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Article

Synthesis and Antibacterial Evaluation of Novel 1,3,4-Oxadiazole Derivatives Containing Sulfonate/Carboxylate Moiety

by
Lei Wang
,
Xia Zhou
*,
Hui Lu
,
Xianfu Mu
and
Linhong Jin
*
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(7), 1488; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25071488
Submission received: 21 February 2020 / Revised: 21 March 2020 / Accepted: 23 March 2020 / Published: 25 March 2020
(This article belongs to the Collection Heterocyclic Compounds)
Browse Figures
Review Reports Versions Notes

Abstract

:
In order to discover new lead compounds with high antibacterial activity, a series of new derivatives were designed and synthesized by introducing a sulfonate or carboxylate moiety into the 1,3,4-oxadiazole structure. Antibacterial activity against two phytopathogens, Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas axonopodis pv. citri (Xac), was assayed in vitro. The preliminary results indicated that ten compounds including 4a-1-4a-4 and 4a-11-4a-16 had good antibacterial activity against Xoo, with EC50 values ranging from 50.1-112.5 µM, which was better than those of Bismerthiazol (253.5 µM) and Thiodiazole copper (467.4 µM). Meanwhile, 4a-1, 4a-2, 4a-3 and 4a-4 demonstrated good inhibitory effect against Xanthomonas axonopodis pv. citri with EC50 values around 95.8-155.2 µM which were better than those of bismerthiazol (274.3 µM) and thiodiazole copper (406.3 µM). In addition, in vivo protection activity of compound 4a-2 and 4a-3 against rice bacterial leaf blight was 68.6% and 62.3%, respectively, which were better than bismerthiazol (49.6%) and thiodiazole copper (42.2%). Curative activity of compound 4a-2 and 4a-3 against rice bacterial leaf blight was 62.3% and 56.0%, which were better than bismerthiazol (42.9%) and thiodiazole copper (36.1%). Through scanning electron microscopy (SEM) analysis, it was observed that compound 4a-2 caused the cell membrane of Xanthomonas oryzae pv. oryzae ruptured or deformed. The present results indicated novel derivatives of 5-phenyl sulfonate methyl 1,3,4-oxadiazole might be potential antibacterial agents.

Graphical Abstract

1. Introduction

Bacterial diseases of rice plants will lead to the reduction of rice yield and hence serious decreases in crop quality and insufficient food supply [1,2,3]. Bacterial leaf blight of rice infected by Xanthomonas oryzae pv. oryzae (Xoo) will reduce rice yield by affecting rice growth [4,5]. Citrus canker, the devastating citrus disease caused by Xanthomonas axonopodis pv. citri (Xac), can severely affect citrus production [6,7]. Bismerthiazol (BT) and thiodiazole copper (TC) are traditional systemic fungicides, which are commonly used to treat rice bacterial leaf blight and citrus canker [8,9]. However, the long-term frequent application of them has led to bactericide-resistant, therefore the phenomenon that rice bacterial leaf blight and citrus canker cannot be effectively controlled has emerged [10]. So, it is urgent to develop efficient new chemical pesticides to deal with this problem.
We previously found that 1,3,4-oxadiazole derivatives have a variety of biological effects, including antibacterial [11,12,13], antifungal [14,15], antiviral [16], nematocidal [17] and insecticidal [18,19] activity. 1,3,4-oxadiazole has the ideal heterocyclic structure to be developed into efficient pesticides. Meantime, sulfonate or carboxylate derivatives have broad-spectrum biological activity in agriculture, such as insecticidal [20], antibacterial [21], antiviral [22] and antifungal [23] activity. For example, pyraoxystrobin [24], chlorfenson [25] and nimrod [26] (Figure 1) containing sulfonate or carboxylate respectively have been widely used in agriculture [27,28,29].
In addition, we reported the splicing of oxymethyl and 1,3,4-oxadiazole sulfone derivatives could provide excellent antibacterial activity [10,30]. Based on those prior works, we hypothesized that sulfonate/carboxylate moiety functionalized 1,3,4-oxadiazole derivatives might also show promising antibacterial activity. Hence in the present work, a series of novel compounds were synthesized by introducing sulfonate or carboxylate moiety to 1,3,4-oxadiazole to discover new structures with potential antibacterial activity. The design and synthesis of the targets are depicted in Figure 1 and Scheme 1 respectively.

2. Results and Discussion

2.1. Chemistry

As described in Scheme 1, starting from ethyl glycolate, the key intermediate (5-mercapto-1,3,4-oxadiazol-2-yl) methanol 2 was synthesized in two steps involving acylation and cyclization. Subsequently, intermediate 2 was converted into its corresponding thioether derivative 3 by thioetherification with R1I. Finally, the target compounds 4a/5a was obtained by esterification with R2SOOCl/R3COCl. The structures of all target compounds were confirmed by nuclear magnetic resonance spectra including 1H NMR, 13C NMR and electrospray ionization high-resolution mass spectrometry (ESI-HRMS). Fluorine nuclear magnetic resonance (19F NMR) was involved for some fluoride structures.

2.2. In Vitro Antibacterial Activity

The antibacterial activity of all the compounds was evaluated in vitro against Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas axonopodis pv. (Xac) via the turbidimeter test [10]. Bismerthiazol and thiodiazole copper served as positive controls to compare the bactericidal potency of the tested compounds.
As shown in Table 1, most of the compounds 4a exhibited higher antibacterial activity than either bismerthiazol or thiodiazole copper against the tested plant bacteria. Among them, inhibitory rates for Xoo of compounds 4a-1–4a-5 and 4a-11-4a-16 at 100 µg/mL as well as 4a-1, 4a-2, 4a-14 at 50 µg/mL were all above 90%. Inhibitory rates for Xac of compounds 4a-1–4a-3, 93%–97% at 200 µg/mL and 69%–82% at 100 µg/mL were also superior to those of positive controls. At the same time, the present tests were parallelly conducted on compounds 5a. Actually, no similar tendency was observed on 5a against tested bacteria. It was confirmed that compounds 4a bearing sulfonate moiety were more potent in combating Xoo and Xac and presented remarkable higher activity as compared to compounds 5a and positive controls.
Further, compounds acting better than positive controls bismerthiazol or thiodiazole copper (Table 1) were performed for their EC50 values (Table 2). Compounds 4a-1-4a-4 and 4a-11-4a-16 revealed outstanding activity against Xoo with EC50 values around 50.1–112.5 µM, which was lower than bismerthiazol (253.5 µM) and thiodiazole copper (467.4 µM). Meanwhile, EC50 (95.8–155.2 µM) values of 4a-1-4a-4 against Xac were also lower than 274.3 µM displayed by bismerthiazol and 406.3 µM by thiodiazole copper.
In particular, 4a-2 bearing 4-F substituted benzenesulfonate, performed the best on Xoo and Xac with EC50 values of 50.1 and 95.8 µM respectively, which were quite better than two commercial positive controls. So, compound 4a-2 appeared to be promising antibacterial agents against plant bacterial diseases.

2.3. In Vivo Antibacterial Activity

With outstanding bactericidal activity of compounds 4a-1, 4a-2, 4a-3 in vitro, they were further explored for their antibacterial potency in vivo against rice bacterial leaf blight via the leaf-cutting method [10]. Bismerthiazol and thiodiazole copper served as positive controls for this investigation. All inoculated plants in 14 days exhibited blight symptoms with 100% morbidity.
At the concentration of 200 µg/mL, as shown in Figure 2 and Table 3, the control efficiency of the protection activity of compounds 4a-2 and 4a-3 were 68.6% and 62.3%, which were superior to Bismerthiazol (49.6%) and Thiodiazole copper (42.2%). As shown in Figure 3 and Table 4, the control efficiency of the curative activity of compound 4a-1, 4a-2 and 4a-3 were 44.6%, 62.3% and 56.0%, which were superior to bismerthiazol (42.9%) and thiodiazole copper (36.1%).

2.4. Scanning Electron Microscopy Studies

Scanning electron microscopy offers the ability to observe the bacterial cell surface [30]. Based on the analysis of antibacterial against Xoo results in vitro and in vivo, the antibacterial mechanism of compound 4a-2 was studied by SEM. As shown in the Figure 4, when the compound 4a-2 was at a concentration of 25 µg/mL, the bacterial cell was deformed, and part of the bacterial cell wall was slightly ruptured. When the compound 4a-2 concentration was increased to 50 µg/mL, most cell membrane were wrinkled and ruptured. Then observing the control group (A), these bacterial cells were round and smooth, without any breakage. Scanning electron microscopy images had further demonstrated that the compounds 4a-2 have antibacterial activity against Xoo.

2.5. Structure-Activity Relationship (SAR) Analyses

Based on the activity values shown in Table 1 and Table 2, a preliminary conclusion could be drawn about the structure-activity relationship. First, according to the antibacterial research of those 4a and 5a derivatives, it had shown that compound 5a derivatives containing the sulfonate structure was significantly higher efficient than the corresponding 5a containing the carboxylate structure. Obviously, the existence of the sulfonate structure was very important to improve inhibitory effect.
Further antibacterial evaluation on Xoo and Xac showed that 4-substituted halogenated phenyl sulfonate derivatives expressed significant antibacterial activity. Three (4a-2, 4a-3, 4a-4) of them worked well on both Xoo and Xac, which appeared an obvious decreasing potency (50.1, 87.2, 99.4 µM) with increasing halogen size in 4a-2(R2 = F), 4a-3(R2 = Cl), 4a-4(R2 = Br) respectively. In this regard, it was consistent with previous reports [10]. The other six compounds 4a-11-4a-16 (R1 = C2H5) also showed extensive potency on the Xoo. However, their EC50 are slightly decreased like 98, 95, 86.4 µM and not necessarily following the tendency 4a-11(F) >4a-12(Cl) >4a-13(Br). It can be refereed that R1 in thioether side chain also make difference in the activity of the structure. So in particular, when R1 = CH3, R2 = F, compound 4a-2 would be the most promising compound both in vitro and in vivo against the tested plant bacteria.

3. Experimental

3.1. Chemicals and Instruments

All reagent products from the Chinese Chemical Reagent Company were analytical or chemical pure. Thin-layer chromatography (TLC) of a GF254 silica gel pre-coated plate (Qingdao Haiyang Chemical Co., Ltd., Qingdao China) was used to evaluate the progress of the reaction and the purity of the compounds. Melting points were determined using an XT-4 digital melting-point apparatus (Beijing Tech. Instrument Co., Beijing, China) and reading was uncorrected. 1H NMR, 13C NMR and 19F NMR spectra were recorded on a 400 MHz spectrometer (Swiss Bruker, Swiss, Germany) with CDCl3 or (CD3)2CO-d6 as the solvent. The antibacterial mechanism was studied by scanning electron microscopy (FEI, Hillsboro Oregon, America). Single crystal structure was collected by single crystal diffractometer (Gemini E, Oxford, United Kingdom). High-resolution mass spectral (HRMS) data were performed with Thermo Scientific Q Exactive (Thermo, Waltham, MA, USA).

3.2. General Synthetic Procedure for the Target Compounds

3.2.1. Preparation of Intermediate 1

Ethyl glycolate (0.05 mol) was dissolved with 100 mL ethanol in a round bottom flask. Then, 80% of hydrazine hydrate (0.1 mol) was slowly added to the round bottom flask at room temperature. After a day of reaction, white product 1 will precipitate out in 85%–90% yields.

3.2.2. Preparation of Intermediate 2

To a three-necked round bottom flask was added intermediate 1 (0.01 mol), KOH (0.012 mol) and 100 mL of ethanol in this order. Then, carbon disulfide (0.012mol) was slowly added under a stirred condition. The mixture was reacted at room temperature for 1–2 h and then heated to 78 °C for refluxing of six hours. The solution was removed under reduced pressure on a rotary evaporator, and product 2 was obtained in 65%–70% yields.

3.2.3. Preparation of Intermediate 3

Tetrahydrofuran was used for dissolving intermediate 2 (0.01 mmol), then added KOH (0.012 mmol) and R1I (0.012 mmol). The reaction was judged complete by TLC, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Intermediate 3 in yield of 70%–80%.

3.2.4. Preparation of Target Compound 4a/5a

At room temperature, added intermediate 3 (0.001 mol), tetrahydrofuran (10 mL), and sodium hydride (0.001 mol) to the round-bottomed flask in order. After stirring for 30 min, R2SOOCl/R2COCl (0.001 mol) was slowly added, and the reaction was followed by TLC and filtered to get 4a/5a.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl benzenesulfonate (4a-1). White solid; m.p.: 54–55 °C; yield, 80.5%; 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 8.4, 1.2 Hz, 2H, Ar-H), 7.70 (t, J = 7.5 Hz, 1H, Ar-H), 7.58 (t, J = 7.8 Hz, 2H, Ar-H), 5.23 (s, 2H, -CH2-), 2.69 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.60, 160.69, 135.10, 134.50, 129.49, 128.13, 59.75, 14.51. HRMS calculated for C10H11O4N2S2 [M + H]+ 287.01547, found 287.01529.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 4-fluorobenzenesulfonate (4a-2). White solid; m.p.: 64–65 °C; yield, 86.5%; 1H NMR (400 MHz, Acetone) δ 8.04 (dd, J = 9.0, 5.0 Hz, 2H, Ar-H), 7.48 (t, J = 8.8 Hz, 2H, Ar-H), 5.44 (s, 2H, -CH2-), 2.71 (s, 3H, -CH3). 13C NMR (100 MHz, Acetone) δ 166.81, 166.10 (d, J = 254.9 Hz), 161.21, 131.72 (d, J = 3.5 Hz), 131.30 (d, J = 10.2 Hz), 116.91 (d, J = 23.3 Hz), 60.57, 13.67. 19F NMR (376 MHz, Acetone) δ -104.45. HRMS calculated for C10H10FO4N2S2 [M + H]+ 305.00605, found 305.00592.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 4-chlorobenzenesulfonate (4a-3). White solid; m.p.: 85–86 °C; yield, 86.5%; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.8 Hz, 2H, Ar-H), 7.47 (d, J = 8.8 Hz, 2H, Ar-H), 5.18 (s, 2H, -CH2-), 2.63 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.73, 160.51, 141.34, 133.69, 129.80, 129.53, 59.92, 14.52. HRMS calculated for C10H10O4N2ClS2 [M + H]+ 320.97650, found 320.97629.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 4-bromobenzenesulfonate (4a-4). White solid; m.p.: 79–80 °C; yield, 76.5%; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.7 Hz, 2H, Ar-H), 7.64 (d, J = 8.7 Hz, 2H, Ar-H), 5.18 (s, 2H, -CH2-), 2.63 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.76, 160.48, 134.18, 132.80, 129.93, 129.55, 59.97, 14.55. HRMS calculated for C10H10O4N2BrS2 [M + H]+ 364.92599, found 364.92548.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 4-methoxybenzenesulfonate (4a-5). White solid; m.p.: 63–64 °C; yield, 66.5%; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 9.0 Hz, 2H, Ar-H), 7.02 (d, J = 8.9 Hz, 2H, Ar-H), 5.19 (s, 2H, -CH2-), 3.90 (s, 3H, -CH3), 2.69 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.50, 164.34, 160.87, 130.46, 126.20, 114.67, 59.51, 55.83, 14.50. HRMS calculated for C11H13O5N2S2 [M + H]+ 317.02604, found 317.02472.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 4-nitrobenzenesulfonate (4a-6). White solid; m.p.: 86–87 °C; yield, 74.5%; 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 9.0 Hz, 2H, Ar-H), 8.12 (d, J = 9.0 Hz, 2H, Ar-H), 5.36 (s, 2H, -CH2-), 2.70 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.88, 160.22, 151.07, 140.95, 129.52, 124.59, 60.42, 14.50. HRMS calculated for C10H10O6N3S2 [M + H]+ 332.00055, found 332.00040.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 4-(trifluoromethyl)benzenesulfonate (4a-7). White solid; m.p.: 60–61 °C; yield, 84.5%; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.2 Hz, 2H, Ar-H), 7.77 (d, J = 8.3 Hz, 2H, Ar-H), 5.23 (s, 2H, -CH2-), 2.61 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 166.76, 159.29, 137.84, 135.19, 134.86, 127.66, 125.55 (q, J = 3.6 Hz), 123.24, 120.53, 59.16, 13.39. 19F NMR (376 MHz, CDCl3) δ -63.36. HRMS calculated for C11H10O4N2F3S2 [M + H]+ 355.00286, found 355.00241.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 2-fluorobenzenesulfonate (4a-8). White solid; m.p.: 51–52 °C; yield, 82.5%; 1H NMR (400 MHz, Acetone) δ 7.97–7.87 (m, 2H, Ar-H), 7.52–7.46 (m, 2H, Ar-H), 5.52 (s, 2H, -CH2-), 2.71 (s, 3H, -CH3). 13C NMR (100 MHz, Acetone) δ: 166.87, 161.12, 159.11 (d, J = 257.6 Hz), 137.54 (d, J = 8.8 Hz), 130.94, 125.17 (d, J = 3.9 Hz), 123.50 (d, J = 13.9 Hz), 117.59 (d, J = 20.7 Hz), 61.03, 13.68. 19F NMR (376 MHz, Acetone) δ -109.11. HRMS calculated for C10H10FO4N2S2 [M + H]+ 305.00605, found 305.00592.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 3-fluorobenzenesulfonate (4a-9). White liquid; yield, 72.5%; 1H NMR (400 MHz, CDCl3) δ 7.66 (ddd, J = 7.9, 1.6, 1.0 Hz, 1H, Ar-H), 7.59–7.54 (m, 1H, Ar-H), 7.51 (td, J = 8.1, 5.2 Hz, 1H, Ar-H), 7.34 (tdd, J = 8.3, 2.5, 0.9 Hz, 1H, Ar-H), 5.19 (s, 2H, -CH2-), 2.63 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.75, 162.34 (d, J = 253.3 Hz), 160.43, 136.89 (d, J = 7.2 Hz), 131.38 (d, J = 7.8 Hz), 123.94 (d, J = 3.5 Hz), 121.87 (d, J = 21.1 Hz), 115.51 (d, J = 24.9 Hz), 60.01, 14.50. 19F NMR (376 MHz, CDCl3) δ -108.20. HRMS calculated for C10H10FO4N2S2 [M + H]+ 305.00605, found 305.00571.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 3-chlorobenzenesulfonate (4a-10). White liquid; yield, 81.5%; 1H NMR (400 MHz, CDCl3) δ 7.90 (t, J = 1.9 Hz, 1H, Ar-H), 7.84–7.79 (m, 1H, Ar-H), 7.67 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H, Ar-H), 7.53 (t, J = 8.0 Hz, 1H, Ar-H), 5.27 (s, 2H, -CH2-), 2.71 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.77, 160.41, 136.71, 135.75, 134.65, 130.76, 128.07, 126.18, 60.02, 14.51. HRMS calculated for C10H10ClO4N2S2 [M + H]+ 320.97650, found 320.97635.
(5-(ethylthio)-1,3,4-oxadiazol-2-yl)methyl 4-fluorobenzenesulfonate (4a-11). White liquid; yield, 80.5%; 1H NMR (400 MHz, Acetone-d6) δ 8.04 (dd, J = 9.0, 5.0 Hz, 2H, Ar-H), 7.48 (t, J = 8.8 Hz, 2H, Ar-H), 5.45 (s, 2H, -CH2-), 3.26 (q, J = 7.3 Hz, 2H, -CH2-), 1.42 (t, J = 7.3 Hz, 3H, -CH3). 13C NMR (100 MHz, Acetone-d6) δ 166.09 (d, J = 254.8 Hz), 166.04, 161.15, 131.73 (d, J = 3.4 Hz), 131.29 (d, J = 10.2 Hz), 116.92 (d, J = 23.3 Hz), 60.58, 26.54, 14.19. 19F NMR (376 MHz, Acetone-d6) δ -104.41. HRMS calculated for C11H12O4N2ClS2 [M + H]+ 319.02170, found 319.02142.
(5-(ethylthio)-1,3,4-oxadiazol-2-yl)methyl 4-chlorobenzenesulfonate (4a-12). White liquid; yield, 78.5%; 1H NMR (400 MHz, CDCl3) δ 7.80–7.75 (m, 2H, Ar-H), 7.50–7.45 (m, 2H, Ar-H), 5.19 (s, 2H, -CH2-), 3.17 (q, J = 7.4 Hz, 2H, -CH2-), 1.40 (t, J = 7.4 Hz, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.14, 160.31, 141.34, 133.66, 129.82, 129.53, 59.96, 26.97, 14.55. HRMS calculated for C11H12O4N2ClS2 [M + H]+ 334.99215, found 334.99191.
(5-(ethylthio)-1,3,4-oxadiazol-2-yl)methyl 4-bromobenzenesulfonate (4a-13). White liquid; yield, 72.5%; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.8 Hz, 2H, Ar-H), 7.63 (d, J = 8.8 Hz, 2H, Ar-H), 5.19 (s, 2H, -CH2-), 3.17 (q, J = 7.4 Hz, 2H, -CH2-), 1.40 (t, J = 7.4 Hz, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.13, 160.30, 134.22, 132.80, 129.92, 129.54, 59.98, 26.99, 14.55. HRMS calculated for C11H12O4N2BrS2 [M + H]+ 378.94164, found 378.94110.
(5-((2-fluoroethyl)thio)-1,3,4-oxadiazol-2-yl)methyl 4-fluorobenzenesulfonate (4a-14). White liquid; yield, 62.5%; 1H NMR (400 MHz, Acetone-d6) δ 8.05 (dd, J = 9.0, 5.0 Hz, 2H, Ar-H), 7.48 (t, J = 8.8 Hz, 2H, Ar-H), 5.45 (s, 2H, -CH2-), 4.81 (t, J = 5.8 Hz, 1H, -CH-), 4.69 (t, J = 5.8 Hz, 1H, -CH-), 3.64 (t, J = 5.8 Hz, 1H, -CH-), 3.59 (t, J = 5.8 Hz, 1H, -CH-).13C NMR (100 MHz, Acetone-d6) δ 166.12 (d, J = 254.9 Hz), 165.41, 161.48, 131.69 (d, J = 3.2 Hz), 131.32 (d, J = 10.1 Hz), 116.93 (d, J = 23.2 Hz), 80.99 (d, J = 169.1 Hz), 60.50, 32.06 (d, J = 22.0 Hz). 19F NMR (376 MHz, Acetone-d6) δ -104.33, -216.98. HRMS calculated for C11H11O4N2F2S2 [M + H]+ 337.01228, found 337.01169.
(5-((2-fluoroethyl)thio)-1,3,4-oxadiazol-2-yl)methyl 4-chlorobenzenesulfonate (4a-15). White liquid; yield, 80.5%; 1H NMR (400 MHz, CDCl3) δ 7.81–7.75 (m, 2H, Ar-H), 7.50–7.45 (m, 2H, Ar-H), 5.19 (s, 2H, -CH2-), 4.72 (t, J = 5.7 Hz, 1H, -CH-), 4.60 (t, J = 5.7 Hz, 1H, -CH-), 3.49 (t, J = 5.7 Hz, 1H, -CH-), 3.43 (t, J = 5.7 Hz, 1H, -CH-). 13C NMR (100 MHz, CDCl3) δ 166.17, 160.81, 141.37, 133.62, 129.81, 129.51, 80.62 (d, J = 172.1 Hz), 59.74, 32.33 (d, J = 22.2 Hz). 19F NMR (376 MHz, CDCl3) δ -215.71. HRMS calculated for C11H11O4N2ClFS2 [M + H]+ 352.98273, found 352.98209.
(5-((2-fluoroethyl)thio)-1,3,4-oxadiazol-2-yl)methyl 4-bromobenzenesulfonate (4a-16). White solid; m.p.: 90–91 °C; yield, 80.5%; 1H NMR (400 MHz, CDCl3) δ 7.73–7.68 (m, 2H, Ar-H), 7.68–7.61 (m, 2H, Ar-H), 5.19 (s, 2H, -CH2-), 4.72 (t, J = 5.7 Hz, 1H, -CH-), 4.61 (t, J = 5.7 Hz, 1H, -CH-), 3.49 (t, J = 5.7 Hz, 1H, -CH-), 3.44 (t, J = 5.7 Hz, 1H, -CH-); 13C NMR (100 MHz, CDCl3) δ 166.21, 160.80, 134.20, 132.83, 129.98, 129.55, 80.66 (d, J = 172.3 Hz), 59.78, 32.37 (d, J = 22.2 Hz). 19F NMR (376 MHz, CDCl3) δ -215.68. HRMS calculated for C11H11O4N2BrFS2 [M + H]+ 396.93222, found 396.93161.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl dimethylsulfamate (4a-17). White liquid; yield, 80.5%; 1H NMR (400 MHz, CDCl3) δ 5.27 (s, 2H, -CH2-), 2.92 (s, 6H, -N(CH3)2), 2.76 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.55, 161.45, 59.55, 38.46, 14.56. HRMS calculated for C6H12O4N3S2 [M + H]+ 254.02637, found 254.02617.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 2-(trifluoromethyl)benzenesulfonate (4a-18). White liquid; yield, 64.5%; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.5 Hz, 1H, Ar-H), 7.88 (d, J = 7.5 Hz, 1H, Ar-H), 7.73 (ddd, J = 14.0, 11.1, 6.7 Hz, 2H, Ar-H), 5.26 (s, 2H, -CH2-), 2.63 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.77, 160.48, 134.50, 133.84, 132.58, 132.35, 128.84 (d, J = 6.1 Hz), 123.47, 120.75, 60.04, 14.48. 19F NMR (376 MHz, CDCl3) δ -58.49. HRMS calculated for C11H10O4N2F3S2 [M + H]+ 355.00286, found 355.00241.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl benzoate (5a-1). White solid; m.p.: 30–31 °C; yield, 77.5%; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.1 Hz, 2H, Ar-H), 7.62 (t, J = 7.4 Hz, 1H, Ar-H), 7.48 (t, J = 7.7 Hz, 2H, Ar-H), 5.52 (s, 2H, -CH2-), 2.76 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 166.92, 165.49, 162.81, 133.74, 130.00, 128.70, 128.58, 55.53, 14.60. HRMS calculated for C11H11O3N2S [M + H]+ 251.04849, found 251.04831.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 4-fluorobenzoate (5a-2). White solid; m.p.: 53–54 °C; yield, 75.5%; 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 9.0, 5.4 Hz, 2H, Ar-H), 7.06 (t, J = 8.7 Hz, 2H, Ar-H), 5.42 (s, 2H, -CH2-), 2.67 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 166.99, 166.22 (d, J = 255.3 Hz), 164.52, 162.68, 132.66 (d, J = 9.5 Hz), 124.94 (d, J = 3.0 Hz), 115.85 (d, J = 22.1 Hz), 55.62, 14.61. 19F NMR (376 MHz, CDCl3) δ -104.05. HRMS calculated for C11H10O3N2FS [M + H]+ 269.03907, found 269.03897.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 4-chlorobenzoate (5a-3). White solid; m.p.: 53–54 °C; yield, 74.5%; 1H NMR (400 MHz, CDCl3) δ 7.95–7.90 (m, 2H, Ar-H), 7.39–7.34 (m, 2H, Ar-H), 5.42 (s, 2H, -CH2-), 2.67 (s, 3H, -CH3), 13C NMR (100 MHz, CDCl3) δ 166.98, 164.64, 162.60, 140.32, 131.37, 128.97, 127.15, 55.70, 14.61. HRMS calculated for C11H10O3N2ClS [M + H]+ 285.00952, found 285.00958.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 4-bromobenzoate (5a-4). White solid; m.p.: 82–83 °C; yield, 70.5%; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.7 Hz, 2H, Ar-H), 7.54 (d, J = 8.7 Hz, 2H, Ar-H), 5.42 (s, 2H, -CH2-), 2.68 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 167.01, 164.81, 162.57, 131.98, 131.48, 129.06, 127.59, 55.70, 14.61. HRMS calculated for C11H10O3N2BrS [M + H]+ 328.95900, found 328.95895.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl 4-methoxybenzoate (5a-5). White solid; m.p.: 35–36 °C; yield, 79.5%; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 9.0 Hz, 2H, Ar-H), 6.95 (d, J = 9.0 Hz, 2H, Ar-H), 5.49 (s, 2H, -CH2-), 3.89 (s, 3H, -CH3), 2.76 (s, 3H, -CH3).13C NMR (100 MHz, CDCl3) δ 166.83, 165.18, 163.97, 163.02, 132.13, 121.01, 113.84, 55.52, 55.28, 14.60. HRMS calculated for C12H13O4N2S [M + H]+ 281.05905, found 281.05884.
(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl dimethylcarbamate (5a-6). White liquid; yield, 81.5%; 1H NMR (400 MHz, CDCl3) δ 5.28 (s, 2H, -CH2-), 2.97 (s, 3H, -CH3), 2.95 (s, 3H, -CH3), 2.75 (s, 3H, -CH3). 13C NMR (100 MHz, CDCl3) δ 166.51, 163.49, 155.10, 56.13, 36.79, 36.05, 14.60. HRMS calculated for C7H12O3N3S [M + H]+ 218.05939, found 218.05922.

3.3. X-ray Diffraction Analysis

All target compounds had been confirmed by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). After a preliminary in vitro and in vivo bactericidal analysis, Compound 4a-2 had the best bactericidal activity. The structural composition of compound 4a-2 was determined by single crystal X-ray analysis.
Crystal structure of compound 4a-2 (C10H9FO4N2S2) is shown in Figure 5. Colorless crystal of compound 4a-2 (0.4 × 0.28 × 0.2 mm) is monoclinic system and space group C 2/C. Cell parameters: a = 26.431(2), b = 5.1560(5), c = 21.7311(18), alpha = 90, beta = 121.147(4), gamma = 90, V = 2534.5(4), Z = 8. Cell dimensions and intensities were measured at 298 K on Bruker SMART diffractometer with MoK\a radiation (λ = 0.71073 Å). A total of 2215 reflections were measured, of which 1662 were unique in the range of 3.10 <θ< 25.02° (h, -18 to 31; k, -6 to 6; l, -25 to 24), The structure was solved by direct method with the SHELXL-2014 program. All of the non-H atoms were refined anisotropically by full-matrix least-squares to give the final R = 0.0409 and WR2 = 0.1075. All hydrogen atoms were computed and refined using a riding model. The completeness of the crystal data is 99.4%. The atomic coordinates for 4a-2 have been deposited at the Cambridge Crystallographic Data Centre. CCDC 1,975,227 contains the supplementary crystallographic data for this paper.

3.4. Antibacterial Bioassay by Scanning Electron Microscopy

The sample preparation method was as follows [30]. A certain quantity of microcentrifuge tube (2 ml) was prepared and added bacteria solution of Xoo (1.5 mL). Then microcentrifuge tubes were washed with PBS buffer and centrifuged 3 times, in order to discard supernatant, microcentrifuge tubes were centrifuge at 7000 rpm for one minute. Compound 4a-2 was added into the centrifuge tube to prepare 0 µg/mL, 25 µg/mL and 50 µg/mL solution, three parallel groups for each concentration. 2.5% glutaraldehyde fixing solution was added to each microcentrifuge tube for 12 h and removed. Next, microcentrifuge tubes were washed by 30%, 50%, 70%, 90% and absolute ethanol in this order. At last, the samples were flattened and sprayed gold (45s) for observing by SEM.

3.5. Antibacterial Bioassay In Vitro

The inhibitory efficiency of target compounds on two bacteria in vitro was tested by the turbidimeter method at different concentrations [10]. For initial screening of all 24 compounds, the solution concentration was set at 200 and 100 μg/mL which was incubated with bacterial solution and then procedurally measured for the OD value. A solution with no compound was set as a negative check and bismerthiazol and thiodiazole copper served as the positive control. Compounds that were active at this concentration were further tested at five lower gradient concentrations to get EC50. Data were collected in triplicate for each compound concentration. Based on the OD value, the inhibitory effect of the compound on bacteria was calculated. I (%) = (CK-T)/T × 100%. I (%) meant inhibition rate. CK meant the OD value of non-drug control group. T meant the OD value of drug group.

3.6. Antibacterial Activity Bioassay In Vivo

Compounds 4a-1, 4a-2 and 4a-3 were tested for the protective and curative activity in vivo against rice bacterial leaf blight by leaf-cutting method [10,30] at 200 µg/mL, with comparing to bismerthiazol and thiodiazole copper. A negative control check (CK) was set up identically with absence of the test compound. Data were collected in triplicate treatment. Then the control efficiency could be calculated by analyzing plant disease index. Control efficiency (%) = (C − T)/C × 100%, where C represented the plant disease index of the negative control CK; T represented the disease index of plant with the compound treatment.

4. Conclusions

In summary, 24 novel sulfonate/carboxylate functionalized 1,3,4-oxadiazole derivatives were synthesized and evaluated for antibacterial activity on both bacteria Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri. Among them, ten compounds (4a-1 to 4a-4 and 4a-11 to 4a-16) showed extensive potency on the Xoo in vitro. Four (4a-1 to 4a-4) of them also performed well on Xac in vitro. In particular, compound 4a-2 with the best antibacterial activity in vitro indicated excellent protective and curative activity against rice bacterial leaf blight in vivo. Furtherly, scanning electron microscope analysis on 4a-2 verified its antibacterial action mechanism. Structure-activity relationship illustrated that sulfonate structure (4a), rather than carboxylate moiety(5a), play important role for inhibitory effect of target compounds. In conclusion, as expected, 1,3,4-Oxadiazole derivatives containing sulfonate moiety showed promise antibacterial activity and might provide potent plant bactericide.

Supplementary Materials

The following are available online. 1H, 13C and 19F NMR spectra of all the compounds are presented as Supporting Information; crystallographic data of compound 4a-2 (CCDC 1975227) for this paper could be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.

Author Contributions

L.J. conceived the project; L.W. performed most of the experimental work while H.L. and X.M. implemented the biological test protocols; X.Z. supervised the project and wrote the manuscript. All authors analyzed the data and contributed to manuscript preparation. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Nature Science Foundation of China NSFC 21967006, and by The Excellent Young Science and Technology Talent Cultivation Plan 201122, and by International Science and Technology Cooperation Program of Guizhou province 2009700112.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 4a/5a are available from the authors.
Molecules 25 01488 g001 550
Figure 1. Design of the target compounds.
Figure 1. Design of the target compounds.
Molecules 25 01488 g001
Molecules 25 01488 sch001 550
Scheme 1. Synthesis of the target compounds 4a-1-4a-18 and 5a-1-5a-6.
Scheme 1. Synthesis of the target compounds 4a-1-4a-18 and 5a-1-5a-6.
Molecules 25 01488 sch001
Molecules 25 01488 g002 550
Figure 2. Protective activity of compounds against Xanthomonas orzae pv. oryzae under greenhouse condition.
Figure 2. Protective activity of compounds against Xanthomonas orzae pv. oryzae under greenhouse condition.
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Molecules 25 01488 g003 550
Figure 3. Curative activity of compounds against Xanthomonas oryzae pv. oryzae under greenhouse condition.
Figure 3. Curative activity of compounds against Xanthomonas oryzae pv. oryzae under greenhouse condition.
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Molecules 25 01488 g004 550
Figure 4. SEM images for Xoo after incubated using different concentrations of compound 4a-2, (A) 0 µg/mL, (B) 25 µg/mL and (C) 50 µg/mL. Scale bar for (A), (B) and (C) are 5 µm.
Figure 4. SEM images for Xoo after incubated using different concentrations of compound 4a-2, (A) 0 µg/mL, (B) 25 µg/mL and (C) 50 µg/mL. Scale bar for (A), (B) and (C) are 5 µm.
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Figure 5. Crystal structure of compound 4a-2.
Figure 5. Crystal structure of compound 4a-2.
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Table
Table 1. Inhibition rate (%) of target compounds against Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri a.
Table 1. Inhibition rate (%) of target compounds against Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri a.
Compd.Xanthomonas Oryzae Pv. OryzaeXanthomonas Axonopodis Pv. Citri
100 µg/mL50 µg/mL200 µg/mL100 µg/mL
4a-198.3 ± 1.290.4 ± 1.494.2 ± 0.279.4 ± 1.3
4a-299.5 ± 1.894.1 ± 2.197.1 ± 0.382.1 ± 2.0
4a-394.0 ± 1.185.4 ± 0.993.8 ± 0.469.3 ± 2.7
4a-491.2 ± 2.878.7 ± 2.280.4 ± 0.245.8 ± 4.6
4a-591.8 ± 2.641.5 ± 2.362.4 ± 3.648.1 ± 3.0
4a-620.0 ± 1.95.0 ± 2.220.2 ± 2.715.9 ± 2.7
4a-710.1 ± 1.272.7 ± 1.122.9 ± 4.119.1 ± 4.7
4a-876.8 ± 1.539.8 ± 2.192.3 ± 4.625.5 ± 2.7
4a-960.7 ± 1.520.2 ± 2.118.8 ± 1.510.5 ± 2.1
4a-1048.9 ± 2.618.5 ± 1.117.3 ± 2.315.2 ± 1.8
4a-1197.5 ± 1.282.2 ± 1.447.3 ± 1.833.2 ± 1.2
4a-1296.4 ± 2.278.4 ± 2.145.5 ± 2.132.4 ± 1.8
4a-1394.9 ± 1.781.2 ± 2.441.9 ± 0.830.0 ± 2.8
4a-1499.1 ± 1.594.0 ± 1.941.2 ± 4.833.0 ± 3.8
4a-1597.0 ± 0.972.5 ± 1.038.7 ± 3.632.1 ± 1.8
4a-1694.0 ± 1.248.0 ± 1.536.9 ± 2.820.0 ± 1.9
4a-1730.2 ± 1.818.1 ± 0.925.6 ± 1.511.4 ± 1.2
4a-1810.4 ± 2.36.2 ± 1.548.3 ± 3.724.2 ± 5.3
5a-135.1 ± 1.218.2 ± 1.547.9 ± 6.023.8 ± 4.0
5a-296.4 ± 2.511.5 ± 1.555.1 ± 1.535.5 ± 3.9
5a-315.2 ± 5.37.3 ± 4.968.5 ± 1.438.5 ± 1.2
5a-412.5 ± 2.17.0 ± 3.232.4 ± 1.712.0 ± 2.2
5a-511.0 ± 1.12.3 ± 2.145.1 ± 1.829.8 ± 2.7
5a-67.2 ± 2.83.5 ± 1.732.2 ± 2.518.8 ± 1.5
Bismerthiazol b60.2 ± 3.128.3 ± 2.872.5 ± 2.858.2 ± 2.1
Thiodiazole Copper b57.3 ± 1.930.2 ± 2.179.1 ± 1.853.1 ± 1.1
a Average of three replicates; b The commercial agricultural antibacterial agents bismerthiazol and thiodiazole copper were used as positive control.
Table
Table 2. EC50 (µM) of some target compounds against Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri a.
Table 2. EC50 (µM) of some target compounds against Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri a.
Compd.Xanthomonas Oryzae Pv. OryzaeXanthomonas Axonopodis Pv. Citri
EC50 (µM) cEC50 (µM) c
4a-163.4 ± 3.8114.0 ± 6.6
4a-250.1 ± 4.295.8 ± 4.6
4a-387.2 ± 4.7132.5 ± 7.5
4a-499.4 ± 4.7155.2 ± 5.8
4a-1198.0 ± 6.6/
4a-1295.3 ± 3.9/
4a-1386.4 ± 4.8/
4a-1469.0 ± 4.4/
4a-1583.4 ± 6.0/
4a-16112.5 ± 6.0/
Bismerthiazol b253.5 ± 7.6274.3 ± 8.6
Thiodiazole copper b467.4 ± 15.5406.3 ± 13.0
a 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); b Commercial agricultural antibacterial agents bismerthiazol, and thiodiazole copper were used as positive control. c Corresponding regression equations and r values for this EC50 were provided in supplementary data.
Table
Table 3. Protective effect of compounds 4a-1, 4a-2 and 4a-3 against Xanthomonas oryzae pv. oryzae.
Table 3. Protective effect of compounds 4a-1, 4a-2 and 4a-3 against Xanthomonas oryzae pv. oryzae.
Treatment14 Days after Spraying
Morbidity (%)Disease Index (%)Control Efficiency (%) a
4a-110034.648.1 ± 2.5
4a-210016.768.6 ± 3.5
4a-310022.262.3 ± 4.3
Bismerthiazol10033.349.6 ± 3.1
Thiodiazole copper 10039.942.2 ± 3.0
CK (negative control)10087.6/
a Average of three replicates. 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).
Table
Table 4. Curative effect of compounds 4a-1, 4a-2 and 4a-3 against Xanthomonas oryzae pv. oryzae.
Table 4. Curative effect of compounds 4a-1, 4a-2 and 4a-3 against Xanthomonas oryzae pv. oryzae.
Treatment14 Days after Spraying
Morbidity (%)Disease Index (%)Control Efficiency (%) a
4a-110037.844.6 ± 2.9
4a-210022.262.3 ± 3.8
4a-310027.856.0 ± 3.5
Bismerthiazol10039.242.9 ± 2.4
Thiodiazole copper10045.236.1 ± 2.5
CK (negative control)10087.6/
a Average of three replicates. 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).

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Wang, L.; Zhou, X.; Lu, H.; Mu, X.; Jin, L. Synthesis and Antibacterial Evaluation of Novel 1,3,4-Oxadiazole Derivatives Containing Sulfonate/Carboxylate Moiety. Molecules 2020, 25, 1488. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25071488

AMA Style

Wang L, Zhou X, Lu H, Mu X, Jin L. Synthesis and Antibacterial Evaluation of Novel 1,3,4-Oxadiazole Derivatives Containing Sulfonate/Carboxylate Moiety. Molecules. 2020; 25(7):1488. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25071488

Chicago/Turabian Style

Wang, Lei, Xia Zhou, Hui Lu, Xianfu Mu, and Linhong Jin. 2020. "Synthesis and Antibacterial Evaluation of Novel 1,3,4-Oxadiazole Derivatives Containing Sulfonate/Carboxylate Moiety" Molecules 25, no. 7: 1488. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25071488

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