Synthesis of <i>N</i>-Methylmorpholinium Derivatives Possessing a 1,3,4-Oxadiazole Core as Feasible Antibacterial Agents against Plant Bacterial Diseases

Tuo, Xinxin; Yang, Jie; Zhang, Yedong; Wang, Peiyi

doi:https://doi.org/10.1155/2021/5415950

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Advanced Catalysis and Synthesis for Sustainable and Environmental Processes

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Research Article | Open Access

Volume 2021 | Article ID 5415950 | https://doi.org/10.1155/2021/5415950

Synthesis of N-Methylmorpholinium Derivatives Possessing a 1,3,4-Oxadiazole Core as Feasible Antibacterial Agents against Plant Bacterial Diseases

Xinxin Tuo,¹Jie Yang,¹Yedong Zhang,¹and Peiyi Wang¹

Academic Editor: Andrea Mastinu

Received14 Jul 2021

Revised21 Aug 2021

Accepted26 Aug 2021

Published02 Sept 2021

Abstract

To develop a kind of quaternary ammonium compounds that can safely apply in agriculture for managing the plant bacterial diseases, herein, a series of N-methylmorpholinium derivatives possessing a classical 1,3,4-oxadiazole core were prepared and the antibacterial activities both in vitro and in vivo were screened. Bioassay results revealed that compounds 3l and 3i showed the strongest antibacterial activity toward pathogens Xanthomonas oryzae pv. oryzae and X. axonopodis pv. citri with the lowest EC₅₀ values of 1.40 and 0.90 μg/mL, respectively. Phytotoxicity test trials indicated that target compounds bearing a bulky N-methylmorpholinium pendant are safe for plants. The following in vivo bioassays showed that compound 3l could control the rice bacterial blight disease, thereby affording good control efficiencies of 55.95% (curative activity) and 53.09% (protective activity) at the dose of 200 μg/mL. Preliminary antibacterial mechanism studies suggested that target compounds had strong interactions with the cell membrane of bacteria via scanning electron microscopy imaging. Additionally, this kind of framework also displayed certain antifungal activity toward Fusarium oxysporum and Phytophthora cinnamomi. Given the above privileged characteristics, this kind of 1,3,4-oxadiazole-tailored N-methylmorpholinium derivatives could stimulate the design of safe quaternary ammonium bactericides for controlling plant bacterial diseases.

1. Introduction

Phytopathogens are a group of aggressive microorganisms that can invade all sorts of plants for nutrient competition and/or self-reproduction, thereby seriously threatening the quality and yield of agricultural products [1–4]. The representative notorious bacterial strains, namely, Xanthomonas oryzae pv. oryzae (Xoo) and X. axonopodis pv. citri (Xac), are the widely distributed pathogens worldwide and can lead to the development of severe diseases on major crops, exemplified by the bacterial leaf blight on rice and canker on citrus [5–9]. As for the bacterial blight disease, it can occur in all stages of rice growth, thereby reducing approximately 10 to 50 percent rice production annually in rice-growing countries [10–14]. This outcome has strongly strained the demand for food supply. Currently, the long-term use and/or abuse of traditional bactericides have contributed to the development of immeasurable microorganic resistance and ineffective control efficiency toward plant infections [15–19]. Therefore, novel and safe frameworks with highly efficient bioactivity should be urgently excavated and developed [20–23].

In the development of bactericides, quaternary ammonium compounds possessing the typical positive charge on the nitrogen atom have been intensively highlighted in consideration of their versatile biological profiles, especially in the antibacterial and antifungal aspects [24–30]. Investigations found that these kinds of quaternary ammonium salts (QASs) displayed strong interactions with the cell membrane of microorganisms, thereby leading to cell membrane destruction and finally bacterial death [31–38]. Given this feature, many QASs were commercialized and exploited to sterilize medical instruments, hospital protective clothing, medical implants, wound dressings, food packaging materials, and daily consumer goods [39]. Although this kind of substrates have many prominent properties, most of which are only used in industries. To date, rare QASs are applied in agriculture due to the possible phytotoxicity. Thus, exploration and development of a kind of quaternary ammonium compounds that can safely apply in agriculture for managing the plant bacterial diseases is highly pursued and approved.

On the other hand, morpholinium salts, owning a large steric hindrance scaffold, as a member of QASs, were used in medicine and pesticides (Figure 1). The representative structure of N,N-dimethylmorpholine chloride was used as a type of plant growth regulator that can increase the yield of cotton [40–42]. Another morpholinium salt, namely, pinaverium bromide has been applied as a gastrointestinal crystallizer that can inhibit the flow of calcium ions into intestinal smooth muscle cells. Based on this, the associated pinaverium bromide tablets are safely used for intestinal-related pain [43–45]. Meanwhile, novel biological ingredients possessing the typical morpholinium moiety were constantly prepared and evaluated. For instance, Bakhite et al. screened the insecticidal activity of a kind of morpholinium derivatives and found that compound 1 showed good insecticidal activities against nymphs of cowpea aphid, which was superior to that of the insecticide acetamiprid [46]. Yang et al. prepared the morpholinium-tailored substrate soyaethyl morpholinium ethosulfate (SME) that could self-assemble into micelles with excellent antibacterial effects toward both the Staphylococcus aureus and methicillin-resistant S. aureus. Additionally, SME presented a relatively low toxicity to mammalian cells [47]. Given the unique superiority of this morpholinium scaffold, it should be introduced into the final target framework for the development of safe agricultural chemicals.

In our previous work, we developed and evaluated the antibacterial functions of an array of pyridinium-tailored compounds and found that they showed excellent antibacterial activities but high phytotoxicity toward rice leaves [15, 48]. To sequentially develop a kind of safe quaternary ammonium compounds that can safely apply in agriculture for managing the plant bacterial diseases, herein, the morpholinium scaffold was used to replace the planar pyridinium group to yield 1,3,4-oxadiazole-tailored N-methylmorpholinium derivatives. The following in vitro and in vivo bioassays against Xoo and Xac and the relevant phytotoxicity test were evaluated. Simultaneously, the antifungal activity toward Fusarium oxysporum (F. oxysporum) and Phytophthora cinnamomi (P. cinnamomi) was also screened.

2. Materials and Methods

2.1. Instruments and Chemicals

The NMR spectra of synthesized compounds were measured using the Bruker Biospin-AG-500 apparatus (BRUKEROPTICS, Switzerland). DMSO and TMS were used as the solvent and internal standard, respectively. All chemicals were purchased from Energy Chemical and used without further purification. All solvents meet the standard of analytical purity. The reaction process was monitored by using thin-layer chromatography.

2.2. In Vitro Antibacterial Bioassays

The antibacterial activity against pathogens Xoo and Xac was evaluated by the turbidimeter test [3, 22, 48]. All the synthesized compounds were tested under different concentrations (such as 50.0, 25.0, 12.5, 6.25, 3.125, and 1.5625 μg/mL). Bismerthiazol and thiadiazole copper served as positive controls, whereas dimethyl sulfoxide (DMSO) in sterile distilled water was the blank control. Absorbing 40 μL bacteria solution (OD₅₉₅ = 0.8, logarithmic phase of growth) was added into a 5 mL nutrient broth medium (components: 3 g beef extract, 5 g peptone, 1 g yeast powder, 10 g glucose, 18 g agar in 1 L of distilled water, pH 7.0–7.2) containing different dosages of target compounds and controls. Then, these samples were incubated in a constant shaker (180 rpm) at 28 ± 1°C for about 24–48 h until the DMSO control reached the logarithmic growth phase. After that, 200 μL samples were tested the optical density at 595 nm (OD₅₉₅) through a microplate reader. The turbidity corrected values = OD_{bacterial wilt} − OD_{no bacterial wilt}, and the inhibition rate I was calculated by I = (C − T)/C × 100%. C is the corrected turbidity value of bacterial growth on untreated NB (blank control), and T is the corrected turbidity value of bacterial growth on treated NB. By using SPSS 17.0 software and the obtained inhibition rates at different concentrations, a regression equation was provided. The results of antibacterial activities (expressed by EC₅₀) against Xoo and Xac were calculated from the equation. The experiment was repeated three times.

2.3. In Vivo Bioassays against Rice Bacterial Blight

Compound 3l, thiadiazole copper (TC, 20% suspending agent) as the positive control, and an equivalent DMSO as a blank control in sterile distilled water were used to test the bioactivity against rice bacterial blight [22]. The rice variety “Fengyouxiangzhan” was planted for about 8 weeks before use. For the curative activity, an aseptic scissor dipped with Xoo cells was used to infect rice leaves. One day later, compound 3l and TC with a concentration of 200 μg/mL were evenly sprayed on leaves. Meanwhile, the drug-free solution was used for the negative group. All the treated plants were cultured in the constant temperature (28°C) and humidity (90% RH) incubator for 14 days before testing the disease index. For the protective effects, the difference was that the drug solution with the same dosage was firstly sprayed before inoculation with Xoo cells. The related disease index could be obtained after 14 days. The corresponding control efficiencies I were provided according to the formula: I = (CK − T)/CK × 100%. CK and T represent the disease index of negative and drug-treated controls, respectively.

2.4. Scanning Electron Microscopy (SEM) Imaging

Scanning electron microscopy (SEM) imaging of Xoo cells triggered by compound 3l. 1.5 mL Xoo cells incubated at the logarithmic phase were centrifuged and washed with PBS (pH = 7.2) and resuspended in 1.5 mL of PBS buffer (pH = 7.2). Then, these Xoo cells were incubated with compound 3l at a dose of 14.0 μg/mL and an equivalent volume of DMSO (solvent control) for 8 h in a shaker under 180 rpm at 28°C. After incubation, these samples were washed 3 times with PBS (pH = 7.2). Subsequently, the bacterial cells were fixed for 8 h at 4°C with 2.5% glutaraldehyde and then dehydrated with graded ethanol series and pure tert-butanol (2 times with 10 min/time). Following dehydration, samples were freeze-dried and coated with gold and visualized using Nova Nano SEM 450 [3,22].

2.5. In Vitro Antifungal Bioassay against F. oxysporum and P. cinnamomi

All target molecules were dissolved in DMSO (1.0 mL) and then added into 9.0 mL sterilized water containing Tween 20 (volume ratio 0.1%) before mixing with potato dextrose agar (PDA, 90.0 mL). These compounds were tested at a concentration of 25 μg/mL. The stock solution was transferred into three 9 cm diameter Petri dishes evenly. Then, mycelia dishes of approximately 4 mm diameter were cut from the culture medium and inoculated in the middle of the PDA plate aseptically. The inoculated plates were incubated at 28 ± 1°C for 3–5 days. DMSO in sterile distilled water was used as the negative control, whereas hymexazol served as the positive control. Each treatment condition contained three replicates. Radial growth of the fungal colonies was measured, and the data were statistically analyzed. Inhibitory effects toward these fungi were calculated by the formula I = [(C − T)/(C − 0.4)] × 100%, where C represents the diameter of fungal growth on untreated PDA, T represents the diameter of fungi on treated PDA, and I represents the inhibition rate [49].

2.6. General Procedures for Preparing Intermediate 2

Intermediate 1 was prepared by following our previous works [48, 49]. Then, intermediate 1 (1 mmol) was dissolved in 8 mL DMF containing K₂CO₃ (1.3 mmol) and 1,8-dibromooctane, 1,10-dibromodecane, or 1,12-dibromododecane (1.3 mmol). After stirring the mixture for 2 h at 25°C, the organic matter was extracted with EtOAc, washed twice with purified water, and dried with anhydrous sodium sulfate. After that, the solvent was removed under a reduced pressure. Finally, intermediate 2 was obtained by silica gel column chromatography using petroleum ether/EtOAc (10/1, V/V) as the eluent.

2.7. General Procedures for Preparing Target Compounds 3a–3o

Intermediate 2 (0.15 g) and 4-methylmorpholine (0.5 mL) in 4 mL CH₃CN were refluxed at 85°C for 8 h. After that, the solvent was removed under a reduced pressure. Finally, target compounds 3a–3o were obtained by silica gel column chromatography using CH₂Cl₂/CH₃OH (20/1, V/V) as the eluent.

2.8. 4-Methyl-4-(8-((5-phenyl-1,3,4-oxadiazol-2-yl)thio)octyl)morpholin-4-ium Bromide (3a)

A yellow solid, m. p. 102.5∼104.6°C, yield 63.2%; ¹H NMR (500 MHz, CD₃OD) δ 7.96 (dd, J = 7.8, 1.3 Hz, 2H, Ben-H), 7.52–7.45 (m, 3H, Ben-H), 4.16–4.01 (m, 4H, morpholine-H), 3.89–3.78 (m, 4H, morpholine-H), 3.66 (t, J = 9.3 Hz, 2H, N⁺-CH₂), 3.54 (s, 3H, CH₃), 3.25 (t, J = 7.3 Hz, 2H, S-CH₂), 1.81 (dt, J = 14.5, 7.4 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.48–1.33 (m, 8H, S-(CH₂)₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 165.8, 164.8, 131.8, 129.2, 126.7, 123.7, 60.9, 59.8, 32.5, 29.1, 28.8, 28.5, 28.2, 26.1, 21.9; HRMS (ESI) [M-Br]⁺ calcd for C₂₁H₃₂N₃O₂S: 390.2210, found: 390.2209.

2.9. 4-Methyl-4-(10-((5-phenyl-1,3,4-oxadiazol-2-yl)thio)octyl)morpholin-4-ium Bromide (3b)

A white solid, m. p. 144.1∼146.4°C, yield 65%; ¹H NMR (500 MHz, CD₃OD) δ 7.98 (t, J = 1.5 Hz, 1H, Ben-H), 7.97 (t, J = 1.9 Hz, 1H, Ben-H), 7.61–7.53 (m, 4H, Ben-H), 3.98 (s, 4H, morpholine-H), 3.45 (dd, J = 14.6, 6.9 Hz, 6H, morpholine-H and N⁺-CH₂), 3.29 (t, J = 1.6 Hz, 2H, S-CH₂), 3.19 (s, 3H, CH₃), 1.82 (dt, J = 17.1, 8.5 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.49–1.45 (m, 2H, S-(CH₂)₂CH₂), 1.36 (d, J = 18.2 Hz, 10H, S-(CH₂)₃CH₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 165.9, 165.3, 131.9, 129.1, 126.3, 123.3, 60.3, 59.7, 32.1, 29.2, 29.0, 29.0, 28.8, 28.6, 28.1, 26.0, 21.2; HRMS (ESI) [M-Br]⁺ calcd for C₂₃H₃₆N₃O₂S: 418.2523, found: 418.2522.

2.10. 4-Methyl-4-(12-((5-phenyl-1,3,4-oxadiazol-2-yl)thio)octyl)morpholin-4-ium Bromide (3c)

A white solid, m. p. 111.2∼113.8°C, yield 67%; ¹H NMR (500 MHz, CD₃OD) δ 7.98 (dd, J = 8.2, 1.5 Hz, 2H, Ben-H), 7.59–7.53 (m, 3H, Ben-H), 3.98 (s, 4H, morpholine-H), 3.49–3.42 (m, 6H, morpholine-H and N⁺-CH₂), 3.29–3.28 (m, 2H, S-CH₂), 3.19 (s, 3H, CH₃), 1.82 (dt, J = 15.0, 7.4 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.50–1.44 (m, 2H, S-(CH₂)₂CH₂), 1.34 (d, J = 36.0 Hz, 14H, S-(CH₂)₃CH₂CH₂CH₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 165.9, 165.3, 131.9, 129.1, 126.3, 123.3, 60.3, 59.7, 59.7, 59.7, 32.1, 29.2, 29.2, 29.2, 28.9, 28.7, 28.1, 26.1, 21.2; HRMS (ESI) [M-Br]⁺ calcd for C₂₅H₄₀N₃O₂S: 446.2836, found: 446.2835.

2.11. 4-(8-((5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl)thio)octyl)-4-methylmorpholin-4-ium Bromide (3d)

A brown oily liquid, yield 60%; ¹H NMR (500 MHz, CD₃OD) δ 7.91 (d, J = 7.8 Hz, 1H, Ben-H), 7.62 (d, J = 8.0 Hz, 1H, Ben-H), 7.57 (t, J = 7.7 Hz, 1H, Ben-H), 7.49 (t, J = 7.5 Hz, 1H, Ben-H), 3.98 (s, 4H, morpholine-H), 3.49 (dd, J = 11.0, 6.1 Hz, 6H, morpholine-H and N⁺-CH₂), 3.34–3.28 (m, 2H, S-CH₂), 3.21 (s, 3H, CH₃), 1.87–1.75 (m, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.53–1.44 (m, 2H, S-(CH₂)₂CH₂), 1.43–1.35 (m, 6H, S-(CH₂)₃CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 165.9, 164.0, 132.9, 132.5, 131.1, 130.9, 127.5, 122.5, 60.3, 59.7, 59.7, 47.6, 32.1, 29.2, 28.6, 28.4, 28.0, 25.9, 21.2; HRMS (ESI) [M-Br]⁺ calcd for C₂₁H₃₁ClN₃O₂S: 424.1820, found: 424.1820.

2.12. 4-(10-((5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl)thio)octyl)-4-methylmorpholin-4-ium Bromide (3e)

A brown solid, m. p. 93.6–94.5°C, yield 64%; ¹H NMR (500 MHz, CD₃OD) δ 7.92 (dd, J = 7.8, 1.5 Hz, 1H, Ben-H), 7.62 (dd, J = 8.0, 1.1 Hz, 1H, Ben-H), 7.59–7.55 (m, 1H, Ben-H), 7.52–7.47 (m, 1H, Ben-H), 3.99 (d, J = 9.9 Hz, 4H, morpholine-H), 3.53–3.43 (m, 6H, morpholine-H and N⁺-CH₂), 3.31 (d, J = 7.3 Hz, 2H, CH_2, S-CH₂), 3.20 (s, 3H, CH₃), 1.87–1.76 (m, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.47 (dt, J = 14.8, 7.4 Hz, 2H, S-(CH₂)₂CH₂), 1.36 (dd, J = 18.3, 6.0 Hz, 10H, S-(CH₂)₃CH₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 165.9, 164.0, 132.9, 132.6, 131.1, 130.9, 127.4, 122.5, 60.3, 59.7, 32.1, 29.3, 29.0, 29.0, 28.8, 28.7, 28.1, 26.0, 21.2; HRMS (ESI) [M-Br]⁺ calcd for C₂₃H₃₅ClN₃O₂S: 452.2133, found: 452.2133.

2.13. 4-(12-((5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl)thio)octyl)-4-methylmorpholin-4-ium Bromide (3f)

A brown solid, m. p. 79.6–81.5°C, yield 66%; ¹H NMR (500 MHz, CD₃OD) δ 7.92 (dd, J = 7.8, 1.7 Hz, 1H, Ben-H), 7.62 (dd, J = 8.1, 1.3 Hz, 1H, Ben-H), 7.60–7.54 (m, 1H, Ben-H), 7.48–7.51 (m, 1H, Ben-H), 4.03–3.94 (m, 4H, morpholine-H), 3.53–3.41 (m, 6H, morpholine-H and N⁺-CH₂), 3.34–3.27 (m, 2H, S-CH₂), 3.20 (s, 3H, CH₃), 1.89–1.72 (m, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.51–1.41 (m, 2H, S-(CH₂)₂CH₂), 1.35 (dd, J = 34.1, 10.6 Hz, 14H, S-(CH₂)₃CH₂CH₂CH₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 165.9, 164.0, 132.9, 132.6, 131.0, 130.9, 127.4, 122.6, 120.0, 65.4, 63.9, 60.3, 60.1, 59.7, 53.4, 32.2, 29.3, 29.2, 29.2, 28.9, 28.7, 28.2, 26.1, 21.3; HRMS (ESI) [M-Br]⁺ calcd for C₂₅H₃₉ClN₃O₂S: 480.2446, found: 480.2446.

2.14. 4-(8-((5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl)thio)octyl)-4-methylmorpholin-4-ium Bromide (3g)

A brown solid, m. p. 131.4∼132.6°C, yield 58.2%; ¹H NMR (500 MHz, CD₃OD) δ 7.92 (t, J = 1.7 Hz, 1H, Ben-H), 7.87 (dt, J = 7.5, 1.5 Hz, 1H, Ben-H), 7.59–7.56 (m, 1H, Ben-H), 7.53 (t, J = 7.7 Hz, 1H, Ben-H), 4.01–3.96 (m, 4H, morpholine-H), 3.50 (dd, J = 17.5, 7.3 Hz, 6H, morpholine-H and N⁺-CH₂), 3.30 (d, J = 7.3 Hz, 2H, S-CH₂), 3.22 (s, 3H, CH₃), 1.82 (dd, J = 14.8, 7.4 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.51–1.46 (m, 2H, S-(CH₂)₂CH₂), 1.41 (s, 6H, S-(CH₂)₃CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 165.8, 164.6, 135.0, 131.7, 130.9, 126.0, 125.1, 124.7, 60.4, 59.8, 32.1, 29.1, 28.6, 28.4, 28.0, 25.9, 21.2; HRMS (ESI) [M-Br]⁺ calcd for C₂₁H₃₁ClN₃O₂S: 424.1820, found: 424.1820.

2.15. 4-(10-((5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl)thio)octyl)-4-methylmorpholin-4-ium Bromide (3h)

A yellow solid, m. p. 54.9∼56.3°C, yield 60%; ¹H NMR (500 MHz, CD₃OD) δ 7.96 (t, J = 1.8 Hz, 1H, Ben-H), 7.91–7.88 (m, 1H, Ben-H), 7.60–7.57 (m, 1H, Ben-H), 7.54 (t, J = 7.9 Hz, 1H, Ben-H), 3.98 (s, 4H, morpholine-H), 3.47 (dd, J = 17.6, 9.5 Hz, 6H, morpholine-H and N⁺-CH₂), 3.30–3.28 (m, 2H, S-CH₂), 3.20 (s, 3H, CH₃), 1.81 (dd, J = 15.0, 7.1 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.47 (dd, J = 14.4, 6.8 Hz, 2H, S-(CH₂)₂CH₂), 1.36 (d, J = 20.9 Hz, 10H, S-(CH₂)₃CH₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 165.8, 164.6, 135.0, 131.7, 130.9, 126.0, 125.1, 124.7, 60.3, 59.7, 59.7, 32.1, 29.2, 29.1, 29.0, 28.9, 28.7, 28.2, 26.0, 21.2; HRMS (ESI) [M-Br]⁺ calcd for C₂₃H₃₅ClN₃O₂S: 452.2133, found: 452.2133.

2.16. 4-(12-((5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl)thio)octyl)-4-methylmorpholin-4-ium Bromide (3i)

A white solid, m. p. 114.5∼115.1°C, yield 62%; ¹H NMR (500 MHz, CD₃OD) δ 7.96 (t, J = 1.7 Hz, 1H, Ben-H), 7.91–7.89 (m, 1H, Ben-H), 7.59 (m, J = 8.1, 2.1, 1.2 Hz, 1H, Ben-H), 7.54 (t, J = 7.8 Hz, 1H, Ben-H), 3.99 (d, J = 9.8 Hz, 4H, morpholine-H), 3.50–3.44 (m, 6H, morpholine-H and N⁺-CH₂), 3.29 (dt, J = 3.2, 1.7 Hz, 2H, S-CH₂), 3.20 (s, 3H, CH₃), 1.81 (dt, J = 14.9, 7.4 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.46 (dd, J = 15.1, 7.6 Hz, 2H, S-(CH₂)₂CH₂), 1.34 (d, J = 40.9 Hz, 14H, S-(CH₂)₃CH₂CH₂CH₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 165.8, 164.6, 135.0, 131.7, 130.9, 126.0, 125.1, 124.7, 65.4, 63.6, 60.3, 59.7, 45.9, 43.4, 32.1, 29.3, 29.2, 28.9, 28.8, 28.2, 26.1, 21.3; HRMS (ESI) [M-Br]⁺ calcd for C₂₅H₃₉ClN₃O₂S: 480.2446, found: 480.2446.

2.17. 4-Methyl-4-(8-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)thio)octyl)morpholin-4-ium Bromide (3j)

A white solid, m. p. 113.1–114.6°C, yield 64.8%; ¹H NMR (500 MHz, CDCl₃) δ 7.80 (d, J = 8.2 Hz, 2H, Ben-H), 7.24 (dd, J = 8.5, 0.5 Hz, 2H, Ben-H), 4.16–4.10 (m, 2H, morpholine-H), 4.02 (d, J = 14.1 Hz, 2H, morpholine-H), 3.80 (d, J = 13.2 Hz, 2H, morpholine-H), 3.75–3.70 (m, 2H, morpholine-H), 3.64 (t, J = 10.8 Hz, 2H, N⁺-CH₂), 3.48 (s, 3H, N-CH₃), 3.23–3.18 (m, 2H, S-CH₂), 2.36 (s, 3H, Ben-CH₃), 1.76 (dt, J = 14.8, 7.4 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.44–1.28 (m, 8H, S-(CH₂)₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CDCl₃) δ 165.9, 164.3, 142.3, 129.9, 126.6, 120.8, 120.0, 65.5, 60.9, 59.9, 47.5, 32.5, 29.2, 28.9, 28.6, 28.3, 26.2, 21.9, 21.7; HRMS (ESI) [M-Br]⁺ calcd for C₂₂H₃₄N₃O₂S: 404.2366, found: 404.2366.

2.18. 4-Methyl-4-(10-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)thio)octyl)morpholin-4-ium Bromide (3k)

A white solid, m. p. 136.5–137.4°C, yield 66%; ¹H NMR (500 MHz, CD₃OD) δ 7.83 (d, J = 8.1 Hz, 2H, Ben-H), 7.35 (d, J = 7.9 Hz, 2H, Ben-H), 4.02–3.95 (m, 4H, morpholine-H), 3.47 (m, J = 8.8, 3.7 Hz, 6H, morpholine-H and N⁺-CH₂), 3.28 (dd, J = 7.6, 4.5 Hz, 2H, S-CH₂), 3.21 (s, 3H, N-CH₃), 2.40 (s, 3H, Ben-CH₃), 1.80 (dt, J = 14.8, 7.4 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.45 (dd, J = 14.0, 6.6 Hz, 2H, S-(CH₂)₂CH₂), 1.35 (d, J = 24.5 Hz, 10H, S-(CH₂)₂CH₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 166.0, 164.8, 142.8, 129.7, 126.3, 120.5, 65.4, 60.3, 59.7, 46.0, 32.1, 29.2, 29.0, 28.8, 28.7, 28.1, 26.0, 21.3, 20.3; HRMS (ESI) [M-Br]⁺ calcd for C₂₄H₃₈N₃O₂S: 432.2679, found: 432.2679.

2.19. 4-Methyl-4-(12-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)thio)octyl)morpholin-4-ium Bromide (3l)

A white solid, m. p. 141.5–144.1°C, yield 65%; ¹H NMR (500 MHz, CD₃OD) δ 7.83 (d, J = 8.2 Hz, 2H, Ben-H), 7.35 (d, J = 7.9 Hz, 2H, Ben-H), 3.99 (d, J = 10.5 Hz, 4H, morpholine-H), 3.51–3.44 (m, 6H, morpholine-H and N⁺-CH₂), 3.29–3.26 (m, 2H, S-CH₂), 3.21 (s, 3H, N-CH₃), 2.40 (s, 3H, Ben-CH₃), 1.79 (dd, J = 14.7, 7.3 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.44 (dd, J = 15.0, 7.4 Hz, 2H, S-(CH₂)₂CH₂), 1.39–1.27 (m, 14H, S-(CH₂)₃CH₂CH₂CH₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 165.9, 164.8, 142.8, 129.7, 126.3, 120.4, 60.3, 59.7, 32.1, 29.3, 29.2, 29.2, 28.9, 28.8, 28.2, 26.1, 21.3, 20.4; HRMS (ESI) [M-Br]⁺ calcd for C₂₆H₄₂N₃O₂S: 460.2992, found: 460.2992.

2.20. 4-Methyl-4-(8-((5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl)thio)octyl)morpholin-4-ium Bromide (3m)

A brown oily liquid, yield 64%; ¹H NMR (500 MHz, CDCl₃) δ 8.82 (t, J = 1.9 Hz, 1H, Ben-H), 8.37 (dd, J = 6.4, 1.6 Hz, 1H, Ben-H), 8.36 (d, J = 4.1 Hz, 1H, Ben-H), 7.72 (t, J = 8.0 Hz, 1H, Ben-H), 3.40 (t, J = 6.8 Hz, 3H, morpholine-H), 3.35–3.29 (m, 3H, morpholine-H), 1.92–1.86 (m, 2H, morpholine-H), 3.64 (t, J = 10.8 Hz, 2H, N⁺-CH₂), 1.84 (dd, J = 9.7, 4.6 Hz, 3H, N-CH₃), 1.49 (d, J = 7.5 Hz, 2H, S-CH₂), 1.44 (dd, J = 15.7, 9.1 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.36 (dt, J = 9.5, 6.5 Hz, 8H, S-(CH₂)₃CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CDCl₃) δ 166.0, 163.8, 148.7, 147.1, 132.2, 130.5, 126.1, 125.4, 121.6, 34.1, 32.8, 32.7, 29.2, 28.9, 28.7, 28.6, 28.1; HRMS (ESI) [M-Br]⁺ calcd for C₂₁H₃₁N₄O₄S: 435.2061, found: 435.2061.

2.21. 4-Methyl-4-(10-((5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl)thio)octyl)morpholin-4-ium Bromide (3n)

A white solid, m. p. 72.7–74.9°C, yield 64%; ¹H NMR (500 MHz, CD₃OD) δ 8.75–8.74 (m, 1H, Ben-H), 8.42 (dd, J = 9.2, 2.3 Hz, 1H, Ben-H), 8.36–8.34 (m, 1H, Ben-H), 7.83 (t, J = 8.1 Hz, 1H, Ben-H), 3.99 (d, J = 9.5 Hz, 4H, morpholine-H), 3.51–3.45 (m, 6H, morpholine-H and N⁺-CH₂), 3.34–3.31 (m, 2H, S-CH₂), 3.21 (s, 3H, CH₃), 1.88–1.79 (m, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.51–1.46 (m, 2H, S-(CH₂)₂CH₂), 1.37 (dd, J = 11.9, 8.5 Hz, 10H, S-(CH₂)₃CH₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 166.3, 164.1, 131.9, 130.8, 126.0, 125.0, 120.9, 120.0, 60.3, 59.7, 59.7, 59.5, 32.1, 29.2, 29.1, 29.0, 28.9, 28.7, 28.2, 26.0, 21.2; HRMS (ESI) [M-Br]⁺ calcd for C₂₃H₃₅N₄O₄S: 463.2374, found: 463.2373.

2.22. 4-Methyl-4-(12-((5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl)thio)octyl)morpholin-4-ium Bromide (3o)

A white solid, m. p. 72.7–74.9°C, yield 64%; ¹H NMR (500 MHz, CD₃OD) δ 8.76 (d, J = 1.8 Hz, 1H, Ben-H), 8.45–8.41 (m, 1H, Ben-H), 8.36 (d, J = 7.9 Hz, 1H, Ben-H), 7.83 (t, J = 8.1 Hz, 1H, Ben-H), 3.98 (s, 4H, morpholine-H), 3.47 (m, J = 12.7, 8.3, 5.0 Hz, 6H, morpholine-H and N⁺-CH₂), 3.29 (dd, J = 2.9, 1.4 Hz, 2H, S-CH₂), 3.19 (s, 3H, CH₃), 1.84 (dd, J = 14.9, 7.4 Hz, 4H, S-CH₂CH₂ and N⁺-CH₂CH₂), 1.50–1.45 (m, 2H, S-(CH₂)₂CH₂), 1.31 (s, 14H, S-(CH₂)₃CH₂CH₂CH₂CH₂CH₂CH₂CH₂); ¹³C NMR (126 MHz, CD₃OD) δ 166.3, 164.1, 148.8, 131.9, 130.8, 126.0, 125.0, 120.9, 65.4, 60.3, 59.7, 45.9, 32.2, 29.3, 29.2, 28.9, 28.8, 28.2, 26.1, 21.2; HRMS (ESI) [M-Br]⁺ calcd for C₂₅H₃₉N₄O₄S: 491.2687, found: 491.2679.

3. Results and Discussion

3.1. Synthesis of Target Compounds 3a–3o

As shown in Figure 2, the starting material 1 was reacted with the dibromo alkane to give a key intermediate 2 bearing a bromine atom at the tail. Later, the target compounds 3a–3o were synthesized through the substitution reaction between intermediate 2 and 4-methylmorpholine in the solvent CH₃CN at 85°C for 8 hours. Finally, all the molecular structures were characterized by using the correlative NMR and HRMS analyses (Figures S1–S45, supporting information).

3.2. Antibacterial Activities of Compounds 3a–3o and Structure-Activity Relationship (SAR)

The turbidimetric method was used to screen the antibacterial activity against pathogens Xoo and Xac [41–43]. Meanwhile, the commercial agrochemicals bismerthiazol (BT) and thiadiazole copper (TC) were used as the positive controls. Bioassay results showed that most of these designed molecules displayed good to excellent antibacterial functions (Table 1), indicating that the introduction of N-methylmorpholinium pattern could still endow the final target compounds with appreciable bactericidal effects. Among them, compounds 3l and 3i displayed the strongest antibacterial activity toward pathogens Xoo and Xac with the lowest EC₅₀ values of 1.40 and 0.90 μg/mL, respectively. Those values were quite superior to those of BT (34.69 and 94.96 μg/mL) and TC (67.45 and 77.04 μg/mL). Meanwhile, compounds 3c, 3e, 3f, 3h, 3i, 3k, and 3o gave excellent anti-Xoo activity with EC₅₀ values within 1.70–3.27 μg/mL. For the anti-Xac activity, compounds 3b, 3c, 3e, 3f, 3h, 3l, and 3o provided the EC₅₀ values ranging from 1.45 to 3.39 μg/mL. The SAR was summarized as follows: (1) Increasing the alkyl chain lengths can enhance the anti-Xoo and anti-Xac activity, illustrated by the bioactivity comparison of compounds 3a–3c, 3d–3f, 3g–3i, 3j–3l, and 3m–3o with different alkyl chains. (2) Introducing an electron-donating group (4-CH₃, 3l) provides the best anti-Xoo activity than those compounds bearing electron-withdrawing groups (2-Cl, 3f; 3-Cl, 3i; 3-NO₂, 3o). (3) Fusion of a meta-position chlorine atom (3i) displays better anti-Xac activity than that of compounds with an ortho-position chlorine atom (3f) and a meta-position nitro group (3o). Given the above analysis, compounds 3l and 3i with the best antibacterial ability should be further studied.

3.3. Phytotoxicity Study, In Vivo Antibacterial Activity, and Antibacterial Mechanism

Phytotoxicity test trials at 200 µg/mL showed that the bioactive compound 3l gave a lower phytotoxicity against rice leaves (Figure 3), indicating that this kind of compounds bearing a bulky N-methylmorpholinium pendant are safe for rice plants. The following in vivo bioassays showed that compound 3l could control the rice bacterial leaf blight disease and thus providing good control efficiencies of 55.95% (curative activity) and 53.09% (protective activity) at the dose of 200 μg/mL (Table 2 and Figure 4). Those data were superior to those of TC (37.53% and 36.68%), suggesting that this kind of 1,3,4-oxadiazole-tailored N-methylmorpholinium derivatives can serve as safe quaternary ammonium bactericides for controlling plant bacterial diseases. The preliminary antibacterial mechanism was investigated via scanning electron microscopy imaging. As displayed in Figure 5, the morphology of Xoo cells were transformed from well shaped to corrugated and/or broken after treating Xoo with compound 3l (14 μg/mL, 10 × EC₅₀), suggesting that target compounds had strong interactions with the cell membrane of bacteria.

(a)

(b)

3.4. Antifungal Activities

The antifungal activity against two kinds of plant fungal pathogens was screened by the mycelium growth rate method [49], while hymexazol was co-assayed for comparison. Table 3 shows that some target compounds were identified with good antifungal activities at 25.0 µg/mL. Among them, the inhibition rate of compounds 3b, 3c, 3f, 3h, 3i, and 3o against the F. oxysporum strain was 43.45–59.52%, which was superior to the positive drug hymexazol (39.22%). For the anti-P. cinnamomi activity, compounds 3e and 3f exhibited the inhibitory effects of 50.16% and 44.98%, respectively. This outcome manifests that this kind of 1,3,4-oxadiazole-tailored N-methylmorpholinium derivatives also can serve as antifungal leads for the future design of novel fungicides.

4. Conclusions

In summary, a novel type of N-methylmorpholinium derivatives bearing a typical 1,3,4-oxadiazole scaffold was prepared to explore a kind of quaternary ammonium compounds that could safely apply in agriculture for controlling the plant bacterial diseases. In vitro bioassay screening results showed that compounds 3l and 3i displayed the best antibacterial activity toward pathogens Xoo and Xac with the minimal EC₅₀ values of 1.40 and 0.90 μg/mL, respectively. Interestingly, this kind of N-methylmorpholinium salts gave the lower phytotoxicity toward rice plants. In vivo bioassays revealed that the bioactive compound 3l could control the rice bacterial blight disease and thus providing good curative activity and protective activity of 55.95% and 53.09% at the dose of 200 μg/mL, respectively. Given the above superiority, 1,3,4-oxadiazole-tailored N-methylmorpholinium compounds could be further investigated as safe quaternary ammonium bactericides for managing plant bacterial diseases.

Data Availability

The data supporting these results are available from the corresponding author upon request.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Xinxin Tuo contributed to investigation, data curation, formal analysis, and methodology and prepared the original draft. Jie Yang and Yedong Zhang contributed to data curation, formal analysis, and methodology. Peiyi Wang contributed to data curation, supervision, and formal analysis and reviewed and edit the manuscript.

Acknowledgments

The authors acknowledge the financial supports of the National Natural Science Foundation of China (31860516, 21662009, and 21702037).

Supplementary Materials

The supplementary data contain the related NMR and HRMS spectra of the target compounds 3a–3o and statistical results for the bioactivity by using ANOVA and post hoc analysis. . (Supplementary Materials)

References

R. N. Strange and P. R. Scott, “Plant disease: a threat to global food security,” Annual Review of Phytopathology, vol. 43, no. 1, pp. 83–116, 2005.
View at: Publisher Site | Google Scholar
S. Chakraborty and A. C. Newton, “Climate change, plant diseases and food security: an overview,” Plant Pathology, vol. 60, no. 1, pp. 2–14, 2011.
View at: Publisher Site | Google Scholar
P.-Y. Wang, M.-W. Wang, D. Zeng et al., “Rational optimization and action mechanism of novel imidazole (or imidazolium)-labeled 1,3,4-oxadiazole thioethers as promising antibacterial agents against plant bacterial diseases,” Journal of Agricultural and Food Chemistry, vol. 67, no. 13, pp. 3535–3545, 2019.
View at: Publisher Site | Google Scholar
P. Lo Cantore, N. S. Iacobellis, A. De Marco, F. Capasso, and F. Senatore, “Antibacterial activity of Coriandrum sativum L. and Foeniculum vulgare Miller var.vulgare (miller) essential oils,” Journal of Agricultural and Food Chemistry, vol. 52, no. 26, pp. 7862–7866, 2004.
View at: Publisher Site | Google Scholar
D. O. Niño-Liu, P. C. Ronald, and A. J. Bogdanove, “Xanthomonas oryzae pathovars: model pathogens of a model crop,” Molecular Plant Pathology, vol. 7, no. 5, pp. 303–324, 2006.
View at: Publisher Site | Google Scholar
A. G. de Oliveira, L. S. Murate, F. R. Spago et al., “Evaluation of the antibiotic activity of extracellular compounds produced by the pseudomonas strain against the Xanthomonas citri pv. Citri 306 strain,” Biological Control, vol. 56, no. 2, pp. 125–131, 2011.
View at: Publisher Site | Google Scholar
J. Xia, X. Zhang, D. Yuan, L. Chen, J. Webster, and A. C. Fang, “Gene prioritization of resistant rice gene against xanthomas oryzae pv. oryzae by using text mining technologies,” BioMed Research International, vol. 2013, Article ID 853043, 9 pages, 2013.
View at: Publisher Site | Google Scholar
M. L. Tondo, H. G. Ramon, E. A. Ceccarelli, M. Medina, E. G. Orellano, and M. J. Marta, “Crystal structure of the FAD-containing ferredoxin-NADP+ reductase from the plant pathogen Xanthomonas axonopodis pv. Citri,” Journal of Chemistry, vol. 2013, Article ID 906572, 6 pages, 2013.
View at: Publisher Site | Google Scholar
Y. Abdallah, S. O. Ogunyemi, A. Abdelazez et al., “The green synthesis of MgO nano-flowers using Rosmarinus officinalis L. (Rosemary) and the antibacterial activities against Xanthomonas oryzae pv. Oryza,” Journal of Chemistry, vol. 2019, Article ID 5620989, 8 pages, 2019.
View at: Publisher Site | Google Scholar
W. Lu, L. Pan, H. Zhao et al., “Molecular detection of Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicola, and Burkholderia glumae in infected rice seeds and leaves,” The Crop Journal, vol. 2, no. 6, pp. 398–406, 2014.
View at: Publisher Site | Google Scholar
X. Song, P. Li, M. Li et al., “Synthesis and investigation of the antibacterial activity and action mechanism of 1,3,4-oxadiazole thioether derivatives,” Pesticide Biochemistry and Physiology, vol. 147, pp. 11–19, 2018.
View at: Publisher Site | Google Scholar
B. Li, B. Liu, C. Shan et al., “Antibacterial activity of two chitosan solutions and their effect on rice bacterial leaf blight and leaf streak,” Pest Management Science, vol. 69, no. 2, pp. 312–320, 2013.
View at: Publisher Site | Google Scholar
A. M. Brunings and D. W. Gabriel, “Xanthomonas citri: breaking the surface,” Molecular Plant Pathology, vol. 4, no. 3, pp. 141–157, 2003.
View at: Publisher Site | Google Scholar
J. H. Graham, T. R. Gottwald, J. Cubero, and D. S. Achor, “Xanthomonas axonopodispv.citri: factors affecting successful eradication of citrus canker,” Molecular Plant Pathology, vol. 5, no. 1, pp. 1–15, 2004.
View at: Publisher Site | Google Scholar
P. Wang, M. Gao, L. Zhou et al., “Synthesis and antibacterial activity of pyridinium-tailored aromatic amphiphiles,” Bioorganic & Medicinal Chemistry Letters, vol. 26, no. 4, pp. 1136–1139, 2016.
View at: Publisher Site | Google Scholar
P. Li, D. Hu, D. Xie, J. Chen, L. Jin, and B. Song, “Design, synthesis, and evaluation of new sulfone derivatives containing a 1,3,4-oxadiazole moiety as active antibacterial agents,” Journal of Agricultural and Food Chemistry, vol. 66, no. 12, pp. 3093–3100, 2018.
View at: Publisher Site | Google Scholar
Y. Lin, Z. He, E. N. Rosskopf, K. L. Conn, C. A. Powell, and G. Lazarovits, “A nylon membrane bag assay for determination of the effect of chemicals on soilborne plant pathogens in soil,” Plant Disease, vol. 94, no. 2, pp. 201–206, 2010.
View at: Publisher Site | Google Scholar
J. Shuai, F. Guan, B. He et al., “Self-assembled nanoparticles of symmetrical cationic peptide against citrus pathogenic bacteria,” Journal of Agricultural and Food Chemistry, vol. 67, no. 20, pp. 5720–5727, 2019.
View at: Publisher Site | Google Scholar
S. Manandhar, S. Luitel, and R. K. Dahal, “In vitro antimicrobial activity of some medicinal plants against human pathogenic bacteria,” Journal of tropical medicine, vol. 2019, Article ID 1895340, 5 pages, 2019.
View at: Publisher Site | Google Scholar
H.-P.-T. Ngo, T.-H. Ho, I. Lee et al., “Crystal structures of peptide deformylase from rice pathogen Xanthomonas oryzae pv. oryzae in complex with substrate peptides, actinonin, and fragment chemical compounds,” Journal of Agricultural and Food Chemistry, vol. 64, no. 39, pp. 7307–7314, 2016.
View at: Publisher Site | Google Scholar
A. Piazza, T. Zimaro, B. S. Garavaglia et al., “The dual nature of trehalose in citrus canker disease: a virulence factor for Xanthomonas citri subsp. citri and a trigger for plant defence responses,” Journal of Experimental Botany, vol. 66, no. 9, pp. 2795–2811, 2015.
View at: Publisher Site | Google Scholar
Y.-L. Zhao, X. Huang, L.-W. Liu et al., “Identification of racemic and chiral carbazole derivatives containing an isopropanolamine linker as prospective surrogates against plant pathogenic bacteria: in vitro and in vivo assays and quantitative proteomics,” Journal of Agricultural and Food Chemistry, vol. 67, no. 26, pp. 7512–7525, 2019.
View at: Publisher Site | Google Scholar
Y. Zhang, X. Pan, Y. Duan et al., “The screening of bismerthiazol-resistant genes in Xanthomonas oryzae pv. oryzae,” Australasian Plant Pathology, vol. 44, no. 5, pp. 541–543, 2015.
View at: Publisher Site | Google Scholar
P. Li, L. Shi, M.-N. Gao et al., “Antibacterial activities against rice bacterial leaf blight and tomato bacterial wilt of 2-mercapto-5-substituted-1,3,4-oxadiazole/thiadiazole derivatives,” Bioorganic & Medicinal Chemistry Letters, vol. 25, no. 3, pp. 481–484, 2015.
View at: Publisher Site | Google Scholar
H. Choi, K.-J. Kim, and D. G. Lee, “Antifungal activity of the cationic antimicrobial polymer-polyhexamethylene guanidine hydrochloride and its mode of action,” Fungal Biology, vol. 121, no. 1, pp. 53–60, 2017.
View at: Publisher Site | Google Scholar
A.-G. Xie, X. Cai, M.-S. Lin et al., “Long-acting antibacterial activity of quaternary phosphonium salts functionalized few-layered graphite,” Materials Science and Engineering: B, vol. 176, no. 15, pp. 1222–1226, 2011.
View at: Publisher Site | Google Scholar
C. Peng, A. Vishwakarma, S. Mankoci, H. A. Barton, and A. Joy, “Structure-activity study of antibacterial poly(ester urethane)s with uniform distribution of hydrophobic and cationic groups,” Biomacromolecules, vol. 20, no. 4, pp. 1675–1682, 2019.
View at: Publisher Site | Google Scholar
P. A. Araújo, M. Lemos, F. Mergulhão, L. Melo, and M. Simões, “The influence of interfering substances on the antimicrobial activity of selected quaternary ammonium compounds,” International journal of food science, vol. 2013, Article ID 237581, 9 pages, 2013.
View at: Publisher Site | Google Scholar
Y. F. Ira, J. Golenser, N. Beyth, E. I. Weiss, and A. J. Domb, “Quaternary ammonium polyethyleneimine: antibacterial activity,” Journal of Chemistry, vol. 2010, Article ID 826343, 11 pages, 2010.
View at: Publisher Site | Google Scholar
N. V. Shtyrlin, S. V. Sapozhnikov, A. S. Galiullina et al., “Synthesis and antibacterial activity of quaternary ammonium 4-deoxypyridoxine derivatives,” BioMed Research International, vol. 2016, Article ID 3864193, 8 pages, 2016.
View at: Publisher Site | Google Scholar
I. Sovadinova, E. F. Palermo, M. Urban, P. Mpiga, G. A. Caputo, and K. Kuroda, “Activity and mechanism of antimicrobial peptide-mimetic amphiphilic polymethacrylate derivatives,” Polymers, vol. 3, no. 3, pp. 1512–1532, 2011.
View at: Publisher Site | Google Scholar
J. Huang, R. R. Koepsel, H. Murata et al., “Nonleaching antibacterial glass surfaces via “grafting onto”: the effect of the number of quaternary ammonium groups on biocidal activity,” Langmuir, vol. 24, no. 13, pp. 6785–6795, 2008.
View at: Publisher Site | Google Scholar
W. Lou, S. Venkataraman, G. Zhong et al., “Antimicrobial polymers as therapeutics for treatment of multidrug-resistant Klebsiella pneumoniae lung infection,” Acta Biomaterialia, vol. 78, pp. 78–88, 2018.
View at: Google Scholar
A. Muñoz-Bonilla and M. Fernández-García, “Polymeric materials with antimicrobial activity,” Progress in Polymer Science, vol. 37, no. 2, pp. 281–339, 2012.
View at: Publisher Site | Google Scholar
P. Gilbert and L. E. Moore, “Cationic antiseptics: diversity of action under a common epithet,” Journal of Applied Microbiology, vol. 99, no. 4, pp. 703–715, 2005.
View at: Publisher Site | Google Scholar
L. C. Paslay, B. A. Abel, T. D. Brown et al., “Antimicrobial poly(methacrylamide) derivatives prepared via aqueous RAFT polymerization exhibit biocidal efficiency dependent upon cation structure,” Biomacromolecules, vol. 13, no. 8, pp. 2472–2482, 2012.
View at: Publisher Site | Google Scholar
K. Lienkamp, A. E. Madkour, A. Musante, C. F. Nelson, K. Nüsslein, and G. N. Tew, “Antimicrobial polymers prepared by ROMP with unprecedented selectivity: a molecular construction kit approach,” Journal of the American Chemical Society, vol. 130, no. 30, pp. 9836–9843, 2008.
View at: Publisher Site | Google Scholar
N. D. Koromilas, G. C. Lainioti, G. Vasilopoulos, A. Vantarakis, and J. K. Kallitsis, “Synthesis of antimicrobial block copolymers bearing immobilized bacteriostatic groups,” Polymer Chemistry, vol. 7, no. 21, pp. 3562–3575, 2016.
View at: Publisher Site | Google Scholar
J. Hoque, P. Akkapeddi, V. Yadav et al., “Broad spectrum antibacterial and antifungal polymeric paint materials: synthesis, structure-activity relationship, and membrane-active mode of action,” ACS Applied Materials & Interfaces, vol. 7, no. 3, pp. 1804–1815, 2015.
View at: Publisher Site | Google Scholar
K. S. Malgorzata, B. Malgorzata, and C. Hanna, “The effect of 4,4-dimethylmorpholine chloride (Stymulen) on the Ames tester strains of Salmonella typhimurium,” Acta Biochimica Polonica, vol. 40, no. 1, pp. 46-47, 1993.
View at: Google Scholar
J. S. Knypl, “Control of shoot growth in Agrostemma githago L. by 4,4-dimethylmorpholinium chloride and related compounds,” Acta Societatis Botanicorum Poloniae, vol. 48, no. 3, pp. 483–488, 2015.
View at: Publisher Site | Google Scholar
J. S. Knypl and K. M. Janas, “Effect of 4,4-dimethylmorpholinium chloride and allied compounds on growth of the lettuce hypocotyl,” Acta Societatis Botanicorum Poloniae, vol. 46, no. 1, pp. 129–134, 2015.
View at: Publisher Site | Google Scholar
M. Bouchoucha, A. Faye, G. Devroede, and M. Arsac, “Effects of oral pinaverium bromide on colonic response to food in irritable bowel syndrome patients,” Biomedicine & Pharmacotherapy, vol. 54, no. 7, pp. 381–387, 2000.
View at: Publisher Site | Google Scholar
C. L. Lu, C. Y. Chen, F. Y. Chang et al., “Effect of a calcium channel blocker and antispasmodic in diarrhoea‐predominant irritable bowel syndrome,” Journal of Gastroenterology and Hepatology, vol. 15, no. 8, pp. 925–930, 2000.
View at: Publisher Site | Google Scholar
X.-L. Wang, J.-N. Zhou, L. Ren, X.-L. Pan, H.-Y. Ren, and J. Liu, “Improvement of quality of nonanesthetic colonoscopy by preoperative administration of pinaverium bromide,” Chinese Medical Journal, vol. 130, no. 6, pp. 631–635, 2017.
View at: Publisher Site | Google Scholar
E. A. Bakhite, A. A. Abd-Ella, M. E. A. El-Sayed, and S. A. A. Abdel-Raheem, “Pyridine derivatives as insecticides. Part 1: synthesis and toxicity of some pyridine derivatives against cowpea aphid, Aphis craccivora koch (Homoptera: aphididae),” Journal of Agricultural and Food Chemistry, vol. 62, no. 41, pp. 9982–9986, 2014.
View at: Publisher Site | Google Scholar
S.-C. Yang, I. A. Aljuffali, C. T. Sung, C.-F. Lin, and J.-Y. Fang, “Antimicrobial activity of topically-applied soyaethyl morpholinium ethosulfate micelles against Staphylococcus species,” Nanomedicine, vol. 11, no. 6, pp. 657–671, 2016.
View at: Publisher Site | Google Scholar
P.-Y. Wang, L. Zhou, J. Zhou et al., “Synthesis and antibacterial activity of pyridinium-tailored 2,5-substituted-1,3,4-oxadiazole thioether/sulfoxide/sulfone derivatives,” Bioorganic & Medicinal Chemistry Letters, vol. 26, no. 4, pp. 1214–1217, 2016.
View at: Publisher Site | Google Scholar
Q.-Q. Tao, L.-W. Liu, P.-Y. Wang et al., “Synthesis and in vitro and in vivo biological activity evaluation and quantitative proteome profiling of oxadiazoles bearing flexible heterocyclic patterns,” Journal of Agricultural and Food Chemistry, vol. 67, no. 27, pp. 7626–7639, 2019.
View at: Publisher Site | Google Scholar

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Copyright © 2021 Xinxin Tuo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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