design, synthesis, and antiviral activity of α-aminophosphonates bearing a benzothiophene moiety

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Design, Synthesis, and Antiviral Activity of α-Aminophosphonates Bearing a Benzothiophene moietyPeiwei Zhang a , Chenghao Tang a , Zhiwei Chen a , Bo Wang a , Xiang Wang a , Linhong Jin a ,Song Yang a & Deyu Hu aa State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering /Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education ,Guizhou University , Guiyang , 550025 , P. R. ChinaAccepted author version posted online: 23 Sep 2013.

To cite this article: Phosphorus, Sulfur, and Silicon and the Related Elements (2013): Design, Synthesis, and Antiviral Activityof α-Aminophosphonates Bearing a Benzothiophene moiety, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:10.1080/10426507.2013.829837

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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT 1

Design, Synthesis, and Antiviral Activity of α-Aminophosphonates Bearing a

Benzothiophene moiety

Peiwei Zhang, Chenghao Tang, Zhiwei Chen, Bo Wang, Xiang Wang, Linhong Jin, Song Yang,

Deyu Hu*

State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering / Key

Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou

University, Guiyang, 550025, P. R. China

E-Mails:[email protected](P.W.Z.);[email protected](C.H.T);yan.zhilie(Z.W.

C);[email protected](B.W);[email protected](X.W);[email protected](L.H.J.

); [email protected](S.Y.)

* Author to whom correspondence should be addressed; E-Mails: [email protected]; Tel.:

+86-851-829-2170; Fax: +86-851-829-2170.

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Abstract

A series of α-aminophosphonates containing a benzothiophene moiety was designed and

synthesized. All synthesized compounds were confirmed by 1H NMR, 13C NMR, 31P NMR,

infrared spectroscopy, and elemental analysis. The half-leaf method was used to determine the in

vivo efficacy of α-aminophosphonates bearing a benzothiophene moiety against the tobacco

mosaic virus (TMV). Bioassay results showed that all compounds exhibited certain anti-TMV

activity at 500 µg/mL concentration. Compound 2f exhibited a curative effect of up to 48.1%

against TMV, which was almost similar to that obtained from the standard ningnanmycin (51.9%).

[Supplementary materials are available for this article. Go to the publisher’s online edition of

Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental

files: Additional text, figures, and tables.]

Keywords: α-aminophosphonate, benzothiophene moiety, synthesis, tobacco mosaic virus,

anti-TMV activity.

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Introduction

Plant viruses bring about various detrimental effects on agriculture and horticulture [1]. Tobacco

mosaic virus (TMV), one of the most prevalent plant viruses in the world, is known to infect more

than 400 plant species belonging to 36 families, such as tobacco, tomato, potato, cucumber, and

several ornamental flowers. TMV can change plant phenotypes by destroying mitochondria and

thus impair plant quality. In some fields, nearly 90% to 100% of plants manifest mosaic or leaf

necrosis at harvest. Effectively controlling TMV remains a challenge. No chemical treatment

completely protects plants from TMV infection or eliminates TMV from infected plant tissues

under field conditions. Given the unsatisfactory cure rate (30% to 60%) of common antiviral

agents (e.g., Ningnanmycin and Ribavirin; Figure 1) and the associated huge economic losses of

tobacco companies, this plant virus is named “plant cancer” [2–4].

[Insert Figure 1]

Perhaps the most successful registered anti-plant viral agent, ningnanmycin (Figure 1) produces

a 51.9% in vivo curative effect at 500 µg/mL. Ningnanmycin is a microbial pesticide that destroys

the protein coat of TMV and builds plant host resistance. However, the use of ningnanmycin in

field trials is heavily limited by its photosensitivity and water stickiness. It has been reported that

many chemicals such as pyrazole derivatives [5,6], nucleotides [7], α-aminophosphonate

derivatives [8,9], 3-acetonyl-3-hydroxyoxindole [10], triazolyl compounds [11], oxidized

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polyamines [12], thiadiazoles [13], substituted phenylureas [14], and several natural products

[15–17] exhibit antiviral activity. However, only a few economically viable antiviral chemicals are

available for agricultural applications [18]. Thus, novel potent and structurally concise antiviral

agents should be developed.

Benzothiophene derivatives have a wide range of biological activity in pesticides, including

insecticide [19,20], antibacterial [21], antifungal [22], and anti-inflammatory [23] properties. One

example of these derivatives is benzo[b]thien-4-yl methylcarbamate (Mobam, Figure 1), which is

prepared by Mobil [24]. This compound exhibits a favorable combination of broad-spectrum

insecticidal activity and low mammalian toxicity. Moreover, the methyl 2-((tert-butoxycarbonyl)

amino)-3-(2,3-dimethylbenzo[b]thiophen-7-yl)-3-phenylacrylate reported by Ana et al. [21]

exhibits strong activity against Bacillus cereus, B. subtilis, and Candida albicans at a minimum

inhibitory concentration of 0.125 µg/mL. Many pesticides with potent bioactivity and

benzothiophene are widely used to control plant diseases [25–28]. With these increasing

applications, research on the synthesis and bioactivity of benzothiophene derivatives is gaining

interest from chemists and biologists.

Several aminophosphonates often display interesting bioactivity, such as antibacterial [29,30],

antifungal [31], plant virucidal [32,33], and herbicidal [34,35] activities. Several of these

derivatives are commercialized as pesticides. Phosfolan, glyphosate, and dufulin protect certain

plants from severe diseases and pests (Figure 1). In our previous work, we have designed and

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synthesized α-aminophosphonates with fluorine and heterocyclic moiety; these derivatives exhibit

moderate antiviral bioactivity against TMV and antitumor activity [36–39]. Nevertheless, to the

best of our knowledge, there has been no report on synthesis of α-aminophosphonates derivatives

containing benzothiophene moiety and antiviral activity against TMV, our group were planned to

introduce the benzothiophene groups to the α-aminophosphonates and gained a series of novel

α-aminophosphonates derivatives.

In view of the growing demand for the development of effective and environmentally benign

antiviral agents to protect crops from the deadly pests and virus, we envisioned that the

introduction of benzothiophene moiety into the parent α-aminophosphonate scaffold might lead to

the generation of novel agents with high bioactivities (Fig. 1). In this study, we mean to design and

synthesize a series of α-aminophosphonates derivatives containing benzothiophene moiety, and

then test the antiviral activity against TMV. The half-leaf method was used to determine the in vivo

efficacy of α-aminophosphonates bearing a benzothiophene moiety against the tobacco mosaic

virus (TMV). Bioassay results showed that all compounds exhibited certain anti-TMV activity at

500 µg/mL concentration. Compound 2f produced a curative effect of up to 48.1% against TMV,

almost similar to that obtained from standard ningnanmycin (51.9%). This study demonstrated that

α-aminophosphonate derivatives with a benzothiophene moiety can be used to develop potential

agrochemicals. To our knowledge, this study is the first one on the anti-TMV activity of

α-aminophosphonate derivatives with a benzothiophene moiety.

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Results and Discusssion

Chemistry

The synthetic route to the title compounds is illustrated in Figure 2. The intermediate 1 imine

was prepared by treating substituted 2-aminobenzothiazole and

benzo[b]thiophene-3-carbaldehyde with readily available starting materials. The reaction mixture

was refluxed for 10 h and then cooled down to room temperature. The solvent was removed under

reduced pressure, and the crude product was purified by recrystallization to yield pure imines

1a–1f. The intermediates 1 were dissolved in toluene solution, and different substituted

phosphonate reactions at 109 °C yielded the final compounds (2a–2p).

[Insert Figure 2]

All synthesized compounds (2a to 2p) were confirmed by 1H NMR, 13C NMR, 31P NMR,

infrared (IR) analysis, and elemental analysis (Table 2). The IR spectrum of all synthesized

compounds showed broad absorption bands at around 3500 cm−1 to 3200 cm−1 for -NH and 1235

cm−1 to 1200 cm−1 for P=O, with distinguishing benzene ring broad absorption peaks at 1650 cm−1

to 1500 cm−1. The 1H-NMR spectrum showed two characteristic peaks near δ 8.16 ppm to 8.07

ppm for the -NH proton and near δ 6.88 ppm to 5.99 ppm for the P-CH proton. A broad multiplet

was observed at δ 6.75 ppm to 7.84 ppm for the -ArH proton, and a singlet near δ 3.79 ppm to 3.81

ppm for the methyl (Ar-OCH3) proton signals.

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[Insert Table 2]

Anti-TMV activity

The half-leaf method was used to determine the in vivo efficacy of the title compounds against

TMV. The bioassay results showed that all compounds exhibited certain anti-TMV activity at 500

µg/mL concentration. Compound 2f produced a curative effect of up to 48.1% against TMV,

almost similar to that obtained from the standard ningnanmycin (51.9%).

Experimental

Chemistry

Materials and Instrumentation

Benzo[b]thiophene-3-carbaldehyde was purchased from Accela ChemBio Co. Ltd.

Substituted 2-aminobenzothiazole was purchased from Adamas. Unless otherwise stated, all

reagents and reactants were purchased from commercial suppliers, and melting points were

uncorrected and determined with an XT-4 binocular microscope (Beijing Tech Instrument, China).

1H-NMR, 13C-NMR, and 31P-NMR spectra were recorded at room temperature on a JEOL ECX

500 NMR spectrometer operated at 500 MHz for 1H-NMR, 125 MHz for 13C-NMR, and 200 MHz

for 31P-NMR using CDCl3 as the solvent and tetramethylsilane as the internal standard. IR spectra

were recorded in KBr on a Bruker VECTOR 22 spectrometer, and elements were analyzed with an

Elemental Vario-III CHN analyzer. The course of reactions was monitored by thin-layer

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chromatography (TLC) performed on silica gel GF 254. The Supplemental Materials contains

sample spectra for 2f and 2l (Figures S 1 – S 6)

Synthesis of compounds

Benzo[b]thiophene-3-carbaldehyde (1.0 equiv.) in toluene (5 mL) was slowly added with

constant stirring to a 50 mL three-necked round-bottom flask containing substituted

2-aminobenzothiazole (1.0 equiv.) and anhydrous toluene (10 mL). The reaction mixture was

refluxed for 10 h and then cooled down to room temperature. The solvent was removed under

reduced pressure, and the crude product was purified by recrystallization using

N,N-dimethylethanamine/acetone/petroleum ether to yield pure imines 1a–1f. Phosphonate (0.6

mmol) in one portion was added to a solution of imines 1a–1f (0.5 mol) in toluene (5.0 mL) at

room temperature. The reaction mixture was refluxed for 8 h, the mixture was concentrated, and

the residue was directly purified by preparative TLC (hexane/ethyl ether, 5:1 to 1:1) to yield

products 2a–2p.

Characterization of final compounds (2a–2p)

Diphenyl(benzo[b]thiophen-3-yl((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonat

e

(2a)

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IR (KBr, cm−1): v 3225 (−NH str.), 1252 (C=N str.), 1211 (P=O str.), 1025 (P-O-C str.); 1H-NMR

(500 MHz, CDCl3, ppm): δ 8.16 (d, J = 5.7 Hz, 1H, NH), 7.79–7.84 (m, 2H, Ar-H), 7.50 (d, J = 9.2

Hz, 1H, Ar-H), 7.36–7.42 (m, 2H, Ar-H), 7.05–7.19 (m, 9H, Ar-H), 6.81–6.91 (m, 4H, Ar-H), 6.59

(d, J = 18.3 Hz, 1H, P-CH), 3.81 (s, 3H, Ar-OCH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 163.6

(Ar-C), 155.5 (Ar-C), 146.0 (Ar-C), 140.2 (Ar-C), 137.9 (Ar-C), 132.3 (Ar-C), 129.8 (Ar-C),

129.6 (Ar-C), 129.3 (Ar-C), 127.3 (Ar-C), 127.2 (Ar-C), 125.5 (Ar-C), 125.3 (Ar-C), 124.8


120.3 (Ar-C), 120.0 (Ar-C), 113.4 (Ar-C), 105.3 (Ar-C), 55.9 (P-CH), 48.7 (OCH3); 31P-NMR

(200 MHz, CDCl3, ppm): δ 13.7.

Diphenyl (benzo[b]thiophen-3-yl((6-chlorobenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2b)


(500 MHz, CDCl3, ppm): δ 8.15 (d, J = 8.0 Hz, 1H, NH), 7.83 (d, J = 8.1 Hz, 1H, Ar-H), 7.72 (d, J

= 2.9 Hz, 1H, Ar-H), 7.59 (d, J = 8.6 Hz, 1H, Ar-H), 7.36–7.50 (m, 4H, Ar-H), 7.23 (s, 1H, Ar-H),

7.06–7.20 (m, 8H, Ar-H), 6.75 (d, J = 8.0 Hz, 1H, Ar-H), 6.61 (dd, J1 = 9.2 Hz, J2 = 9.8 Hz, 1H,

P-CH); 13C-NMR (125 MHz, CDCl3, ppm): δ 165.5 (Ar-C), 165.4 (Ar-C), 150.3 (Ar-C), 149.9



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120.3 (Ar-C), 120.2 (Ar-C), 120.1 (Ar-C), 48.4 (P-CH); 31P-NMR (200 MHz, CDCl3, ppm): δ

13.5.

Bis(2-ethoxyethyl) (benzo[b]thiophen-3-yl((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)

phosphonate (2c)


(500 MHz, CDCl3, ppm): δ 8.08 (d, J = 8.0 Hz, 1H, NH), 7.83-7.86 (m, J = 8.1 Hz, 1H, Ar-H), 7.76

(d, J = 2.8 Hz, 1H, Ar-H), 7.34–7.46 (m, 3H, Ar-H), 7.07 (d, J = 2.9 Hz, 1H, Ar-H), 6.86 (dd, J1 =

2.9 Hz, J2 = 2.3 Hz, 1H, Ar-H), 6.67 (s, 1H, Ar-H), 6.11 (dd, J1 = 5.7 Hz, J2 = 6.3 Hz, 1H, P-CH),

4.13–4.29 (m, 4H, P-OCH2), 3.79 (s, 3H, Ar-OCH3), 3.37–3.57 (m, 8H, P-OCH2CH2OCH2CH3),

1.10-1.13 (m, 6H, OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 163.6 (Ar-C), 155.3 (Ar-C),


(Ar-C), 124.3 (Ar-C), 122.6 (Ar-C), 122.5 (Ar-C), 119.8 (Ar-C), 113.4 (Ar-C), 105.1 (Ar-C), 69.4

(P-OCH2CH2), 69.3 (P-OCH2CH2), 69.2 (P-CH), 66.7 (OCH2CH3), 66.6 (OCH2CH3), 66.3

(P-OCH2), 55.8 (P-OCH2), 50.7 (Ar-OCH3), 16.0 (OCH2CH3); 31P-NMR (200 MHz, CDCl3,

ppm): δ 20.9.

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Bis(2-ethoxyethyl)

(benzo[b]thiophen-3-yl((6-chlorobenzo[d]thiazol-2-yl)amino)methyl)phosphonate (2d)


(500 MHz, CDCl3, ppm): δ 8.07 (d, J = 8.0 Hz, 1H, NH), 7.83 (d, J = 8.0 Hz, 1H, Ar-H), 7.79 (s,

1H, Ar-H), 7.35–7.48 (m, 5H, Ar-H), 7.21–7.23 (m, 1H, Ar-H), 6.19 (d, J = 21.2 Hz, 1H, P-CH),

4.14–4.27 (m, 4H, P-OCH2), 3.36–3.55 (m, 8H, P-OCH2CH2OCH2CH3), 1.11 (t, J = 8.6 Hz, 6H,

OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 165.6 (Ar-C), 150.7 (Ar-C), 140.1 (Ar-C),


(Ar-C), 124.8 (Ar-C), 124.5 (Ar-C), 122.7 (Ar-C), 122.5 (Ar-C), 120.4 (Ar-C), 120.1 (Ar-C), 69.5

(P-OCH2CH2), 69.4 (P-OCH2CH2), 69.3 (P-CH), 66.7 (OCH2CH3), 66.6 (OCH2CH3), 66.5

(P-OCH2), 50.6 (P-OCH2), 15.1 (OCH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 20.7.

Diethyl (benzo[b]thiophen-3-yl((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2e)


(500 MHz, CDCl3, ppm): δ 8.08 (d, J = 8.1 Hz, 1H, NH), 7.84–7.87 (m, 2H, Ar-H), 7.34–7.48 (m,

3H, Ar-H), 7.21 (s, 1H, Ar-H), 7.07 (s, 1H, Ar-H), 6.86 (d, J = 8.0 Hz, 1H, Ar-H), 6.06 (d, J = 18.3

Hz, 1H, P-CH), 3.79 (s, 3H, Ar-OCH3), 3.73–4.28 (m, 4H, OCH2CH3), 1.26 (t, J = 13.7 Hz, 3H,

OCH2CH3), 1.02 (t, J = 14.3 Hz, 3H, OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 164.0

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(Ar-C), 63.8 (P-OCH2), 63.5 (P-OCH2), 55.9 (Ar-OCH3), 50.2 (P-CH), 16.6 (OCH2CH3), 16.2

(OCH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.1.

Diethyl (benzo[b]thiophen-3-yl((6-chlorobenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2f)


(500 MHz, CDCl3, ppm): δ 8.09 (d, J = 8.1 Hz, 1H, NH), 7.20–8.09 (m, 8H, Ar-H), 6.16 (d, J =

20.6 Hz, 1H, P-CH), 3.70–4.30 (m, 4H, OCH2CH3), 1.25 (t, J = 6.6 Hz, 3H, OCH2CH3), 1.02 (t, J

= 6.9 Hz, 3H, OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 165.8 (Ar-C), 150.7 (Ar-C), 140.1


124.4 (Ar-C), 122.8 (Ar-C), 122.5 (Ar-C), 120.4 (Ar-C), 119.9 (Ar-C), 63.9 (P-CH), 50.0

(P-OCH2), 48.8 (P-OCH2), 16.5 (OCH2CH3), 16.2 (OCH2CH3); 31P-NMR (200 MHz, CDCl3,

ppm): δ 20.9.

Diethyl (benzo[b]thiophen-3-yl((6-ethoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2g)

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(500 MHz, CDCl3, ppm): δ 8.07 (d, J = 8.0 Hz, 1H, NH), 7.83 (d, J = 12.1 Hz, 2H, Ar-H),

7.35–7.47 (m, 3H, Ar-H), 7.06 (s, 1H, Ar-H), 6.86 (d, J = 9.2 Hz, 1H, Ar-H), 6.66 (s, 1H, Ar-H),

5.99 (d, J = 21.2 Hz, 1H, P-CH), 4.14–4.28 (m, 2H, Ar-OCH2CH3), 3.71–4.02 (m, 4H,

P-OCH2CH3), 1.39 (t, J = 13.8 Hz, 3H, Ar-OCH2CH3), 1.27 (t, J = 13.8 Hz, 3H, P-OCH2CH3),

1.02 (t, J = 14.3 Hz, 3H, P-OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 163.7 (Ar-C), 154.6



(Ar-C), 64.1 (P-OCH2CH3), 63.6 (P-OCH2CH3), 50.3 (P-CH), 49.1 (Ar-OCH2CH3), 16.4

(P-OCH2CH3), 16.1 (P-OCH2CH3), 14.9 (Ar-OCH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ

21.1.

Diethyl (benzo[b]thiophen-3-yl((6-methylbenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2h)


(500 MHz, CDCl3, ppm): δ 8.07 (d, J = 8.0 Hz, 1H, NH), 7.84 (d, J = 7.2 Hz, 2H, Ar-H), 7.34–7.47

(m, 4H, Ar-H), 7.08 (d, J = 8.6 Hz, 1H, Ar-H), 6.65 (s, 1H, Ar-H), 6.01 (dd, J1 = 8.6 Hz, J2 = 8.0

Hz,1H, P-CH), 3.74–4.25 (m, 4H, P-OCH2CH3), 2.37 (s, 3H, Ar-CH3), 1.26 (t, J = 6.9 Hz, 3H,

P-OCH2CH3), 1.03 (t, J = 6.9 Hz, 3H, P-OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 164.7

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(Ar-C), 63.8 (P-OCH2CH3), 63.5 (P-OCH2CH3), 55.9 (P-CH), 49.0 (Ar-CH3), 16.6 (P-OCH2CH3),

16.2 (P-OCH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.0.

Diethyl (benzo[b]thiophen-3-yl((4-methylbenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2i)



= 7.4 Hz, 1H, Ar-H), 7.34–7.43 (m, 3H, Ar-H), 6.96–7.00 (m, 3H, Ar-H), 6.10 (dd, J1 = 8.6 Hz, J2

= 8.6 Hz, 1H, CH), 4.20–4.29 (m, 2H, P-OCH2CH3), 3.75–4.07 (m, 2H, P-OCH2CH3), 2.37 (s, 3H,

Ar-CH3), 1.28 (t, J = 7.2 Hz, 3H, P-OCH2CH3), 1.03 (t, J = 6.9 Hz, 3H, P-OCH2CH3); 13C-NMR

(125 MHz, CDCl3, ppm): δ 164.6 (Ar-C), 151.0 (Ar-C), 140.1 (Ar-C), 138.2 (Ar-C), 130.9 (Ar-C),


(Ar-C), 122.5 (Ar-C), 121.8 (Ar-C), 118.2 (Ar-C), 63.8 (C-N), 49.9 (POCH2CH3), 48.6

(POCH2CH3), 18.5 (Ar-CH3), 16.6 (P-OCH2CH3), 16.2 (P-OCH2CH3); 31P-NMR (200 MHz,

CDCl3, ppm): δ 21.2.

Diethyl (benzo[b]thiophen-3-yl(benzo[d]thiazol-2-ylamino)methyl)phosphonate (2j)

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(500 MHz, CDCl3, ppm): δ 8.11–8.12 (m, 1H, NH), 7.84–7.89 (m, 2H, Ar-H), 7.26–7.59 (m, 6H,

Ar-H), 7.05–7.09 (m, 1H, Ar-H), 6.12 (d, J = 21.2 Hz, 1H, CH), 4.15–4.31 (m, 2H, POCH2CH3),

3.97–4.06 (m, 1H, POCH2CH3), 3.73–3.82 (m, 1H, POCH2CH3), 1.26 (t, J = 9.2 Hz, 3H,

POCH2CH3), 1.03 (t, J = 9.7 Hz, 3H, POCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 165.6



(Ar-C), 119.4 (Ar-C), 63.8 (C-N), 63.6 (P-OCH2CH3), 48.9 (P-OCH2CH3), 16.5 (P-OCH2CH3),

16.2 (P-OCH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.0.

Dibutyl (benzo[b]thiophen-3-yl((6-ethoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2k)


(500 MHz, CDCl3, ppm): δ 8.07 (d, J = 8.1 Hz, 1H, NH), 7.84 (t, J = 2.9 Hz, 2H, Ar-H), 7.35–7.46

(m, 3H, Ar-H), 7.06 (s, 1H, Ar-H), 6.86 (d, J = 9.8 Hz, 1H, Ar-H), 6.80 (s, 1H, Ar-H), 6.02 (d, J =

21.2 Hz, 1H, CH), 4.20-4.32 (m, 2H, P-OCH2CH2CH2CH3), 4.00-4.12 (m, 2H,

P-OCH2CH2CH2CH3), 3.89-3.99 (m, 1H, P-OCH2CH2CH2CH3), 3.64–3.71 (m, 1H,

P-OCH2CH2CH2CH3), 1.54–1.60 (m, 2H, POCH2CH2CH2CH3), 1.38 (t, J = 13.7 Hz, 3H,

Ar-OCH2CH3), 1.26–1.33 (m, 4H, P-OCH2CH2CH2CH3), 1.04–1.11 (m, 2H, Ar-OCH2CH3), 0.79

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(t, J = 7.5 Hz, 3H, P-OCH2CH2CH2CH3), 0.71 (t, J = 7.5 Hz, 3H, P-OCH2CH2CH2CH3); 13C-NMR

(125 MHz, CDCl3, ppm): δ 163.8 (Ar-C), 154.7 (Ar-C), 146.2 (Ar-C), 140.2 (Ar-C), 137.9 (Ar-C),


(Ar-C), 119.8 (Ar-C), 114.1 (Ar-C), 106.0 (Ar-C), 67.4 (C-N), 67.1 (POCH2CH2CH2CH3), 64.2

(OCH2), 50.2 (Ar-OCH2CH3), 48.9 (P-OCH2CH2CH2CH3), 32.6 (P-OCH2CH2CH2CH3), 32.2

(P-OCH2CH2CH2CH3),18.7(P-OCH2CH2CH2CH3),18.5(Ar-OCH2CH3),15.0(P-OCH2CH2CH2C

H3),13.5 (P-OCH2CH2CH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.2.

Dibutyl (benzo[b]thiophen-3-yl((6-chlorobenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2l)


(500 MHz, CDCl3, ppm): δ 8.08 (d, J = 8.1 Hz, 1H, NH), 7.86 (t, J = 7.5 Hz, 2H, Ar-H), 7.36–7.49

(m, 4H, Ar-H), 7.22–7.24 (m, 2H, Ar-H), 6.07 (dd, J1 = 8.6 Hz, J2 = 8.6 Hz,1H, CH), 4.08–4.20

(m, 2H, P-OCH2CH2CH2CH3), 3.64–3.96 (m, 2H, P-OCH2CH2CH2CH3), 1.54–1.60 (m, 2H,

P-OCH2CH2CH2CH3), 1.30–1.33 (m, 2H, P-OCH2CH2CH2CH3), 1.04–1.11 (m, 4H,

P-OCH2CH2CH2CH3), 0.79 (t, J = 7.4 Hz, 3H, P-OCH2CH2CH2CH3), 0.71 (t, J = 6.9 Hz, 3H,

P-OCH2CH2CH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 165.6 (Ar-C), 150.6 (Ar-C), 140.1


124.3 (Ar-C), 122.7 (Ar-C), 122.3 (Ar-C), 120.3 (Ar-C), 119.9 (Ar-C), 67.2 (C-N), 50.0

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(P-OCH2CH2CH2CH3), 48.7 (P-OCH2CH2CH2CH3), 32.4 (P-OCH2CH2CH2CH3), 32.1

(P-OCH2CH2CH2CH3), 18.6 (P-OCH2CH2CH2CH3), 18.4 (P-OCH2CH2CH2CH3), 13.4

(P-OCH2CH2CH2CH3), 13.3 (P-OCH2CH2CH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.0.

Dibutyl (benzo[b]thiophen-3-yl((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2m)


(500 MHz, CDCl3, ppm): δ 8.07 (t, J = 8.0 Hz, 1H, NH), 7.84 (t, J = 7.4 Hz, 3H, Ar-H), 7.35–7.48

(m, 3H, Ar-H), 7.07 (d, J = 2.3 Hz, 1H, Ar-H), 6.87 (d, J = 9.2 Hz, 1H, Ar-H), 6.06–6.11 (m, 1H,

CH), 4.10–4.21 (m, 2H, P-OCH2CH2CH2CH3), 3.91–3.94 (m, 1H, P-OCH2CH2CH2CH3 ), 3.79 (s,

3H, OCH3), 3.65–3.70 (m, 1H, P-OCH2CH2CH2CH3), 1.55–1.60 (m, 2H, P-OCH2CH2CH2CH3),

1.28–1.33 (m, 4H, P-OCH2CH2CH2CH3), 1.06–1.12 (m, 2H, P-OCH2CH2CH2CH3), 0.80 (t, J =

6.9 Hz, 3H, P-OCH2CH2CH2CH3), 0.71 (t, J = 7.4 Hz, 3H, P-OCH2CH2CH2CH3); 13C-NMR (125

MHz, CDCl3, ppm): δ 163.8 (Ar-C), 155.2 (Ar-C), 146.2 (Ar-C), 140.1 (Ar-C), 137.8 (Ar-C),


(Ar-C), 119.6 (Ar-C), 113.2 (Ar-C), 105.1 (Ar-C), 67.3 (C-N), 67.2 (P-OCH2CH2CH2CH3), 67.0

(P-OCH2CH2CH2CH3), 55.8 (OCH3), 32.5 (P-OCH2CH2CH2CH3), 32.2 (P-OCH2CH2CH2CH3),

18.6 (P-OCH2CH2CH2CH3), 18.4 (P-OCH2CH2CH2CH3), 13.5 (P-OCH2CH2CH2CH3), 13.4

(P-OCH2CH2CH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.2.

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Dipropyl

(benzo[b]thiophen-3-yl((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate (2n)


(500 MHz, CDCl3, ppm): δ 8.10 (d, J = 8.1 Hz, 1H, NH), 7.91 (s, 1H, Ar-H), 7.83 (d, J = 13.0 Hz,

1H, Ar-H), 7.34–7.47 (m, 4H, Ar-H), 7.07 (s, 1H, Ar-H), 6.86 (d, J = 11.2 Hz, 1H, CH), 6.11 (dd,

J1 = 8.6 Hz, J2 = 9.2 Hz, 1H, CH), 4.05–4.15 (m, 2H, P-OCH2CH2CH3), 3.89–3.92 (m, 1H,

P-OCH2CH2CH3), 3.70 (s, 3H, OCH3), 3.61–3.67 (m,1H, P-OCH2CH2CH3), 1.58–1.64 (m, 2H,

P-OCH2CH2CH3), 1.35–1.41 (m, 2H, P-OCH2CH2CH3), 0.84 (t, J = 7.5 Hz, 3H,

P-OCH2CH2CH3), 0.68 (t, J = 7.5 Hz, 3H, P-OCH2CH2CH3); 13C-NMR (125 MHz, CDCl3, ppm):

δ 164.0 (Ar-C), 155.3 (Ar-C), 146.3 (Ar-C), 140.1 (Ar-C), 138.0 (Ar-C), 132.2 (Ar-C), 130.6


113.3 (Ar-C), 105.2 (Ar-C), 69.2 (C-N), 55.9 (OCH3), 50.0 (P-OCH2CH2CH3), 48.7

(P-OCH2CH2CH3), 24.0 (P-OCH2CH2CH3), 23.7 (P-OCH2CH2CH3), 10.0 (P-OCH2CH2CH3), 9.9

(P-OCH2CH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.2.

Dipropyl (benzo[b]thiophen-3-yl((6-chlorobenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2o)

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= 7.5 Hz, 1H, Ar-H), 7.35–7.48 (m, 5H, Ar-H), 7.21–7.23 (m, 1H, Ar-H), 6.21 (dd, J1 = 9.2 Hz, J2

= 10.9 Hz, 1H, CH), 4.06–4.19 (m, 2H, P-OCH2CH2CH3), 3.89–3.94 (m, 1H, P-OCH2CH2CH3),

3.61–3.64 (m, 1H, P-OCH2CH2CH3), 1.59–1.65 (m, 2H, P-OCH2CH2CH3), 1.36–1.41 (m, 2H,

P-OCH2CH2CH3), 0.84 (t, J = 7.5 Hz, 3H, P-OCH2CH2CH3), 0.68 (t, J = 7.5 Hz, 3H,

P-OCH2CH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 150.8 (Ar-C), 140.1 (Ar-C), 140.0


124.7 (Ar-C), 124.4 (Ar-C), 122.7 (Ar-C), 122.5 (Ar-C), 120.4 (Ar-C), 119.9 (Ar-C), 69.3 (C-N),

49.8 (P-OCH2CH2CH3), 48.5 (P-OCH2CH2CH3), 24.0 (P-OCH2CH2CH3), 23.7

(P-OCH2CH2CH3), 10.0 (P-OCH2CH2CH3), 9.9 (P-OCH2CH2CH3); 31P-NMR (200 MHz, CDCl3,

ppm): δ 21.1.

Dipropyl (benzo[b]thiophen-3-yl((6-methylbenzo[d]thiazol-2-yl)amino)methyl)phosphonate

(2p)


(500 MHz, CDCl3, ppm): δ 8.08 (t, J = 9.2 Hz, 1H, NH), 7.83–7.90 (m, 2H, Ar-H), 7.33–7.49 (m,

4H, Ar-H), 7.10 (t, J = 9.2 Hz, 2H, Ar-H), 6.08–6.14 (m, 1H, CH), 4.03–4.16 (m, 2H,

P-OCH2CH2CH3), 3.87–3.92 (m, 1H, P-OCH2CH2CH3), 3.61–3.66 (m, 1H, P-OCH2CH2CH3),

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2.37 (d, J = 11.5 Hz, 3H, Ar-CH3), 1.58–1.64 (m, 2H, P-OCH2CH2CH3), 1.35–1.41 (m, 2H,

P-OCH2CH2CH3), 0.85 (t, J = 7.5 Hz, 3H, P-OCH2CH2CH3), 0.68 (t, J = 14.8 Hz, 3H,

P-OCH2CH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 164.8 (Ar-C), 149.9 (Ar-C), 140.1


124.7 (Ar-C), 124.4 (Ar-C), 122.7 (Ar-C), 122.5 (Ar-C), 120.9 (Ar-C), 119.0 (Ar-C), 69.2 (C-N),

50.1 (P-OCH2CH2CH3), 48.9 (P-OCH2CH2CH3), 24.0(P-OCH2CH2CH3), 23.6(P-OCH2CH2CH3),

21.3(Ar-CH3), 10.0 (P-OCH2CH2CH3), 9.8 (P-OCH2CH2CH3); 31P-NMR (200 MHz, CDCl3,

ppm): δ 21.1.

Conclusion

New types of α-aminophosphonate derivatives with a benzothiophene moiety were designed

and synthesized, and the anti-TMV activity of compounds 2a to 2p was evaluated in vitro. The

synthesized compounds exhibited weak to good anti-TMV activity. In particular, compound 2f

produced a curative effect of up to 48.1% against TMV at 500 µg/mL concentration. When the

aminophosphonate group had an ethyl substituent, the compound exhibited significantly higher

activity than the other compounds. To our knowledge, this study is the first one on the synthesis

and anti-TMV activity of α-aminophosphonate derivatives with a benzothiophene moiety.

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Acknowledgements

This work was supported by the National Key Project for Basic Research (Grant

No.2010CB126105) and the National Key Technologies R & D Program of China (Grant No.

2011BAE06B05-6) and the Special Fund for Agro-Scientific Research in the Public Interest

(Grant No. 201203022).

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Table Captions

Table 1: Physical and analytical data on newly synthesized compounds 2a–2p

Figure Captions

Figure 1: Chemical structures of ningnanmycin, commercialized pesticide α-aminophosphonates,

and benzothiophene derivatives

Figure 2: Schematic diagram of synthesis of final compounds (2a–2p)

ONH

C

OHN

HO

HN

HN

O

CH2OH

O NH2

NO

NH2O

Ningnanmycin

OHOH2C N

OHHO

N

N

CONH2

Ribavirin

Phosfolan

S

SN

PO

OO

Glyphosate

HOHN P

OHOH

OO

S

N HN

HC

F

POO

O

Dufulin

HN

O

O

S

Mobam Figure: 1: Chemical structures of Ningnanmycin, Ribavirin, the commercialized pesticide of α-aminophosphonates and benzothiophene derivatives

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NH2

N

SS

CHO

S

HC N

S

N

R1R1

1a-f

S

CH

PO

O OR2

R2HN

S

NR1

2a-p

a

b

Figure 2: Schematic diagram for synthesis of final compounds; a: PhCH3, CH3COOH, reflux, 10h; b: HPO(OR2)2, PhCH3, reflux, 8h; 2 (a-p): R1, R2= a. 6-OCH3, Ph; b. 6-Cl, Ph; c. 6-OCH3, CH2CH2OEt; d. 6-Cl, CH2CH2OEt; e. 6-OCH3, Et; f. 6-Cl, Et; g. 6-OCH2CH3, Et; h. 6-CH3, Et; i. 4-CH3, Et; j. H, Et; k. 6-OCH2CH3, n-Bu; l. 6-Cl, n-Bu; m. 6-OCH3, n-Bu; n. 6-OCH3, n-Pr; o. 6-Cl, n-Pr, p. 6- CH3, n-Pr

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Table 1: Physical and analytical data of the newly synthesized compounds 2a-p Elemental Analysis

Found (%) Calculated (%) Entry Mol. Formula Yield% M.W

C H N C H N

2a C29H23N2O4PS2 65 558.08 61.92 4.32 4.98 62.35 4.15 5.01

2b C28H20ClN2O3PS2 68 562.03 60.18 4.14 5.12 59.73 3.58 4.98

2c C25H31N2O6PS2 57 550.14 54.69 6.02 5.26 54.53 5.67 5.09

2d C24H28ClN2O5PS2 42 554.09 51.32 5.62 5.20 51.93 5.08 5.05

2e C21H23N2O4PS2 62 462.08 54.66 5.56 6.00 54.53 5.01 6.06

2f C20H20ClN2O3PS2 51 466.03 51.37 4.61 5.96 51.44 4.32 6.00

2g C22H25N2O4PS2 42 476.10 55.42 5.47 6.02 55.45 5.29 5.88

2h C21H23N2O3PS2 46 446.09 56.86 5.38 6.42 56.49 5.19 6.27

2i C21H23N2O3PS2 54 446.09 56.49 5.26 6.47 56.49 5.19 6.27

2j C20H21N2O3PS2 52 432.07 55.86 5.42 6.53 55.54 4.89 6.48

2k C26H33N2O4PS2 50 532.16 58.10 6.52 5.47 58.63 6.24 5.26

2l C24H28ClN2O3PS2 47 522.10 55.08 5.86 5.46 55.11 5.40 5.36

2m C25H31N2O4PS2 57 518.15 57.82 6.39 5.49 57.90 6.02 5.40

2n C23H27N2O4PS2 40 490.11 56.00 5.58 5.67 56.31 5.55 5.71

2o C22H24ClN2O3PS2 62 494.07 53.52 5.04 5.89 53.38 4.89 5.66

2p C23H27N2O3PS2 52 474.12 58.06 5.51 5.88 58.21 5.73 5.90

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2013

design, synthesis, and antiviral activity of α-aminophosphonates bearing a benzothiophene moiety

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