• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Synthesis, Crystal Structure and Biological Activity of 2-(3,4-Dichloroisothiazol-5-yl)-4-(trifluoromethyl)-4,5-dihydrothiazol-4-yl-3-methylbenzoate①

    2015-07-18 11:14:50ZONGGungNingLIFengYunFANZhiJinMAOWuToSONGHiBinCHENLiZHUYuJieXUJingHuSONGYinQiWANGJiRnStteKeyLortoryofElementoorgnicChemistryCollortiveInnovtionCenterofChemiclSciencendEngineeringTinjinNnkiUniversityTinjin300071Chin
    結(jié)構(gòu)化學(xué) 2015年6期

    ZONG Gung-NingLI Feng-YunFAN Zhi-Jin②MAO Wu-ToSONG Hi-BinCHEN LiZHU Yu-JieXU Jing-HuSONG Yin-QiWANG Ji-Rn(Stte Key Lortory of Elemento-orgnic Chemistry, Collortive Innovtion Center of Chemicl Science nd Engineering (Tinjin), Nnki University, Tinjin 300071, Chin)(College of Chemistry nd Phrmcy Engineering, Nnyng Norml University, Nnyng, Henn 473061, Chin)

    Synthesis, Crystal Structure and Biological Activity of 2-(3,4-Dichloroisothiazol-5-yl)-4-(trifluoromethyl)-4,5-dihydrothiazol-4-yl-3-methylbenzoate①

    ZONG Guang-NingaLI Feng-YunaFAN Zhi-Jina②MAO Wu-TaobSONG Hai-BinaCHEN LaiaZHU Yu-JieaXU Jing-HuaaSONG Yin-QiaWANG Jia-Ranaa(State Key Laboratory of Elemento-organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China)b(College of Chemistry and Pharmacy Engineering, Nanyang Normal University, Nanyang, Henan 473061, China)

    The title compound diethyl 2-(3,4-dichloroisothiazol-5-yl)-4-(trifluoromethyl)-4,5-dihydrothiazol-4-yl-3-methylbenzoate (C15H9Cl2F3N2O2S2, Mr= 441.26) was prepared from methyl 3,4-dichloroisothiazole-5-carboxylate as the starting material by four steps of reaction.Its structure was characterized by IR,1H-NMR,13C-NMR, EA and single-crystal X-ray diffraction.The crystal of the title compound belongs to the monoclinic system, space group P21/c with a = 8.8437(18), b = 16.128(3), c = 12.305(3) ?, β = 91.68(3)o, V = 1754.4(6) ?3, Z = 4, Dc= 1.671 g/cm3, μ(MoKa) = 0.71073 mm-1, F(000) = 888, R = 0.0384 and wR = 0.0778.Weak π-π interactions occur between the isothiazole rings and phenyl rings of adjacent molecules to form a one-dimensional chain and stabilize the crystal structure.Bioassay indicates that the title compound has good activity against the fungi and TMV tested.

    isothiazole, 4,5-dihydrothiazole, synthesis, crystal structure, biological activity;

    1 INTRODUCTION

    Aggressive pathogens cause disease and great losses in agriculture all over the world[1].A great amount of fungicides are used to control plant disease every year.In contrast to traditional fungicide, plant elicitors induce systemic acquired resistance of host plant against abroad spectrum of disease without direct activities against pathogens itself[2-4].Heterocyclic compounds have various biological activities[5,6].Isotianil, a derivative of isothiazole-5-carboxylic acid, is a novel plant elicitor with broad spectrum of diseases controlling effects by cooperating with other fungicides or insecticides[7-9].Isothiazole and their derivatives present a wide range of biological activities including insecticidal activity[10,11], fungicidal activity[7,12], herbicidal activity[13], and systemic acquired resistance[3].Some isothiazoles also present pharmaceutical activity as of acyl guanidine inhibitors[14],antiglycation reagents[15]and dual functional inhibitors[16].

    Phytoalexins are antimicrobial substances produced by plants in response to infection or stress with low molecular weight[17].Types of phytoalexins produced by crucifers have good fungicidal activity, which have unique structures containing isothiazole or thiazole related rings and at least one sulfur atom, for example spirobrassinin[18].Research revealed that the heterocyclic ring with 4,5-dihydrothiazole of spirobrassinin and its analogs played a key role in keeping the antifungal activity[19,20].Some compounds bearing the 4,5-dihydrothiazole ring showed broad-spectrum biological activity[21].A series of substituted 2-(pyridin-3-yl)-4-(trifluoromethyl)-4,5-dihydrothiazol-4-yl benzoates has been found as potential fungicidal chemicals with good activity[22].

    Another type of heterocyclic compounds 2-(3,4-dichloroisothiazol-5-yl)-4-(trifluoromethyl)-4,5-dihydrothiazol-4-yl-3-methylbenzoate with active substructures of 3,4-dichloroisothiazole and 4,5-dihydrothiazole moieties were designed and synthesized here according to the principle of pesticide designation and the description in Scheme 1[2], and their crystal structure and activity were also evaluated.

    Scheme 1.Schematic structure and synthesis of the target compound

    2 EXPERIMENTAL

    All reagents and solvents for synthesis and analyses were of analytical grade and used without further purification.Column chromatography purification was carried out by using silica gel (200~300) with ethyl acetate and petroleum ether as eluent.The melting point was measured on an X-4 binocular microscope (Gongyi Tech.Instrument Co., Henan, China), and the temperature was not corrected.Infrared (IR) spectra were recorded on a Bruker Vector 22 Fourier transform infrared (FTIR) spectrometer using KBr pellets.Hydrogen Nuclear Magnetic Resonance (1H NMR) spectra were measured at 400 MHz using a Bruker AV-400 spectrometer with deutero-chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.Elemental analyses (EA) data were obtained on a Vario EL CUBE instrument made by German.The single-crystal structure was determined on a Rigaku Saturn 724 CCD diffractometer.The equipment was operated using Mo-Kα radiation (λ = 0.71073 ?).

    2.1 Synthesis

    Intermediate 4 was synthesized by a three-step process (Scheme 1).White solid, 3,4-dichloroisothiazole- 5-carboxamide, 2 was synthesized from 2.12 g (10 mmol) ethyl methyl 3,4-dichloroisothiazole-5-carboxylate 1 via an aminolysis reaction at room temperature in a good yield (96%);1H NMR(400 MHz, DMSO-d6): δ 8.35 (s, br, 1H), 8.08 (s, br, 1H).Lawson’s reagent (2.42 g, 6 mmol) was added to a solution of compound 2 (1.97 g, 10 mmol) in anhydrous toluene (50 mL).After refluxing for 3 hours and concentrated under reduced pressure, the obtained residue was purified by chromatography on silica gel (petroleum ether : ethyl acetate, 3:1, v/v) to give a white solid, 3,4-dichloroisothiazole-5-carbothioamide 3;1H NMR(400 MHz, CDCl3): δ 6.80 (s, br, 1H), 6.24 (s, br, 1H).A solution of compound 3 (1.0 g, 5.0 mmol) and 3-bromo-1,1,1-trifluoropropan-2-one (1.0 g, 5.0 mmol) in anhydrousethanol (20 mL) was refluxed and stirred for 16 h.After concentration under reduced pressure, the residue was purified by chromatography on silica gel (petroleum ether : ethyl acetate, 10:1, v/v) to give a yellow solid, 2-(3,4-dichloroisothiazol-5-yl)-4-(trifluoromethyl)-4,5-dihydrothiazol-4-ol 4;1H NMR (400 MHz, CDCl3): δ 3.76 (dd, J=54.5 Hz, 10.2 Hz, 2H), 3.65(s, 1H).

    To a stirred solution of compound 4 (0.32 g, 1.0 mmol) and 3-methylbenzoyl chloride in anhydrous CH2Cl2(15 mL) at 0 ℃ was added triethylamine (0.15 g, 1.5 mmol) dropwise.After being wormed to ambient temperature gradually, the resulting mixture was stirred for about 10 h.Then, the reaction mixture was diluted with CH2Cl2(20 mL) and washed with aqueous HCl (2 mol/L), saturated aqueous NaHCO3and brine, and finally dried over anhydrous Na2SO4.After concentration, the crude product was purified by chromatography on silica gel using petroleum ether (60~90 ℃) and ethyl acetate (v/v = 10:1) as the eluent.The pure title compound was obtained as a white solid with the yield of 65%; m.p.: 100~102 ℃.IR (KBr pellet press, ν, cm-1): 2921 (CH3), 1741 (C=O), 1573(Ar, C=C), 1506(Ar, C=C), 1425(Ar, C=C).1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 5.7 Hz, 2H), 7.46 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 3.99 (s, 2H), 2.44 (s, 3H).13C NMR (101 MHz, CDCl3) δ 168.29 (s), 163.80 (s), 152.32 (s), 138.58 (s), 134.97 (s), 130.58 (s), 128.58 (s), 127.29 (s), 124.24 (s), 123.77 (s), 120.94 (s), 108.44~107.50 (q), 36.69 (s), 21.27 (s).EA clacd.for C15H9Cl2F3N2O2S2: C, 40.83; H, 2.06; N, 6.35%.Found: C, 41.14; H, 2.08; N, 6.37%.

    2.2 Crystal data and structure determination

    The crystal of the target compound was cultivated from the mixture of ethyl acetate and dichloromethane with 1:1 (v/v).The colorless crystal of the title compound with dimensions of 0.20mm × 0.18mm × 0.12mm was selected and mounted on a glass fiber for X-ray diffraction analysis.All measurements were made on a Rigaku Saturn 724 CCD diffractometer MoKα radiation (λ = 0.71073 ?).The data were collected at 113(2) K and the crystal is of monoclinic system, space group P21/c, with a = 8.8437(18), b = 16.128(3), c = 12.305(3) ?, β = 91.68(3)o, V = 1754.4(6) ?3, Z = 4, density (calculated) = 1.671 g/cm3, and linear absorption coefficient 0.200 mm-1.In the range of 2.08≤θ≤27.90°, 17654 integrated reflections were collected, reduced to a data set of 4182 unique with Rint= 0.0384, and completeness of data (to theta = 25.02°) of 99.9%.Data were collected and processed using Crystal Clear (Rigaku).An empirical absorption correction was applied using Crystal Clear (Rigaku).The structure was solved by direct methods with the SHELXS-97 program[23].Refinements were done by the full-matrix least-squares on F2with SHELXL-97[24].All of the non-H atoms were refined anisotropically by full-matrix least-squares to give the final R = 0.0384 and wR = 0.0778 ((0.0310P)2+ 0.6562P], where P =with (Δ/σ)max= 0.004 and S = 1.036 by using the SHELXL program.The hydrogen atoms were located from a difference Fourier map and refined isotropically.The corrections for absorption was multi-scan, Tmin= 0.8808 and Tmax= 0.9259.

    2.3 Biological screening Fungicide screening

    Preliminary screening was conducted by fungi growth inhibition method according to the reference using potato dextrose agar (PDA) as cultivation medium[25].A stock solution of the target compound was prepared at 500 μg/mL using sterilized water containing 2 drops of N,N-dimethylformamide (DMF) as a solvent, then 1 mL of the stock solution was transferred into a 10 cm diameter of Petri dish.9 mL of PDA was then added to prepare the plate containing 50 μg/mL of the test compound.Before the plate solidification, the PDA was thoroughly mixed by turning around the Petri dish in the sterilized hood 5 times to scatter the compound in PDA evenly.Then, a fungi cake in 4 mm diameter was inoculated on the plate and cultured in the culture tank at 24~26 ℃.The diameter of fungi spread was measured 2 days later.Growth inhibitionwas then calculated using the corresponding control.Representative fungi used in this study included Alternaria solani (AS), Botrytis cinerea (BC), Cercospora arachidicola (CA), Gibberella zeae (GZ), Phytophthora infestans (Mont) de Bary (PI), Physalospora piricola (PP), Pellicularia sasakii (PS), Sclerotinia sclerotiorum (SS), and Rhizoctonia cerealis (RC).

    Insecticide activity of the target compound against Mythimna separata

    Insecticidal activity of the target compounds against M.separata was tested using the leaf-disk method[26,27].Fresh corn leaves were dipped into the 200 μg/mL test water solution for 10 s which was prepared with a 5% of acetone to help the compound dissolve.After air-drying for evaporating off the acetone and water, the treated leaves were cut into small pieces and placed in Petri dishes with a 10 cm diameter.Thirty individuals of M.separata were transferred into each Petri dish.The Petri dishes were finally fastened with rubber bands and placed in a standard cultivation room for 72 h at 25 ℃ with 80% humidity.The percentage of mortalities was evaluated according to the corresponding CK which uses water to dispose only.The insects having no reaction by touching with a brush pen were regarded as a death.

    Curative effect of the target compounds on TMV in vivo

    Healthy fresh tobacco plants at six-leaf stage were selected for the tests.TMV at a concentration of 5.88 × 10-2μg/mL was inoculated on the whole leaves using the conventional juice robbing method.After the leaves were dried in greenhouse, the compound solution (100 μg/mL) was smeared on the upper three leaves, and the solvent was smeared on the lower three leaves as control.The local lesion numbers were then recorded 2~3 days after inoculation.Three replicates were performed for the target compound, respectively.

    The activities of protection, inactivation, and curative effects against TMV were calculated by the average number of viral inflammations on the inoculated leaves with the corresponding control according to equation (1):

    Where Y is the antivirus inhibition ratio (protection, inactivation, and curative effects in vivo) (%), CK is the average number of viral inflammations on the control leaves in vivo, and A is the average number of viral inflammations on the target compound treated leaves in vivo.

    Protective effect of the target compound against TMV in vivo

    Healthy fresh tobacco plants at six-leaf stage were selected for the tests.The target compound solution (100 μg/mL) was smeared on the whole leaves, and then the leaves were dried in the greenhouse.After 12 h, TMV at a concentration of 5.88×10-2μg/mL was inoculated on the upper three leaves using the conventional juice robbing method, and the solvent was smeared on the lower three leaves as a control.The local lesion numbers were then recorded 2~3 days after inoculation.Three replicates were performed for the target compound, respectively.

    Inactivation effect of the target compounds against TMV in vivo

    Healthy fresh tobacco plants at six-leaf stage were selected for the tests.The TMV virus at a concentration of 5.88×10-2μg/mL was inhibited by mixing with the target compound solution (100 μg/mL) at the same volume for 30 min.Then the mixture was inoculated on the upper three leaves using the conventional juice robbing method, and the solvent was smeared on the lower three leaves as a control.The local lesion numbers were then recorded 2~3 days after inoculation.Three replicates were performed for the target compound, respectively.

    Screening for systemic acquired resistance

    Systemic acquired resistance of the target compound was detected using tobacco against the tobacco mosaic virus (TMV) system as described in Ref.2.The induction activity was evaluated using the antivirus inhibition ratio, which was calculatedby the average number of viral inflammations on the inoculated leaves with the corresponding control accordingly.Tiadinil, ribavirin and ningnanmycin were used as positive controls, respectively, and the target compound was tested at the concentration of 100 μg/mL.

    3 RESULTS AND DISCUSSION

    The molecular structure is shown in Fig.1.The selected bond lengths, bond angles and torsion angles are listed in Table 1.

    Fig.1.Molecular structure of the title compound shown as thermal probability

    Table 1.Selected Bond Lengths (?), Bond Angles (°) and Torsion Angles (°) for the Title Compound

    As shown in Table 1, bond lengths and bond angles within the isothiazole ring agree well with the values reported[28].The sum of N(2)–C(4)–C(3), N(2)–C(4)–S(2) and C(3)–C(4)–S(2) angles is 360°, indicating the sp2hybridization state of C(4) atom.The dihedral angle between the isothiazole ring and the plane formed by N(2), C(4) and S(2) atoms is 3.318(12)°, which indicates the existence of strong conjugative effect between the imine group including S(2) atom and isothiazole ring; due to this strong conjugative effect, the bond length of C(3)–C(4) is 1.467(3) ?, which is slightly shorter than that of a typical C–C bond (1.53 ?)[29].The torsion angles of C(6)–N(2)–C(4)–S(2) and C(5)–S(2)–C(4)–N(2) are 1.4(2) and 1.02(17)°, respectively, indicating the obvious distortion of the non-aromatic 4,5-dihydrothiazole ring; it is very interesting that, all five atoms of the 4,5-dihydrothiazole ring almost exist coplanar.In the crystal structure, because of sp3hybridization state of the C(6) atom, the stable conformation of the molecule looks like a “L” in Fig.1.Owing to the p-πconjugate effect, the bond lengths of S(1)–C(3) and O(1)–C(8) are 1.7138(19) and 1.370(3) ?, respectively, which are much shorter than that of the S(2)–C(5) (1.810(2) ?) and O(1)–C(6) (1.437(2) ?) bonds.Due to the π-π conjugation of phenyl ring and the carbonyl group at C(9)–C(8)–O(2), the bond length of C(8)=O(2) (1.204(2) ?) is slightly shorter than that of the normal C=O bond (1.22 ?)[30].Not only weak π-π interactions occur between the isothiazole and phenyl rings of the adjacent molecules, but also exist between isothiazole and isothiazole rings, phenyl and phenyl rings of the adjacent molecules, which form a one-dimensional chain structure (Fig.2).

    Fig.2.Crystal packing of the title compound

    Table 2.Fungicidal Activity of the Title Compound (Inhibition Rate, %, 50 μg/mL)

    Table 3.Antiviral Activity of the Title Compound against Tobacco Mosaic Virus (%, 100 μg/mL)±SD

    4 BIOLOGICAL ACTIVITY

    The inhibition effects of the title compound against nine typical fungi were tested.The results as compared with commercialized azoxystrobin are shown in Table 2.The preliminary screening results indicated that the title compound presents good fungicidal activity against GZ, BC and PS with the inhibition rates of 82.35%, 87.18% and 87.95%, respectively, which is higher than that of the azoxystrobin.The title compound also possesses good fungicidal activity against PP, SS and RC with the inhibition rates of 91.03%, 95.77% and 88.10%, respectively, equal to that of azoxystrobin.Furthermore, the title compound showed a potential fungicidal activity with broad-spectrum as above 48% of the inhibition rate against nine fungi.Screening against TMV of the title compound was conducted for protection, inactivation, and curative effect and induction activities in vivo (Table 3).The induction of systemic acquired resistance for tobacco against tobacco mosaic virus (TMV) determination was also detected under the concentration of 100 μg/mL according to the reported reference[2].The result indicated that the title compound had a good antiviral activity as comparedwith the positive controls tiadinil, ribavirin and ningnanmycin, especially it has moderate degree of induction effect with 39.64% of the activity.This is higher than that of ribavirin (23.87%) and ningnanmycin (17.57 %), which is almost equal to that of TDL at 100 μg/mL; moreover, the curative effect is higher than that of ningnanmycin (28.89%) and tiadinil (14.67%); however, inactivation and protection effects were lower than ningnanmycin.The larvicidal activity of the target compound against M.separata was tested by leaf disk method[26,27], and the insect mortality was 35% at 200 μg/mL.The result demonstrated that the title compound had certain extent of insecticidal activity.

    As discussed above, the isothiazole title compound was designed by the principle of combination of bioactive substructure with four steps.The X-ray diffraction confirmed its structure.Bioassay results indicated that the title compound was a good pesticide lead with various biological activities.Dihydrothiazole group will be derived with other sulfur containing heterocycles to enhance its biological activity.

    REFERENCES

    (1) Bos, L.Crop losses caused by viruses.Crop Prot.1982, 1, 263–282.

    (2) Fan, Z.J.; Shi, Z.G.; Zhang, H.K.; Liu, X.F.; Bao, L.L.; Ma, L.; Zuo, X.; Zheng, Q.X.; Mi, N.Synthesis and biological activity evaluation of 1,2,3-thiadiazole derivatives as potential elicitors with highly systemic acquired resistance.J.Agric.Food Chem.2009, 57, 4279–4286.

    (3) Chen, X.Y.; Dai, L.Y.; Li, Y.D.; Mao, W.T.; Fang, Z.; Li, J.J.; Wang, D.; Tatiana, K.; Fan, Z.J.Synthesis and biological activity of 3,4-dichloroisothiazole-5-carboxylic amides.Chin.J.Pest.Sci.2013, 15, 140–144.

    (4) Guo, D.D.; Wang, Z.W.; Fan, Z.J.; Zhao, H.; Zhang, W.; Cheng, J.G.; Yang, J.Q.; Wu, Q.J.; Zhang, Y.J.; Fan, Q.Synthesis, bioactivities and structure activity relationship of N-4-methyl-1,2,3-thiadiazole-5-carbonyl-N?-phenyl ureas.Chin.J.Chem.2012, 30, 2522–2532.

    (5) Hua, X.W.; Mao, W.T.; Fan, Z.J.; Ji, X.T.; Li, F.Y.; Zong, G.N.; Song, H.B.; Li, J.J.; Zhou, L.K.; Zhou, L.F.; Liang, X.W.; Wang, G.H.; Chen, X.Y.Novel anthranilic diamide insecticides: design, synthesis, and insecticidal evaluation.Aust.J.Chem.2014, 67, 1491–1503.

    (6) Kalinina T.A.; Shakhmina Y.S.; Glukhareva T.V.; Morzherin Y.Y.; Fan Z.J.; Borzenkova, R.A.; Skolobanova, E.S.; Kiseleva, I.S.1,2,3-Thiadiazolyl isocyanates in the synthesis of biologically active compounds.Study of the cytotoxic activity of N-(4-methyl-1,2,3-thiadi-azolyl-5-yl)-N'-(4-methylphenyl)urea.Chem.Heterocycl.Comp.2014, 50, 1039–1046.

    (7) Assmann, L.; Elbe, H.L.; Kuhnt, D.; Hanssler, G.; Kuck, K.H.; Kitagawa, Y.; Sawada, H.; Sakuma, H.Isothiazole carboxylic acid amides.WO2000015622 2000.

    (8) Dahmen, P.; Wachendorff-Neumann, U.; Pontzen, R.; Abmann, L.; Sawada, H.Fungicidal active substance combinations.WO2005009130 2005.

    (9) Dahmen, P.; Wachendorff-Neumann, U.; Pontzen, R.; Abmann, L.; Sawada, H.Active compound combinations.EP 2070413 2009.

    (10) Pilkington, B.L.; Armstrong, S.; Barrens, N.J.; Barnett, S.P.; Clarke, E.D.; Fraser, T.E.; Hughes, D.J.; Mathews, C.J.; Salmon, R.; Smith, S.C.; Viner, R.; Whittingham, W.G.; Williams, J.; Whittle, A.J.; Mound, W.R.; Urch, C.J.; Crowley, P.J.Isothiazole derivatives and their use as pesticides.EP1686128 2006.

    (11) Watanabe, Y.; Yamszakid, D.; Otsu, Y.; Shibuya, K.Isothiazolylaminocarbonyl derivatives as pesticides.WO2003051123 2003.

    (12) Yoshikawa, Y.; Kawashimah, H.; Tomitanik, K.; Inami, S.; Tomura, N.; Kishi, A.Preparation of isothiazolecarboxylic acid derivatives as agrochemical fungicides.JP08277277 1996.

    (13) Armstrony, S.; Barnes, N.J.; Barnett, S.P.; Clarke, E.D.; Crowley, P.J.; Fraser, T.E.M.; Hughes, D.J.; Mathews, C.J.; Salmom, R.; Smith, S.C.; Viner, R.; Whittingham, W.G.; Williams, J.; Whittle, A.J.; Mound, W.R.; Urch, C.J.Isothiazole derivatives and their use as pesticides.WO2001055140 2001.

    (14) Gerritz, S.W.; Zhai, W.X.; Shi, S.H.; Zhu, S.R.; Toyn, J.H.; Meredith, J.E.; Iben, L.G.; Burton, C.R.; Albright, C.F.; Good, A.C.; Tebben, A.J.; Muckelbauer, J.K.; Camac, D.M.; Metzler, W.; Cook, L.S.; Padmanabha, R.; Lentz, K.A.; Sofia, M.J.; Poss, M.A.; Macor, J.E.; Thompson, L.A.Acyl guanidine inhibitors of β-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis.J.Med.Chem.2012, 55, 9208?9223.

    (15) Sharma, A.; Suhas, R.; Gowda, D.C.Ureas/thioureas of benzo[d]isothiazole analog conjugated glutamic acid: synthesis and biological evaluation.Arch.Pharm.Chem.Life Sci.2013, 346, 359–366.

    (16) Shang, E.C.; Wu, Y.R.; Liu, P.; Liu, Y.; Zhu, W.; Deng, X.B.; He, C.; He, S.; Li, C.; Lai, L.H.Benzo[d]isothiazole 1,1-dioxide derivatives as dual functional inhibitors of 5-lipoxygenase and microsomal prostaglandin E2synthase-1.Bioorg.Med.Chem.Lett.2014, 24, 2764–2767.

    (17) Jeandet, P.; Clément, C.; Courot, E.; Cordelier, S.Modulation of phytoalexin biosynthesis in engineered plants for disease resistance.Int.J.Mol.Sci.2013, 14, 14136–14170.

    (18) Monde, K.; Osawa, S.; Harada, N.; Takasugi, M.; Suchy, M.; Kutschy, P.; Dzurill, M.Synthesis and absolute stereochemisty of a cruciferous phytoalexin, (?)-spirobrassinin.Chem.Lett.2000, 8, 886–887.

    (19) Monde, K.; Taniguchi, T.; Miura, N.; Kutschy, P.; Curillova, Z.; Pilatova, M.; Mojzis, J.Chiral cruciferous phytoalexins: preparation, absolute configuration, and biological activity.Bioorg.Med.Chem.2005, 13, 5206–5212.

    (20) Pedras, M.S.C.; Hossain, M.Metabolism of crucifer phytoalexins in Sclerotinia sclerotiorum: detoxification of strongly antifungal compounds involves glucosylation.Org.Biomol.Chem.2006, 4, 2581–2590.

    (21) Hazra, A.B.; Han, Y.; Chatterjee, A.; Zhang, Y.; Lai, R.Y.; Ealick, S.E.; Begley, T.P.A missing enzyme in thiamin thiazole biosynthesis: identification of tenl as a thiazole tautomerase.J.Am.Chem.Soc.2011, 133, 9311–9319.

    (22) Mori, T.; Sato, J.; Matsunaga, A.Preparation of thiazoline compounds plant pest control agents containing them, and control of plant pest.JP2005330258 2005.

    (23) Sheldrick, G.M.SHELXS-97, Program for Solution of Crystal Structures.University of Gottingen, Germany 1997.

    (24) Sheldrick, G.M.SHELXL-97, Program for Crystal Structure Refinement.University of Gottingen, Germany 1997.

    (25) Fan, Z.J.; Yang, Z.K.; Zhang, H.K.; Mi, N.; Wang, H.; Cai, F.; Zuo, X.; Zheng Q.X.; Song, H.B.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.J.Agric.Food Chem.2010, 58, 2630–2636.

    (26) Xu, H.; Zhang, J.L.Natural products-based insecticidal agents 11.Synthesis and insecticidal activity of novel 4α-arylsulfonyloxybenzyloxy-2β-chloropodophyllotoxin derivatives against Mythimna separata walker in vivo.Bioorg.Med.Chem.Lett.2011, 21, 5177-5180.

    (27) Cui, J.; Li, M.L.; Yuan, M.S.Antifeedant activities of tutin and 7-hydroxycoumarin acylation derivatives against mythimna separate.J.Pestic.Sci.2012, 37, 95-98.

    (28) Yan, S.Q.; Appleby, T.; Gunic, E.; Shim, J.H.; Tasu, T.; Kim, H.; Yao, N.H.Isothiazoles as active-site inhibitors of HCV NS5B polymerase.Bioorg.Med.Chem.Lett.2007, 17, 28–33.

    (29) Gong, X.W.; Li, X.; Li, W.L.; Gao, X.; Xu, W.F.; Zhai, H.M.Synthesis and crystal structure of (E)-4-(benzyloxy)-2-(cinnamoyloxy)-N,N,N-trimethyl-4-oxobutan-1-aminium chloride as a double-prodrug.Chin.J.Struct.Chem.2008, 27, 177-182.

    (30) Alberth, L.; Matuesz, B.P.; Simon, J.C.; Gregory, J.R.; Stephen, P.D.; Mark, E.S.; John, V.H.; John, D.W.Models for incomplete nucleophilic attack on a protonated carbonyl group and electron-deficient alkenes: salts and zwitterions from 1-dimethylaminonaphthalene-8-carbaldehyde.Org.Biomol.Chem.2012, 10, 7763–7779.

    (31) Bondi, A.Van der waals volumes and radii.J.phys.Chem.1964, 68, 441–451.

    10.14102/j.cnki.0254-5861.2011-0598

    8 December 2014; accepted 31 March 2015 (CCDC 1028315)

    ① This study was funded in part by the Tianjin Natural Science Foundation (No.14JCYBJC20400), the "111" Project of Ministry of Education of China (No.B06005) and NFFTBS (No.J1103306)

    ② Corresponding author.Fan Zhi-Jin, born in 1968, professor.E-mail: fanzj@nankai.edu.cn

    亚洲欧洲国产日韩| 国产综合精华液| 一区二区三区乱码不卡18| 韩国高清视频一区二区三区| 少妇被粗大的猛进出69影院| 免费女性裸体啪啪无遮挡网站| 久久99精品国语久久久| 久久午夜综合久久蜜桃| 国产老妇伦熟女老妇高清| av线在线观看网站| 精品人妻熟女毛片av久久网站| 交换朋友夫妻互换小说| 日韩av免费高清视频| 美国免费a级毛片| 日韩中文字幕欧美一区二区 | 另类精品久久| 一本一本久久a久久精品综合妖精 国产伦在线观看视频一区 | 国产日韩一区二区三区精品不卡| 亚洲四区av| 日日啪夜夜爽| 99国产综合亚洲精品| 免费在线观看黄色视频的| 美女xxoo啪啪120秒动态图| 日韩 亚洲 欧美在线| 日日啪夜夜爽| 免费女性裸体啪啪无遮挡网站| 国产成人免费观看mmmm| 国语对白做爰xxxⅹ性视频网站| 三上悠亚av全集在线观看| 尾随美女入室| 亚洲熟女精品中文字幕| 啦啦啦视频在线资源免费观看| 成人二区视频| 欧美激情 高清一区二区三区| 天天躁夜夜躁狠狠久久av| 中文精品一卡2卡3卡4更新| 色播在线永久视频| 在线亚洲精品国产二区图片欧美| 久久女婷五月综合色啪小说| 搡女人真爽免费视频火全软件| 啦啦啦中文免费视频观看日本| 激情视频va一区二区三区| 久久亚洲国产成人精品v| 久久免费观看电影| 国产视频首页在线观看| 激情视频va一区二区三区| 热99久久久久精品小说推荐| 免费人妻精品一区二区三区视频| 我的亚洲天堂| 黄网站色视频无遮挡免费观看| 久久亚洲国产成人精品v| 亚洲精品久久久久久婷婷小说| 丰满乱子伦码专区| 国产日韩欧美视频二区| 亚洲,欧美,日韩| 欧美亚洲 丝袜 人妻 在线| 久久久精品94久久精品| 亚洲国产最新在线播放| 男女无遮挡免费网站观看| 久久精品国产亚洲av高清一级| 亚洲精品乱久久久久久| 成年人午夜在线观看视频| 亚洲欧美色中文字幕在线| 免费高清在线观看日韩| 成年女人毛片免费观看观看9 | 一本色道久久久久久精品综合| av国产久精品久网站免费入址| 欧美成人午夜免费资源| 狠狠婷婷综合久久久久久88av| 色吧在线观看| 超碰成人久久| 人妻 亚洲 视频| 一级片免费观看大全| 高清av免费在线| 亚洲一区中文字幕在线| 精品视频人人做人人爽| 老鸭窝网址在线观看| 久久久国产一区二区| 亚洲一区中文字幕在线| 亚洲,欧美精品.| 一级片免费观看大全| 亚洲欧洲精品一区二区精品久久久 | 久久人人爽av亚洲精品天堂| 999精品在线视频| 国产精品二区激情视频| 人人妻人人澡人人看| 久久韩国三级中文字幕| 99久久人妻综合| 国产精品一区二区在线观看99| 亚洲综合色惰| 欧美国产精品va在线观看不卡| 在线观看一区二区三区激情| 日韩av在线免费看完整版不卡| 男女高潮啪啪啪动态图| 国产精品久久久久久久久免| 成人亚洲精品一区在线观看| 大码成人一级视频| 国产黄色视频一区二区在线观看| 黄片小视频在线播放| 国产一区二区三区av在线| 日韩成人av中文字幕在线观看| 国产精品蜜桃在线观看| 精品国产露脸久久av麻豆| av免费在线看不卡| 老司机亚洲免费影院| 日韩视频在线欧美| 成人毛片a级毛片在线播放| 有码 亚洲区| 国产精品免费视频内射| 不卡视频在线观看欧美| 精品一区二区三区四区五区乱码 | 成人国语在线视频| 国产精品免费视频内射| 国产在线免费精品| 成人国产av品久久久| 午夜精品国产一区二区电影| 欧美日韩一区二区视频在线观看视频在线| 国产精品三级大全| 久热久热在线精品观看| 夫妻性生交免费视频一级片| 亚洲欧洲日产国产| 国产爽快片一区二区三区| 国产成人精品在线电影| 国产激情久久老熟女| 黄网站色视频无遮挡免费观看| 精品人妻熟女毛片av久久网站| 亚洲美女视频黄频| 下体分泌物呈黄色| 大香蕉久久网| 亚洲内射少妇av| a 毛片基地| 蜜桃在线观看..| 国产精品无大码| 日日摸夜夜添夜夜爱| 久久精品国产a三级三级三级| 香蕉丝袜av| 2018国产大陆天天弄谢| 久久久久精品性色| 黄色一级大片看看| 大片电影免费在线观看免费| 成人二区视频| 满18在线观看网站| 免费观看性生交大片5| 久久精品国产a三级三级三级| 亚洲欧美一区二区三区黑人 | 看免费成人av毛片| 国产麻豆69| 欧美 亚洲 国产 日韩一| 午夜免费观看性视频| 两性夫妻黄色片| 精品卡一卡二卡四卡免费| 亚洲欧美色中文字幕在线| 视频在线观看一区二区三区| 好男人视频免费观看在线| 欧美在线黄色| 日本av免费视频播放| 毛片一级片免费看久久久久| 久久久精品免费免费高清| 街头女战士在线观看网站| 啦啦啦视频在线资源免费观看| 波多野结衣av一区二区av| 永久免费av网站大全| 黄片播放在线免费| 在线观看一区二区三区激情| 婷婷色综合大香蕉| 国产在视频线精品| 欧美黄色片欧美黄色片| 免费播放大片免费观看视频在线观看| 最近手机中文字幕大全| 久久av网站| 亚洲伊人久久精品综合| 国产老妇伦熟女老妇高清| 亚洲,欧美精品.| 极品人妻少妇av视频| 777久久人妻少妇嫩草av网站| 十八禁网站网址无遮挡| 大码成人一级视频| 国产爽快片一区二区三区| 亚洲国产精品一区二区三区在线| 亚洲精品久久午夜乱码| 亚洲少妇的诱惑av| 亚洲精品日韩在线中文字幕| 大片免费播放器 马上看| 一区福利在线观看| 色婷婷av一区二区三区视频| 欧美日韩av久久| 亚洲国产日韩一区二区| 男女国产视频网站| 女人高潮潮喷娇喘18禁视频| 香蕉国产在线看| 亚洲欧美清纯卡通| 亚洲精品美女久久久久99蜜臀 | 日韩中字成人| 久久久久国产精品人妻一区二区| 亚洲人成77777在线视频| 大片电影免费在线观看免费| 久久精品国产鲁丝片午夜精品| 久久久亚洲精品成人影院| 人人妻人人添人人爽欧美一区卜| 精品视频人人做人人爽| 日日撸夜夜添| 婷婷色av中文字幕| 永久免费av网站大全| 一区二区三区四区激情视频| 蜜桃在线观看..| 色婷婷av一区二区三区视频| 欧美成人精品欧美一级黄| av.在线天堂| 中国国产av一级| 久久精品国产a三级三级三级| 精品人妻偷拍中文字幕| 亚洲色图综合在线观看| 欧美变态另类bdsm刘玥| 国产极品粉嫩免费观看在线| 麻豆乱淫一区二区| 欧美精品一区二区大全| 丰满少妇做爰视频| 欧美+日韩+精品| 精品午夜福利在线看| 久久久久久免费高清国产稀缺| 狠狠婷婷综合久久久久久88av| 综合色丁香网| 成人午夜精彩视频在线观看| 极品人妻少妇av视频| 国产日韩欧美视频二区| 成年美女黄网站色视频大全免费| 亚洲色图综合在线观看| 欧美老熟妇乱子伦牲交| 日产精品乱码卡一卡2卡三| 嫩草影院入口| 在线天堂中文资源库| 2018国产大陆天天弄谢| 久久久a久久爽久久v久久| 久久精品亚洲av国产电影网| 亚洲国产色片| 国产av码专区亚洲av| 亚洲av电影在线观看一区二区三区| 极品少妇高潮喷水抽搐| 五月伊人婷婷丁香| 少妇熟女欧美另类| 成人毛片60女人毛片免费| av在线播放精品| 美女午夜性视频免费| 男人操女人黄网站| 侵犯人妻中文字幕一二三四区| 美女高潮到喷水免费观看| 日本猛色少妇xxxxx猛交久久| 18禁动态无遮挡网站| 成人毛片60女人毛片免费| 毛片一级片免费看久久久久| a级片在线免费高清观看视频| av免费在线看不卡| 99久久人妻综合| 91国产中文字幕| 在现免费观看毛片| 国产精品一区二区在线观看99| 国产精品 欧美亚洲| 999久久久国产精品视频| 人成视频在线观看免费观看| 男男h啪啪无遮挡| 80岁老熟妇乱子伦牲交| 日韩大片免费观看网站| 国产精品一二三区在线看| 国产av码专区亚洲av| 成人漫画全彩无遮挡| 亚洲精品一区蜜桃| 免费高清在线观看视频在线观看| 美国免费a级毛片| 国产伦理片在线播放av一区| 高清av免费在线| 中文字幕亚洲精品专区| 久久久亚洲精品成人影院| 男男h啪啪无遮挡| 考比视频在线观看| 十分钟在线观看高清视频www| 天堂俺去俺来也www色官网| 成人亚洲欧美一区二区av| 久久久久人妻精品一区果冻| 亚洲第一av免费看| 最新中文字幕久久久久| 免费日韩欧美在线观看| 国产白丝娇喘喷水9色精品| 国产男女内射视频| 91成人精品电影| 汤姆久久久久久久影院中文字幕| 99九九在线精品视频| 秋霞伦理黄片| 18禁裸乳无遮挡动漫免费视频| 国产精品久久久久久久久免| 如日韩欧美国产精品一区二区三区| 777久久人妻少妇嫩草av网站| 久久久国产精品麻豆| 国产精品欧美亚洲77777| 久久人人97超碰香蕉20202| 母亲3免费完整高清在线观看 | 亚洲av在线观看美女高潮| 久久久亚洲精品成人影院| videossex国产| 国产伦理片在线播放av一区| √禁漫天堂资源中文www| 亚洲国产精品国产精品| 中文字幕人妻熟女乱码| 久久久精品区二区三区| av网站免费在线观看视频| 91精品伊人久久大香线蕉| 久久久欧美国产精品| 亚洲一级一片aⅴ在线观看| 黄色 视频免费看| 男的添女的下面高潮视频| 好男人视频免费观看在线| 在线精品无人区一区二区三| 中文字幕最新亚洲高清| 秋霞伦理黄片| 桃花免费在线播放| 亚洲美女搞黄在线观看| av免费观看日本| 曰老女人黄片| 国产av码专区亚洲av| 看免费av毛片| 另类亚洲欧美激情| 免费av中文字幕在线| 国产野战对白在线观看| 日本午夜av视频| 欧美日韩精品网址| 亚洲国产精品一区二区三区在线| 咕卡用的链子| 色网站视频免费| 人人澡人人妻人| 精品一区二区三卡| 精品一区二区免费观看| 精品99又大又爽又粗少妇毛片| 国产黄色免费在线视频| 黄色视频在线播放观看不卡| av.在线天堂| 久久国产亚洲av麻豆专区| 18禁国产床啪视频网站| 有码 亚洲区| videos熟女内射| 亚洲欧洲国产日韩| 久久久久久人人人人人| 制服诱惑二区| 国产亚洲一区二区精品| 亚洲av中文av极速乱| 亚洲精品国产av成人精品| 看免费成人av毛片| 国产精品一区二区在线不卡| 在线观看免费视频网站a站| 日韩制服骚丝袜av| 国产欧美日韩一区二区三区在线| 波多野结衣一区麻豆| 欧美精品亚洲一区二区| 国产女主播在线喷水免费视频网站| av不卡在线播放| 肉色欧美久久久久久久蜜桃| 99久国产av精品国产电影| 国产精品.久久久| 黄色毛片三级朝国网站| av有码第一页| 男男h啪啪无遮挡| 五月开心婷婷网| av国产精品久久久久影院| 亚洲精品美女久久久久99蜜臀 | 久久ye,这里只有精品| h视频一区二区三区| 2018国产大陆天天弄谢| 赤兔流量卡办理| www.精华液| 青春草视频在线免费观看| 少妇的丰满在线观看| 国产精品麻豆人妻色哟哟久久| 久久久久久伊人网av| 十八禁高潮呻吟视频| 性少妇av在线| 在线观看人妻少妇| 午夜激情久久久久久久| av视频免费观看在线观看| 免费久久久久久久精品成人欧美视频| 秋霞伦理黄片| 亚洲av电影在线观看一区二区三区| 熟女av电影| 久久久久人妻精品一区果冻| 国产探花极品一区二区| 毛片一级片免费看久久久久| 在线天堂最新版资源| 咕卡用的链子| 最近最新中文字幕大全免费视频 | 熟妇人妻不卡中文字幕| 性少妇av在线| 国产成人精品一,二区| 中文字幕色久视频| 日韩一区二区视频免费看| 欧美日韩亚洲国产一区二区在线观看 | 久久热在线av| 天堂8中文在线网| 国产成人一区二区在线| 中文字幕av电影在线播放| 成人免费观看视频高清| 国语对白做爰xxxⅹ性视频网站| 国产男女超爽视频在线观看| 热99国产精品久久久久久7| 亚洲一码二码三码区别大吗| 777久久人妻少妇嫩草av网站| 一级,二级,三级黄色视频| 亚洲精品第二区| 在线观看免费日韩欧美大片| 久久久久久久大尺度免费视频| 婷婷色综合大香蕉| 亚洲伊人色综图| 中国三级夫妇交换| 亚洲精品久久成人aⅴ小说| 色哟哟·www| 久久久精品免费免费高清| 久久ye,这里只有精品| 亚洲男人天堂网一区| 人人澡人人妻人| 看免费成人av毛片| 国产av国产精品国产| 亚洲成色77777| 色播在线永久视频| 寂寞人妻少妇视频99o| 欧美日韩av久久| 汤姆久久久久久久影院中文字幕| 国产精品蜜桃在线观看| av片东京热男人的天堂| 成年动漫av网址| 搡老乐熟女国产| 国产毛片在线视频| 中文字幕av电影在线播放| 波野结衣二区三区在线| 又黄又粗又硬又大视频| 天天操日日干夜夜撸| 黄色视频在线播放观看不卡| 91aial.com中文字幕在线观看| 晚上一个人看的免费电影| 午夜av观看不卡| 亚洲美女搞黄在线观看| 在线观看三级黄色| 熟女av电影| 国精品久久久久久国模美| 日韩熟女老妇一区二区性免费视频| 午夜老司机福利剧场| 成人毛片60女人毛片免费| 秋霞在线观看毛片| 日本午夜av视频| 亚洲国产精品国产精品| 日韩av免费高清视频| 熟女av电影| 久久97久久精品| 美女脱内裤让男人舔精品视频| 超碰成人久久| 日产精品乱码卡一卡2卡三| 女的被弄到高潮叫床怎么办| 国产精品亚洲av一区麻豆 | 亚洲一码二码三码区别大吗| 黄网站色视频无遮挡免费观看| 欧美日韩一级在线毛片| 国产精品久久久av美女十八| 午夜福利视频在线观看免费| 亚洲熟女精品中文字幕| 新久久久久国产一级毛片| 欧美日韩亚洲国产一区二区在线观看 | 黄色毛片三级朝国网站| 成年美女黄网站色视频大全免费| 精品少妇一区二区三区视频日本电影 | 边亲边吃奶的免费视频| 啦啦啦啦在线视频资源| 精品国产一区二区久久| 亚洲第一av免费看| 黑人欧美特级aaaaaa片| 久久久国产精品麻豆| 色婷婷久久久亚洲欧美| 这个男人来自地球电影免费观看 | 看十八女毛片水多多多| 中文字幕精品免费在线观看视频| 18在线观看网站| 亚洲精品国产av蜜桃| 久久久久视频综合| 国产成人午夜福利电影在线观看| 久久韩国三级中文字幕| 人成视频在线观看免费观看| 国产精品久久久久久久久免| 爱豆传媒免费全集在线观看| 亚洲,欧美精品.| 嫩草影院入口| 老鸭窝网址在线观看| 如何舔出高潮| 亚洲av福利一区| kizo精华| 精品国产国语对白av| 国产成人精品无人区| 久久久久久免费高清国产稀缺| 少妇人妻久久综合中文| 少妇的逼水好多| 一二三四中文在线观看免费高清| 天堂中文最新版在线下载| 麻豆精品久久久久久蜜桃| 免费在线观看黄色视频的| 欧美av亚洲av综合av国产av | 国产乱来视频区| 看非洲黑人一级黄片| 亚洲第一av免费看| 观看美女的网站| 国产熟女欧美一区二区| 免费黄色在线免费观看| 99热国产这里只有精品6| 亚洲国产毛片av蜜桃av| 中国国产av一级| 免费高清在线观看日韩| 亚洲五月色婷婷综合| 看非洲黑人一级黄片| 美女午夜性视频免费| 色视频在线一区二区三区| 在线天堂最新版资源| 少妇熟女欧美另类| 色婷婷av一区二区三区视频| kizo精华| 一区二区三区乱码不卡18| 18在线观看网站| 亚洲av在线观看美女高潮| 欧美国产精品一级二级三级| 国产成人精品福利久久| 久久国内精品自在自线图片| 亚洲精品,欧美精品| 新久久久久国产一级毛片| 久久久精品94久久精品| 亚洲av电影在线进入| 久久精品夜色国产| 日韩制服骚丝袜av| kizo精华| 欧美日韩国产mv在线观看视频| 日韩av在线免费看完整版不卡| 欧美成人午夜免费资源| 多毛熟女@视频| 国产成人精品福利久久| 亚洲国产色片| 亚洲欧美成人综合另类久久久| 人妻 亚洲 视频| 日日摸夜夜添夜夜爱| 欧美精品人与动牲交sv欧美| 伊人久久大香线蕉亚洲五| 午夜久久久在线观看| 亚洲国产日韩一区二区| 亚洲精品日本国产第一区| 日韩中字成人| 午夜免费观看性视频| 国产成人免费无遮挡视频| 电影成人av| 日韩制服丝袜自拍偷拍| √禁漫天堂资源中文www| 亚洲经典国产精华液单| 色婷婷久久久亚洲欧美| 观看av在线不卡| 久久婷婷青草| 99久久综合免费| 最新的欧美精品一区二区| videos熟女内射| 青春草亚洲视频在线观看| 色网站视频免费| 久久久精品区二区三区| 亚洲精品乱久久久久久| 国产在线视频一区二区| a 毛片基地| 视频区图区小说| 久热这里只有精品99| 王馨瑶露胸无遮挡在线观看| 丝袜人妻中文字幕| 999久久久国产精品视频| 午夜激情久久久久久久| 日韩熟女老妇一区二区性免费视频| 最近的中文字幕免费完整| 国产精品成人在线| 亚洲国产毛片av蜜桃av| av在线播放精品| 亚洲av欧美aⅴ国产| 免费黄网站久久成人精品| 国产亚洲最大av| 国产精品av久久久久免费| 秋霞在线观看毛片| 爱豆传媒免费全集在线观看| 久久久久国产网址| 水蜜桃什么品种好| 日日撸夜夜添| 精品人妻熟女毛片av久久网站| 老司机影院成人| 搡女人真爽免费视频火全软件| 欧美老熟妇乱子伦牲交| 高清欧美精品videossex| 日韩中字成人| 国产又色又爽无遮挡免| 精品国产国语对白av| 亚洲美女黄色视频免费看| 国产xxxxx性猛交| 最近中文字幕高清免费大全6| 精品福利永久在线观看| 黑人巨大精品欧美一区二区蜜桃| 中文字幕最新亚洲高清| 狠狠婷婷综合久久久久久88av| 中文字幕亚洲精品专区| 成人影院久久| 亚洲第一区二区三区不卡| 天天躁夜夜躁狠狠躁躁| 亚洲欧洲精品一区二区精品久久久 | 99re6热这里在线精品视频| 免费在线观看视频国产中文字幕亚洲 | 一边摸一边做爽爽视频免费| 日韩大片免费观看网站| 九草在线视频观看| www日本在线高清视频| 亚洲国产av新网站| 久久av网站| 成年人午夜在线观看视频| 亚洲伊人久久精品综合| 精品人妻熟女毛片av久久网站| 亚洲欧美中文字幕日韩二区| 国产精品秋霞免费鲁丝片|