Design, Synthesis, and Evaluation of New Sulfone Derivatives

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Agricultural and Environmental Chemistry

Design, Synthesis, and Evaluation of New Sulfone Derivatives Containing a 1,3,4-Oxadiazole Moiety as Active Antibacterial Agents Pei Li, De-Yu Hu, Dandan Xie, Jixiang Chen, Linhong Jin, and Song Baoan J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b06061 • Publication Date (Web): 05 Mar 2018 Downloaded from http://pubs.acs.org on March 5, 2018

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Journal of Agricultural and Food Chemistry

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Design, Synthesis, and Evaluation of New Sulfone Derivatives Containing a

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1,3,4-Oxadiazole Moiety as Active Antibacterial Agents

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Pei Li,†,‡ Deyu Hu,† Dandan Xie,† Jixiang Chen,† Linhong Jin,† Baoan Song†,*

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†

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Bioengineering; Key Laboratory of Green Pesticide and Agricultural Bioengineering,

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Ministry of Education; Research and Development Center for Fine Chemicals,

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Guizhou University, Guiyang 550025, P.R. China

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‡

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Utilization of National Medicine, Kaili University, Kaili 556011, P.R. China

State Key Laboratory Breeding Base of Green Pesticide and Agricultural

Qiandongnan Engineering and Technology Research Center for Comprehensive

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*Corresponding author: Tel.: +86(0851)362-0521. Fax: +86(0851)362-2211. E-mail:

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[email protected]

ACS Paragon Plus Environment


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ABSTRACT: This study aimed to synthesize some new sulfone derivatives

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containing a 1,3,4-oxadiazole moiety and investigate their in vitro antibacterial

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activities against Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas axonopodis

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pv. citri (Xac), the pathogens of rice bacterial leaf blight and citrus canker,

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respectively, by performing turbidimeter tests. Antibacterial-bioassay results showed

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that compound 6d revealed excellent bioactivities against Xoo and Xac, with the 50%

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effective concentration (EC50) values of 0.17 and 1.98 µg/mL, respectively, than

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thiodiazole copper (121.82 and 77.04 µg/mL, respectively) and bismerthiazol (92.61

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and 58.21 µg/mL, respectively). Meanwhile, greenhouse-condition trials indicated

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that, compared with thiodiazole copper and bismerthiazol, compound 6d more

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effectively reduced rice bacterial leaf blight.

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KEYWORDS: synthesis, antibacterial activity, sulfone derivative, 1,3,4-oxadiazole


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INTRODUCTION

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Rice bacterial leaf blight, a prevalent rice bacterial disease and caused by

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Xanthomonas oryzae pv. oryzae (Xoo), can affect rice plants at each growth stage and

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could result in leaf blight at tillering stage and up to 80% yield loss.1,2 Meanwhile,

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citrus canker, a devastating citrus disease and caused by Xanthomonas axonopodis pv.

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citri (Xac), could significantly affect the citrus production.3,4 The long-term use of

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available traditional bactericides, such as thiodiazole copper, bismerthiazol,

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zhongshengmycin, Zn thiazole, etc., not only leads to the drug resistance of bacterial

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populations but also results in a harmful influence on the safety of environment and

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plants.5 Therefore, new active antibacterial agents that possess a novel mechanism of

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action must be discovered and developed.

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Recent works have highlighted that the sulfone group, which has an ideal structure

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for developing agrochemicals and is found in many biologically active compounds,

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also exhibits various biological activities including antibacterial,6–15 antifungal,16–20

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antiviral,21,22 insecticidal,23 and herbicidal24 activities. Meanwhile, 1,3,4-oxadiazole

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ring, a common feature of medicinal agents, exhibits various biological activities,

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such

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herbicidal,32,33 and nematocidal25 activities. In our previous work, we investigated the

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biological properties of some series of sulfone derivatives containing a

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1,3,4-oxadiazole moiety, which, compared with commercial bactericides, showed

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better antibacterial activities against Ralstonia solanacearum (R. solanacearum), Xoo,

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Xac, and Xanthomonas oryzae pv. oryzicola (Xoc), however, the control efficiencies

as

antibacterial,6–15,25

antifungal,16–21

antiviral,21,22,26,27


insecticidal,28–31


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of the greenhouse conditions and field trials were unsatisfactory compared with

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commercial bactericides.7–9

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To extend our previous study and develop new lead compounds with highly

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bioactivity, in this study, we aimed to introduce a sulfone group into the 5-position of

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the 1,3,4-oxadiazole ring or introduce two sulfone groups into the 2,5-positions of the

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1,3,4-oxadiazole ring to build some new sulfone derivatives containing a

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1,3,4-oxadiazole moiety as active antibacterial agents.

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MATERIALS AND METHODS

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Instruments and Chemicals

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Melting points (uncorrected) were measured on an XT-4 micro-melting point

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apparatus (Beijing Tech. Instrument Co., China). Using TMS as an internal standard,

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1

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Tokyo, Japan) in DMSO-d6 or CDCl3. HRMS was conducted using a Q Exactive

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(Thermo Scientific, MO). TLC was used to monitor the chemical reactions and

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visualized under UV light at 254 nm. All reagents products from the Chinese

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Chemical Reagent Company were analytical or chemical pure.

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General Procedures for Preparing Intermediates 2–4

H and 13C NMR spectra were taken in a JEOL ECX-500 NMR spectrometer (JEOL,

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Using different substituted phenthiols as the starting materials, as shown in Figure

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1, intermediates 2–4 were prepared in four steps, namely, substitution, oxidation,

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hydrazidation, and cyclization reactions, according to previously reported methods.8,34

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The substitution reaction proceeded at a reflux temperature in the presence of

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different substituted phenthiols (0.01 mol) in acetonitrile (10 mL), ethyl chloroacetate


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(0.012 mol), and potassium carbonate (0.012 mol) within 6–8 h to obtain intermediate

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1. Using ethanol (10 mL) as the solvent, intermediate 1 (0.01 mol) was treated with 30%

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H2O2 (0.03 mol) and ammonium molybdate (0.5 mmol) to produce intermediate 2.

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Then, 80% hydrazine hydrate (0.015 mol) was added dropwise to intermediate 2

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dissolved in methanol. After refluxing for 6–8 h, the reaction was cooled down to

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room temperature to obtain intermediate 3. Then, to a 250 mL round bottom flask,

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intermediate 3 (0.01 mol) dissolved in ethanol (10 mL), KOH (0.02 mol) in distilled

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water (5 mL), and carbon disulfide (0.03 mol) were added and refluxed for 6–8 h.

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After that, the mixture was acidified with dilute HCl to pH 1–2. Finally, the crude

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products were filtered and recrystallized from ethanol to give intermediate 4.

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General Procedures for Preparing the Target Compounds 5a–5m

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To a 25 mL round bottom flask, intermediate 4 (0.01 mol), K2CO3 (0.012 mol),

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DMF (10 mL), and R2X (0.012 mol) were added. After reacting for 2–4 h at room

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temperature, the mixture was decanted into distilled water. The crude products were

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filtered or extracted using CH2Cl2, then recrystallized from ethanol or purified

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through column chromatography to obtain the pure target compounds 5a–5m with

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yields of 49–82%.

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General Procedures for Preparing the Target Compounds 6a–6h

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To a 25 mL round bottom flask, compound 5 (0.01 mol), acetic acid (10 mL), and

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ammonium molybdate (0.5 mmol) dissolved in 30% H2O2 (0.05 mol) were mixed and

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reacted for 1–3 h at room temperature. The mixture was decanted into distilled water

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and then the crude products were filtered or extracted using CH2Cl2. The crude



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products were recrystallized from ethanol or purified through column chromatography

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to obtain the pure target compounds 6a–6h with yields of 43–66%. The representative

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data for compound 6d are presented in the following.

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Data for 2-(methylsulfonyl)-5-(((4-fluorophenyl)sulfonyl)methyl)-1,3,4-oxadiazole

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(6d). White soil; m.p. 135–136 °C; yield, 46%; 1H NMR (500 MHz, DMSO-d6, ppm)

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δ: 7.88–7.86 (m, 2H, Ph-H), 7.76–7.73 (m, 2H, Ph-H), 5.59 (s, 2H, -CH2-), 3.63 (s,

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3H, -CH3); 13C NMR (125 MHz, DMSO-d6, ppm) δ: 163.92, 160.18, 140.57, 136.96,

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130.88, 130.27, 51.87, 43.21; HRMS (ESI) [M+H]+ calcd for C10H9ClN2O5S2:

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336.9714, found: 336.9713.

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In Vitro Antibacterial Activity Test

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In our present study, their in vitro antibacterial activities of the title compounds

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against Xoo and Xac were determined using the turbidimeter tests.35 To a 15 mL tube,

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4 mL of nutrient broth (NB) media, 1 mL of the test compounds or the commercial

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bactericides solution (final concentration: 200 and 100 µg/mL), and 40 µL Xoo or Xac

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bacterium solution were added. Then, the test tubes were incubated in a constant

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temperature shaker for 24–48 h at 180 rpm and 28 ± 1 °C. The optical density (OD595)

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of the NB media in each test tube was measured on a microplate reader (Model 680,

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BIO-RAD, Hercules, CA) until the bacteria in untreated NB media were at

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logarithmic growth. The in vitro inhibition rates I (%) are calculated as in the

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following formula, where C represents the corrected absorbance value (OD595) of the

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untreated NB media, T represents the corrected absorbance value (OD595) of the

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treated NB media.


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Inhibition rate I (%) = (C − T)/C × 100

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Based on the preliminary biological activity, the EC50 values were also determined

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and calculated via software SPSS 17.0 (SPSS Inc, Chicago, USA). Three times were

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repeated for each experiment.

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In Vivo Antibacterial Activity Test

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The curative and protection activities in potted plants of compound 6d against rice

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bacterial leaf blight were determined by Schaad’s method with some slight

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modifications.36 Bismerthiazol (20% wettable powder) and thiodiazole copper (20%

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suspending agent), the bactericides registered for rice bacterial leaf blight and

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purchased from the market, served as the positive controls.

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The curative activity in potted plants for reducing rice bacterial leaf blight of

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compound 6d was determined under controlled conditions in a greenhouse. After

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sowing the rice seeds of variety ‘Fengyouxiangzhan’ approximately 5 weeks, rice

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leaves were inoculated with Xoo, which was incubated at logarithmic growth, using

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sterilized scissors. One day after inoculation, compound 6d solution at 200 µg/mL

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was uniform sprayed onto the rice leaves until dripping down, whereas distilled water

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was uniform sprayed onto the negative control plants. Then, all the inoculated rice

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plants were placed in a plant growth chamber (28 °C and 90% RH). At 14 days after

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spraying, the disease index of the inoculated rice leaves was measured.

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Similarly, the protection activity in potted plants for reducing rice bacterial leaf

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blight of compound 6d was also conducted under controlled conditions in a

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greenhouse. After sowing the rice seeds of variety ‘Fengyouxiangzhan’ approximately



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5 weeks, compound 6d solution at 200 µg/mL was uniform sprayed onto the rice

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leaves until dripping down, whereas distilled water was uniform sprayed onto the

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negative control plants. One day after spraying, Xoo, which was incubated at

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logarithmic growth, was inoculated on the rice leaves using sterilized scissors. All the

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inoculated rice plants were placed in a growth chamber (28 °C and 90% RH). At 14

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days after inoculation, the disease index of the inoculated rice leaves was measured.

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The control efficiencies I (%) for the curative and protection activities are

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calculated as in the following equation. In the equation, C is the disease index of the

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negative control, and T is the disease index of the treatment group. Control efficiency I (%) = (C − T)/C × 100

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Statistical analysis was conducted by ANOVA with software SPSS 17.0 (SPSS Inc,

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Chicago, USA). Different uppercase letters following the control efficiency values

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indicate that there is significant difference (P < 0.05) among different treatment

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groups.

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RESULTS AND DISCUSSION

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Chemistry

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Using different substituted phenthiols as the starting materials, the target

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compounds 5a–5m were synthesized in five steps (Figure 1), namely, substitution,

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oxidation, hydrazidation, cyclization, and thioetherification reactions. Then, the target

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compounds 6a–6h were prepared through the oxidation reactions of the corresponding

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compound 5.

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In Vitro Antibacterial Activity


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The in vitro bioactivities of the target compounds 5a–5m and 6a–6h against Xoo

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and Xoc were determined by the turbidimeter tests, and the bioassay results are listed

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in Tables 1 and 2. As shown, all test compounds displayed moderate to good

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antibacterial activities against Xoo and Xac. Table 1 shows that compounds 5a, 5f, 5g,

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5h, 5j, 5k, 5l, 5m, 6a, 6b, 6c, 6d, 6e, 6f, 6g, and 6h exhibited excellent in vitro

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antibacterial activity (100%) against Xoo at concentrations of 200 and 100 µg/mL,

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which was superior to thiodiazole copper (64% and 43%, respectively) and

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bismerthiazol (72% and 54%, respectively). Table 2 shows that, at 200 and 100

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µg/mL, compounds 5a, 5f, 5g, 6a, 6b, 6c, 6d, 6e, 6f, 6g, and 6h displayed better in

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vitro antibacterial activity (100%) against Xac than bismerthiazol (89% and 72%).

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The EC50 values of the synthesized compounds were also determined based on the

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preliminary bioassay results and are presented in Tables 1 and 2. Table 1 shows that

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the target compounds displayed excellent in vitro antibacterial activities against Xoo,

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with EC50 values in the range of 0.17–45.78 µg/mL, which were superior to

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thiodiazole copper (121.82 µg/mL) and bismerthiazol (92.61 µg/mL). Meanwhile,

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Table 2 shows that the target compounds expressed moderate to good bioactivities

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(EC50 = 1.98–76.10 µg/mL) against Xac. In particular, compound 6d exhibited the

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best in vitro antibacterial activities against Xoo (EC50 = 0.17 µg/mL) and Xac (EC50 =

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1.98 µg/mL).

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In Vivo Antibacterial Activity

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Table 3 and Figure 2 indicate that compound 6d exerted a better in vivo curative

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activity (45.05%) for reducing rice bacterial leaf blight than bismerthiazol (37.80%)



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and thiodiazole copper (39.89%). Table 4 and Figure 3 show that, compared with

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bismerthiazol (43.31%) and thiodiazole copper (44.70%), compound 6d demonstrated

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excellent in vivo protection activity (51.77%) against rice bacterial leaf blight.

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Structure-Activity Relationship Analysis

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The structure–activity relationships (SAR) analysis was deduced based on the

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antibacterial activity in Tables 1 and 2. First, with the presence of the –Cl group at the

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4-position of the R1 substituent group on phenyl, the corresponding compounds

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presented better in vitro bioactivities against Xoo and Xac following the order of 5f

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(R1 = 4-Cl, R2 = -CH3) > 5a (R1 = 4-F, R2 = -CH3) and 6d (R1 = 4-Cl, R2 = -CH3) >

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6a (R1 = 4-F, R2 = -CH3). Second, compared with the same substituent on the R1

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substituent group, smaller substituent groups, such as methyl, on the R2 substituent

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group can increase the antibacterial activities against Xoo and Xac following the order

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of 5a (R1 = 4-F, R2 = -CH3) > 5b (R1 = 4-F, R2 = -C2H5), 5f (R1 = 4-Cl, R2 = -CH3) >

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5g (R1 = 4-Cl, R2 = -C2H5), and 6d (R1 = 4-Cl, R2 = -CH3) > 6e (R1 = 4-Cl, R2 =

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-C2H5). Third, compared with the same substituent on the R1 and R2 substituent

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groups, the corresponding compound 6 presented better in vitro bioactivities against

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Xoo and Xac than compound 5 following the order of 6a (R1 = 4-F, R2 = -CH3) > 5a

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(R1 = 4-F, R2 = -CH3) and 6d (R1 = 4-Cl, R2 = -CH3) > 5f (R1 = 4-Cl, R2 = -CH3).

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Meanwhile, it worth to note that when two sulfone groups at the 2,5-positions of the

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1,3,4-oxadiazole ring, the corresponding target compounds exhibited excellent

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bioactivities against Xoo and Xac compared with all the compounds that were

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reported by our previously work.


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This study demonstrated that this series of sulfone derivatives containing a

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1,3,4-oxadiazole moiety can be used to develop the potential agrochemicals. In

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accordance with the pesticide registration requirements in China, further field and

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toxicities studies of compound 6d will be undertaken in future studies.

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ASSOCIATED CONTENT

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Supporting Information

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The physical characteristics, 1H NMR,

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C NMR, and HRMS data for the target

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compounds are provided in the Supporting Information. This material is available free

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of charge on the Internet at http://pubs.acs.org.

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Funding

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The authors gratefully acknowledge the Natural Sciences Foundation of China (No.

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21672044).

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Notes

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The authors declare no competing financial interest. ABRREVIATIONS USED

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Xoo, Xanthomonas oryzae pv. oryzae; Xac, Xanthomonas axonopodis pv. citri; Xoc,

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Xanthomonas oryzae pv. oryzicola; R. solanacearum, Ralstonia solanacearum; EC50,

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50%

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relationships.

effective

concentration;

NB,

nutrient

broth;


SAR,

structure–activity


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339

Figure Captions

340

Figure 1. Synthetic route of the target compounds.

341

Figure 2. Curative activity of compound 6d against rice bacterial leaf blight under

342

greenhouse conditions at 200 µg/mL.

343

Figure 3. Protection activity of compound 6d against rice bacterial leaf blight under

344

greenhouse conditions at 200 µg/mL.

345


Page 18 of 28

Page 19 of 28


346

Table 1. In Vitro Antibacterial Activity of the Target Compounds against Xoo. Inhibition rate

EC50

Compounds R1

R2

200 (µg/mL)

100 (µg/mL)

(µg/mL)a

5a

4-F

-CH3

100±0.62

100±0.49

19.44±2.06

5b

4-F

-C2H5

100±0.54

80±2.21

27.66±2.89

5c

4-F

Benzyl

90±3.06

82±1.74

33.95±2.32

5d

4-F

4-Cl-Benzyl

82±5.01

71±4.95

45.78±2.65

5e

4-F

4-F-Benzyl

84±2.34

74±3.34

38.49±1.21

5f

4-Cl

-CH3

100±0.12

100±0.54

10.44±2.30

5g

4-Cl

-C2H5

100±0.58

100±0.51

12.22±3.34

5h

4-Cl

-CH2CH2CH3

100±0.51

100±0.23

16.90±2.38

5i

4-Cl

-CH2CH2CH2CH3

100±0.97

83±2.72

24.27±2.53

5j

4-Cl

-CH2CH2CH2CH2CH3

100±0.65

100±0.52

28.46±3.03

5k

4-Cl

Benzyl

100±0.18

100±0.32

31.44±2.94

5l

4-Cl

4-Cl-Benzyl

100±0.32

100±0.52

23.00±3.86

5m

4-Cl

4-F-Benzyl

100±0.22

100±0.14

17.09±2.77

6a

4-F

-CH3

100±0.43

100±0.36

0.22±0.14

6b

4-F

Benzyl

100±0.42

100±0.48

6.77±2.01

6c

4-F

-OH

100±0.41

100±0.23

5.92±1.14

6d

4-Cl

-CH3

100±0.67

100±0.41

0.17±1.02

6e

4-Cl

-C2H5

100±0.32

100±0.12

0.64±0.24

6f

4-Cl

Benzyl

100±0.16

100±0.40

1.11±0.42



347

a

Page 20 of 28

6g

4-Cl

4-Cl-Benzyl

100±0.12

100±0.54

2.25±0.98

6h

4-Cl

4-F-Benzyl

100±0.43

100±0.51

1.66±0.82

Bismerthiazol

72±0.65

54±1.23

92.61±2.15

Thiodiazole copper

64±2.76

43±3.15

121.82±3.59

The experiments were repeated three times.


Page 21 of 28


348

Table 2. In Vitro Antibacterial Activity of the Target Compounds against Xac. Inhibition rate

EC50

Compounds R1

R2

200 (µg/mL)

100 (µg/mL)

(µg/mL)a

5a

4-F

-CH3

100±0.86

100±0.13

25.61±2.29

5b

4-F

-C2H5

100±0.56

90±1.32

29.50±3.62

5c

4-F

Benzyl

100±0.22

82±2.85

34.82±2.90

5d

4-F

4-Cl-Benzyl

80±1.87

50±2.02

76.10±4.29

5e

4-F

4-F-Benzyl

85±1.93

60±2.87

61.88±1.96

5f

4-Cl

-CH3

100±0.86

100±0.13

21.11±2.06

5g

4-Cl

-C2H5

100±0.43

100±0.23

24.90±2.89

5h

4-Cl

-CH2CH2CH3

100±0.22

87±2.01

29.25±4.40

5i

4-Cl

-CH2CH2CH2CH3

90±1.18

75±2.84

45.27±3.39

5j

4-Cl

-CH2CH2CH2CH2CH3

95±1.92

77±2.07

37.43±3.30

5k

4-Cl

Benzyl

100±0.34

87±1.67

28.00±3.35

5l

4-Cl

4-Cl-Benzyl

84±1.56

76±2.67

49.31±4.04

5m

4-Cl

4-F-Benzyl

89±2.10

79±2.38

43.72±3.35

6a

4-F

-CH3

100±0.43

100±0.24

3.88±1.92

6b

4-F

Benzyl

100±0.49

100±0.37

15.27±1.83

6c

4-F

-OH

100±0.65

100±0.67

12.39±1.92

6d

4-Cl

-CH3

100±0.09

100±0.12

1.98±0.86

6e

4-Cl

-C2H5

100±0.84

100±0.53

8.09±1.06

6f

4-Cl

Benzyl

100±0.33

100±0.84

23.17±2.95



349

a

Page 22 of 28

6g

4-Cl

4-Cl-Benzyl

100±0.98

100±0.65

49.25±4.21

6h

4-Cl

4-F-Benzyl

100±0.33

100±0.76

27.60±1.86

Bismerthiazol

89±2.74

72±4.12

58.21±2.77

Thiodiazole copper

100±1.11

67±2.19

77.04±1.96

The experiments were repeated three times.


Page 23 of 28


350

Table 3. Curative Activity of Compound 6d against Rice Bacterial Leaf Blight under Greenhouse

351

Conditions at 200 µg/mL. 14 Days after spraying Treatment

a

Morbidity (%)

Disease index (%)

Control efficiency (%)b

6d

100

44.07

45.05A

Bismerthiazol

100

49.88

37.80B

Thiodiazole copper

100

48.21

39.89B

CKa

100

80.20

/

Negative control; b Statistical analysis was conducted via the ANOVA method at a condition of

equal variances assumed (P > 0.05) and equal variances not assumed (P < 0.05). Different uppercase letters indicate the values of curative activity with significant difference among different treatment groups at P < 0.05.

352



Page 24 of 28

353

Table 4. Protection Activity of Compound 6d against Rice Bacterial Leaf Blight under Greenhouse

354

Conditions at 200 µg/mL. 14 Days after inoculation Treatment

a

Morbidity (%)

Disease index (%)

Control efficiency (%)b

6d

100

38.68

51.77A

Bismerthiazol

100

45.46

43.31B

Thiodiazole copper

100

45.05

44.70B

CKa

100

80.20

/

Negative control; b The statistical analysis was conducted by ANOVA method at the condition of

equal variances assumed (P > 0.05) and equal variances not assumed (P < 0.05). Different uppercase letters indicate the values of protection activity with significantly difference among different treatment groups at P < 0.05.

355


Page 25 of 28


Figure 1. Synthetic route of the target compounds. 119x78mm (300 x 300 DPI)



Figure 2. Curative activity of compound 6d against rice bacterial leaf blight under greenhouse conditions at 200 µg/mL. 170x124mm (300 x 300 DPI)


Page 26 of 28

Page 27 of 28


Figure 3. Protection activity of compound 6d against rice bacterial leaf blight under greenhouse conditions at 200 µg/mL. 170x124mm (300 x 300 DPI)



Top Graphic 84x47mm (300 x 300 DPI)


Page 28 of 28

Design, Synthesis, and Evaluation of New Sulfone Derivatives

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