (m, 2H, Ar-H), 7.45–7.58 (m, 4H, Ar-H), 7.82 (d, , 2H, Ar-H), 8.12 (d,  Hz, 2H, Ar-H), 8.40 (d,  Hz, 2H, Ar-H), 8.89 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 33.71, 52.08, 60.42, 123.73, 127.85, 128.18, 128.36, 128.34, 128.66, 128.78, 130.66, 130.79, 130.93, 131.13, 138.94, 140.63, 146.84, 149.75, 152.49, 158.56, 159.58, 163.58. ESI-HRMS calcd. for C26H23N6O5S 531.14451; found: 531.14434.

(E)-Methyl-2-(2-(((4-((E)-(2-chlorobenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6j). Pale yellow solid, yield: 63.2%, m.p.: 122-123°C. IR (KBr, cm−1): 3122, 2956, 1650, 1612, 1557, 1524, 1498, 1281. 1H NMR (600 MHz, DMSO-d6) δ: 3.67 (s, 3H, COOCH3), 3.92 (s, 3H, =N-OCH3), 4.34 (s, 2H, CH2), 7.09–7.21 (m, 1H, Ar-H), 7.33–7.40 (m, 2H, Ar-H), 7.48–7.71 (m, 7H, Ar-H), 7.82 (d, , 2H, Ar-H), 8.05 (d,  Hz, 1H), 8.95 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 33.71, 52.08, 60.41, 127.68, 128.14, 128.32, 128.35, 128.66, 128.78, 129.07, 129.14, 129.52, 130.43, 130.65, 130.77, 130.95, 131.13, 133.23, 140.63, 149.75, 152.48, 155.05, 158.54, 163.56. ESI-HRMS calcd. for C26H23ClN5O3S 520.12046; found: 520.12032.

(E)-Methyl-2-(2-(((4-((E)-(3-chlorobenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6k). Pale yellow solid, yield: 60.9%, m.p.: 126-127°C. IR (KBr, cm−1): 3117, 2961, 1652, 1623, 1555, 1529, 1492, 1284. 1H NMR (600 MHz, DMSO-d6) δ: 3.63 (s, 3H, COOCH3), 3.89 (s, 3H, =N-OCH3), 4.32 (s, 2H, CH2), 7.17 (d,  Hz, 1H, Ar-H), 7.30–7.41 (m, 2H, Ar-H), 7.46–7.57 (m, 5H, Ar-H), 7.75–7.82 (m, 2H, Ar-H), 7.92 (d,  Hz, 2H, Ar-H), 8.05 (s, 1H, Ar-H), 8.85 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 33.72, 52.05, 60.44, 126.43, 127.44, 128.18, 128.31, 128.33, 128.66, 128.78, 129.13, 129.51, 130.65, 130.77, 130.98, 131.12, 134.32, 135.05, 140.62, 149.75, 152.49, 158.56, 160.02, 163.56. ESI-HRMS calcd. for C26H23ClN5O3S 520.12046; found: 520.12031.

(E)-Methyl-2-(2-(((4-((E)-(4-chlorobenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6l). Pale yellow solid, yield: 70.1%, m.p.: 131-132°C. IR (KBr, cm−1): 3112, 2952, 1654, 1601, 1552, 1522, 1479, 12820. 1H NMR (600 MHz, DMSO-d6) δ: 3.65 (s, 3H, COOCH3), 3.90 (s, 3H, =N-OCH3), 4.29 (s, 2H, CH2), 7.17 (d,  Hz, 1H, Ar-H), 7.30–7.54 (m, 6H, Ar-H) 7.66 (d,  Hz, 2H, Ar-H), 7.82 (d,  Hz, 2H, Ar-H), 7.89 (d,  Hz, 2H, Ar-H), 8.75 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 33.44. 52.97, 61.75, 126.74, 128.09, 128.28, 129.07, 129.30, 129.89, 130.01, 130.52, 130.68, 130.96, 131.17, 135.09, 138.63, 146.80, 149.10, 151.63, 158.01, 159.56, 163.69. ESI-HRMS calcd. for C26H23ClN5O3S 520.12046; found: 520.11952.

(E)-Methyl-2-(2-(((4-((E)-(2,4-dichlorobenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6m). Pale yellow solid, yield: 71.6%, m.p.: 142-143°C. IR (KBr, cm−1): 3099, 2967, 1646, 1609, 1561, 1514, 1488, 1278. 1H NMR (600 MHz, DMSO-d6) δ: 3.68 (s, 3H, COOCH3), 3.92 (s, 3H, =N-OCH3), 4.33 (s, 2H, CH2), 7.17 (d,  Hz, 1H, Ar-H), 7.32–7.38 (m, 2H, Ar-H), 7.49–7.59 (m, 4H, Ar-H), 7.63 (d,  Hz, 1H, Ar-H), 7.80 (d,  Hz, 2H, Ar-H), 7.86 (s, 1H, Ar-H), 8.03 (d,  Hz, 1H, Ar-H), 8.90 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 33.72, 52.08, 60.30, 128.29, 128.34, 128.36, 128.38, 128.66, 128.68, 129.58, 129.75, 129.96, 130.65, 130.77, 130.97, 131.14, 134.57, 134.72, 140.63, 149.75, 152.48, 155.09, 158.57, 163.57. ESI-HRMS calcd. for C26H22Cl2N5O3S 554.08149; found: 554.08127.

(E)-Methyl-2-(2-(((4-((E)-(3,4-dichlorobenzylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate (6n). Pale yellow solid, yield: 74.6%, m.p.: 101-102°C. IR (KBr, cm−1): 3111, 2957, 1655, 1601, 1547, 1530, 1498, 1279. 1H NMR (600 MHz, DMSO-d6) δ: 3.58 (s, 3H, COOCH3), 3.91 (s, 3H, =N-OCH3), 4.29 (s, 2H, CH2), 7.17 (d,  Hz, 1H, Ar-H), 7.31–7.40 (m, 2H, Ar-H), 7.46–7.55 (m, 4H, Ar-H), 7.81–7.84 (m, 2H, Ar-H), 7.85 (d,  Hz, 2H, Ar-H), 8.09 (s, 1H, Ar-H), 8.75 (s, 1H, CH=N). 13C NMR (125 MHz, DMSO-d6) δ: 33.71, 52.06, 60.31, 128.29, 128.32, 128.33, 128.38, 128.66, 128.66, 129.58, 129.75, 129.97, 130.65, 130.76, 130.97, 131.15, 134.57, 134.73, 140.63, 149.74, 152.48, 155.08, 158.57, 163.56. ESI-HRMS calcd. for C26H22Cl2N5O3S 554.08149; found: 554.08121.

2.7. Antimicrobial Activity Assessment

Inhibitive, active freshly prepared compounds were tested by mycelium growth rate method under the laboratory conditions, and these strobilurin derivatives were screened for antifungal activity against Rhizoctonia solani, Botrytis cinerea Pers., Fusarium graminearum, Cotton rhizoctoniosis, and Blumeria graminis at dosages of 50 μg mL−1. Antifungal activity was determined by measuring the diameter of the inhibition zone. The growth inhibition rates were calculated by using the following equation: . Here, is the growth inhibition rate (%), is the control settlement radius (mm), and is the treatment group fungi settlement radius (mm). Activity of each compound was compared to kresoxim-methyl as standard. The results of preliminary screening are listed in Table 1.

tab1
Table 1: Fungicidal activities of 6a–6n (inhibition rate/%, 50 μg mL−1).

3. Results and Discussion

3.1. Synthetic Chemistry

Scheme 1 shows the schematic representation of the synthetic route for the preparation of target compounds. Compound 2 was prepared by the reaction between ethyl benzoate 1 and 85% hydrazine hydrate in ethanol at room temperature in excellent yield (90.6%). Further, compound 2 was heated with carbon disulfide in the presence of absolute ethanol and potassium hydroxide to afford intermediate potassium acylhydrazine dithioformate 3. This salt underwent ring closure with an excess of 85% hydrazine hydrate to give intermediate 4, which was used directly without further purification for the subsequent reaction. Subsequently, compound 4 was allowed to react with appropriate aromatic aldehydes and 2 to 3 drops of glacial acetic acid to produce series of compounds 5 in moderate yield according to the method reported in the literature [18]. Finally, a series of the target compounds 6 were obtained by the reaction of corresponding compounds 5 with (E)-methyl-2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate in the presence of base following the literature method [26]. The structures of the desired compounds were confirmed by 1H NMR, 13C NMR, IR, and ESI-HRMS.

681364.sch.001
Scheme 1: Synthetic route of target compounds 6a6n. . C6H5; 6b. 4-CH3C6H4; 6c. 4-N(CH3)2C6H4; 6d. 2-OHC6H4; 6e. 3-OHC6H4; 6f. 4-OHC6H4; 6g. 2-NO2C6H4; 6h. 3-NO2C6H4; 6i. 4-NO2C6H4; 6j. 2-ClC6H4; 6k. 3-ClC6H4; 6l. 4-ClC6H4; 6m. 2, 4-Cl2C6H3; 6n. 3,4-Cl2C6H3.
3.2. Biological Evaluation

The fungicidal activities of the series of title compounds 6 were tested at a concentration of 50 μg  by a modified method described in the literature [27]. The five fungi used in the fungicidal bioassay, Rhizoctonia solani, Botrytis cinerea Pers., Fusarium graminearum, Cotton rhizoctoniosis, and Blumeria graminis, were tested by mycelium growth rate method. The commercial agricultural fungicide kresoxim-methyl was used as a standard.The results of preliminary bioassays are listed in Table 1.

The values listed in Table 1 clearly indicate that all the compounds do not exhibit good fungicidal activity against Cotton rhizoctoniosis at the concentration of 50 μg mL−1. However, the compounds 6g and 6j exhibited promising antifungal activity, inhibiting growth of Rhizoctonia solani at 48.96% and 47.91%, Botrytis cinerea Pers. at 62.73% and 60.45%, and Fusarium graminearum at 60.13% and 59.54%, respectively. However, the obtained values were still less than that of kresoxim-methyl (65.32% against Rhizoctonia solani, 81.69% against Botrytis cinerea Pers., and 73.36% against Fusarium graminearum at 50 μg mL−1). Moreover, compounds 6c, 6l, and 6m exhibited 91.41, 92.13, and 91.77% inhibitory activity against Blumeria graminis, respectively.

Interestingly, the fungicidal activities of the synthesized compounds 6 were influenced by the position of substituted group on the benzene ring. The sequence of fungicidal activity against Rhizoctonia solani, Botrytis cinerea Pers., and Fusarium graminearum was as follows: o-substituted-benzylidene derivatives > m-substituted-benzylidene derivatives p-substituted- benzylidene derivatives. Surprisingly, for the p-substituted benzylidene, the fungicidal activity against Blumeria graminis was significantly enhanced.

4. Conclusion

A series of novel (E)-α-methoxyimino-benzeneacetate derivatives were synthesized. They were characterized by IR, 1H NMR, 13C NMR, and ESI-HRMS. All the synthesized compounds were screened for their antifungal activity by mycelium growth rate method. The antifungal tests indicated that compounds 6g and 6j exhibited promising antifungal activity against Rhizoctonia solani, Botrytis cinerea Pers., and Fusarium graminearum. Moreover, compounds 6c, 6l, and 6m exhibited higher fungicidal activities against Blumeria graminis. Therefore, this study demonstrated that methoxyiminoacetate derivatives containing 1,2,4-triazole Schiff base side chain acted as promising candidates for developing novel fungicides. This study provides an impetus to the further exploration of antifungal compounds. Further research involving design, synthesis, and structure optimizations is still in progress.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

The authors would like to thank the Hebei Natural Science Foundation (B2012201053) for financial support.

References

  1. T. Anke, F. Oberwinkler, W. Steglich, and G. Schramm, “The strobilurins: new antifungal antibiotics from the basidiomycete Strobilurus tenacellus (Pers. ex Fr.) Sing.,” Journal of Antibiotics, vol. 30, no. 10, pp. 806–810, 1977. View at Publisher · View at Google Scholar · View at Scopus
  2. W. F. Becker, G. Von Jagow, T. Anke, and W. Steglich, “Oudemansin, strobilurin A, strobilurin B and myxothiazol: new inhibitors of the bc1 segment of the respiratory chain with an E-β-methoxyacrylate system as common structural element,” The FEBS Letters, vol. 132, no. 2, pp. 329–333, 1981. View at Publisher · View at Google Scholar · View at Scopus
  3. X. J. Yan, S. H. Jin, F. H. Chen, and D. Q. Wang, “Advance in research of the target of action of strobilurin fungicides,” Journal of Pesticide Science, vol. 8, no. 3, pp. 299–305, 2006. View at Google Scholar
  4. Y. Li, H. Q. Zhang, J. Liu, X. P. Yang, and Z. J. Liu, “Stereoselective synthesis and antifungal activities of (E)-α-(methoxyimino)benzeneacetate derivatives containing 1,3,5-substituted pyrazole ring,” Journal of Agricultural and Food Chemistry, vol. 54, no. 10, pp. 3636–3640, 2006. View at Publisher · View at Google Scholar · View at Scopus
  5. Y. Li, J. Liu, H. Zhang, X. Yang, and Z. Liu, “Stereoselective synthesis and fungicidal activities of (E)-α-(methoxyimino)-benzeneacetate derivatives containing 1,3,4-oxadiazole ring,” Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 8, pp. 2278–2282, 2006. View at Publisher · View at Google Scholar · View at Scopus
  6. W. Huang, P.-L. Zhao, C.-L. Liu, Q. Chen, Z.-M. Liu, and G.-F. Yang, “Design, synthesis, and fungicidal activities of new strobilurin derivatives,” Journal of Agricultural and Food Chemistry, vol. 55, no. 8, pp. 3004–3010, 2007. View at Publisher · View at Google Scholar · View at Scopus
  7. D. W. Bartlett, J. M. Clough, J. R. Godwin, A. A. Hall, M. Hamer, and B. Parr-Dobrzanski, “The strobilurin fungicides,” Pest Management Science, vol. 58, no. 7, pp. 649–662, 2002. View at Publisher · View at Google Scholar · View at Scopus
  8. U. Gisi, H. Sierotzki, A. Cook, and A. McCaffery, “Mechanisms influencing the evolution of resistance to Qo inhibitor fungicides,” Pest Management Science, vol. 58, no. 9, pp. 859–867, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. H. Sierotzki, S. Parisi, U. Steinfeld, I. Tenzer, S. Poirey, and U. Gisi, “Mode of resistance to respiration inhibitors at the cytochrome bc1 enzyme complex of Mycosphaerella fijiensis field isolates,” Pest Management Science, vol. 56, no. 10, pp. 833–841, 2000. View at Google Scholar
  10. N. Fisher and B. Meunier, “Re-examination of inhibitor resistance conferred by Qo-site mutations in cytochrome b using yeast as a model system,” Pest Management Science, vol. 61, no. 10, pp. 973–978, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. Z. Ma, D. Felts, and T. J. Michailides, “Resistance to azoxystrobin in Alternaria isolates from pistachio in California,” Pesticide Biochemistry and Physiology, vol. 77, no. 2, pp. 66–74, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. A. P. Liu, X. G. Wang, X. M. Ou et al., “Synthesis and fungicidal activities of novel bis(trifluoromethyl)phenyl- based strobilurins,” Journal of Agricultural and Food Chemistry, vol. 56, no. 15, pp. 6562–6566, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. X. L. Zhu, F. Wang, H. Li, W. C. Yang, Q. Chen, and G. F. Yang, “Design, synthesis, and bioevaluation of novel strobilurin derivatives,” Chinese Journal of Chemistry, vol. 30, no. 9, pp. 1999–2008, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. X. Zhang, H. Liu, Y. Gao, H. Wang, B. Guo, and J. Li, “Synthesis and antifungal activities of new type β-methoxyacrylate- based strobilurin analogues,” Chinese Journal of Chemistry, vol. 30, no. 7, pp. 1517–1524, 2012. View at Publisher · View at Google Scholar · View at Scopus
  15. B. F. Abdel-Wahab, E. Abdel-Latif, H. A. Mohamed, and G. E. A. Awad, “Design and synthesis of new 4-pyrazolin-3-yl-1,2,3-triazoles and 1,2,3-triazol-4-yl-pyrazolin-1-ylthiazoles as potential antimicrobial agents,” European Journal of Medicinal Chemistry, vol. 52, no. 3, pp. 263–268, 2012. View at Publisher · View at Google Scholar · View at Scopus
  16. A. Almasirad, S. A. Tabatabai, M. Faizi et al., “Synthesis and anticonvulsant activity of new 2-substituted-5-[2-(2- fluorophenoxy)phenyl]-1,3,4-oxadiazoles and 1,2,4-triazoles,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 24, pp. 6057–6059, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. B. Wang, X. Liu, X. Zhang, J. Zhang, H. Song, and Z. Li, “Synthesis, structure and biological activity of novel 1,2,4-triazole Mannich bases containing a substituted benzylpiperazine moiety,” Chemical Biology and Drug Design, vol. 78, no. 1, pp. 42–49, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. P.-L. Zhao, A.-N. Duan, M. Zou, H.-K. Yang, W.-W. You, and S.-G. Wu, “Synthesis and cytotoxicity of 3,4-disubstituted-5-(3,4,5-trimethoxyphenyl)- 4H-1,2,4-triazoles and novel 5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazole derivatives bearing 3,4,5-trimethoxyphenyl moiety,” Bioorganic & Medicinal Chemistry Letters, vol. 22, no. 13, pp. 4471–4474, 2012. View at Publisher · View at Google Scholar · View at Scopus
  19. Z. J. Fan, Z. K. Yang, H. K. Zhang et al., “Synthesis, crystal structure, and biological activity of 4-methyl-1,2,3-thiadiazole-containing 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles,” Journal of Agricultural and Food Chemistry, vol. 58, no. 5, pp. 2630–2636, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. Z. Xiong, H. Li, N. Liang, J. Yin, P. Lu, and W. Xue, “Synthesis and bioactivity of three-ring heterocyclic Schiff base derivatives,” Chinese Journal of Organic Chemistry, vol. 32, no. 8, pp. 1473–1478, 2012. View at Publisher · View at Google Scholar · View at Scopus
  21. Q. Z. Li, B. A. Song, X. J. Cai, Y. G. Zheng, and Q. Q. Guo, “Synthesis and bioactivities of novel N-1,2,4-Triazole moieties imines containing fluorocinnamylidene,” Chinese Journal of Organic Chemistry, vol. 30, no. 4, pp. 569–575, 2010. View at Google Scholar · View at Scopus
  22. B. N. Prasanna Kumar, K. N. Mohana, and L. Mallesha, “Synthesis and antiproliferative activity of some new fluorinated Schiff bases derived from 1, 2, 4-triazoles,” Journal of Fluorine Chemistry, vol. 156, no. 12, pp. 15–20, 2013. View at Google Scholar
  23. A. R. Jalilian, S. Sattari, M. Bineshmarvasti, A. Shafiee, and M. Daneshtalab, “Synthesis and in vitro antifungal and cytotoxicity evaluation of thiazolo-4H-1,” 4-triazoles , Archiv der Pharmazie, vol. 333, no. 10, pp. 347–354, 2000. View at Google Scholar
  24. A. Shafiee, I. Lalezari, M. Mirrashed, and D. Nercesian, “1,2,3-Selenadiazolyl-1,3,4- oxadiazole , 1, 2, 3-thiadiazolyl-1,3,4-oxadiazole and 5-(1,2,3-thiadiazolyl)-s- triazolo [3,4-b]- 1,3,4- thiadiazole,” Journal of Heterocyclic Chemistry, vol. 14, no. 4, pp. 567–571, 1977. View at Google Scholar
  25. R. R. Jack and D. H. Ned, “Improved synthesis of 5-substituted-4-amino-3-mercapto (4H)-1, 2, 4- traiazoles,” Journal of Heterocyclic Chemistry, vol. 13, no. 4, pp. 925–926, 1976. View at Google Scholar
  26. M. Li, C. Liu, J.-C. Yang, J. O. Zhang, Z. Li, and H. Zhang, “Synthesis and biological activity of new (E)-α-(Methoxyimino) benzeneacetate derivatives containing a substituted pyrazole ring,” Journal of Agricultural and Food Chemistry, vol. 58, no. 5, pp. 2664–2667, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. J. Wilamowski, E. Kulig, J. J. Sepio, and Z. J. Burgie, “Synthesis and in vitro antifungal activity of 1-amino-3,4-dialkylnaphthalene-2-carbonitriles and their analogues,” Pest Management Science, vol. 57, no. 7, pp. 625–632, 2001. View at Publisher · View at Google Scholar · View at Scopus