Synthesis and antiviral activity of novel thioether derivatives containing 1,3,4-oxadiazole/thiadiazole and emodin moieties

Article abstract of DOI:10.1080/10426507.2015.1114944

A series of novel thioether derivatives containing 1,3,4-oxadiazole/thiadiazole and emodin moieties were designed and synthesized. The structures of the target compounds were confirmed by 1H NMR, 13C NMR, Infrared, and elemental analysis. The results of bioactivity analysis showed that most of the target compounds exhibited moderate to good antiviral activity against tobacco mosaic virus at a concentration of 500 mg/L. Especially, among the title compounds, Y2, Y8, and Y10 possessed appreciable curative activity in vivo, with inhibition rates of 50.51, 52.08, and 54.62%, respectively, which were similar to that of Ningnanmycin (53.40%).

Full text of DOI:10.1080/10426507.2015.1114944

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis and antiviral activity of novel thioether
derivatives containing 1,3,4-oxadiazole/thiadiazole
and emodin moieties
Liangrun Dong, Baojing Song, Jian Wu, Zengxue Wu, Yunying Zhu, Xuewen
Chen & Deyu Hu
To cite this article: Liangrun Dong, Baojing Song, Jian Wu, Zengxue Wu, Yunying Zhu,
Xuewen Chen & Deyu Hu (2016): Synthesis and antiviral activity of novel thioether derivatives
containing 1,3,4-oxadiazole/thiadiazole and emodin moieties, Phosphorus, Sulfur, and Silicon
and the Related Elements, DOI: 10.1080/10426507.2015.1114944
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1114944
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Jan 2016.
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Synthesis and antiviral activity of novel thioether derivatives containing
1,3,4-oxadiazole/thiadiazole and emodin moieties
Liangrun Donga, Baojing Songb, Jian Wua, Zengxue Wua, Yunying Zhua, Xuewen Chena, Deyu
Hua,*
aState 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
bCollege of Chemistry and Chemistry Engineering, Guizhou University, Guiyang, 550025, P. R.
China
E-Mails: dlr0711@163.com (L.R.D); bjsong1119@gmail.com (B.J.S);wujian2691@126.com
(J.W); wzx3120@163.com(Z.X.W); yyingzhu@sina.com (Y.Y.Z); Chenxuewen_2009@
163.com (X.W.C).
*Author to whom correspondence should be addressed; E-Mail: fcc.dyhu@gzu.edu.cn; Tel.:
+86-851-829-2170; Fax: +86-851-829-2170.
Abstract
A series of novel thioether derivatives containing 1,3,4-oxadiazole/thiadiazole and emodin
moieties were designed and synthesized. The structures of the target compounds were confirmed
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by 1HNMR, 13CNMR, IR, and elemental analysis. The results of bioactivity analysis showed that
most of the target compounds exhibited moderate to good antiviral activity against tobacco
mosaic virus (TMV) at a concentration of 500 mg/L. Especially, among the title compounds, Y2,
Y8 and Y10 possessed appreciable curative activity in vivo, with inhibition rates of 50.51%,
52.08% and 54.62%, respectively, which were similar to that of Ningnanmycin (53.40%).
Keywords
Thioether derivative;1,3,4-oxadiazole/thiadiazole; emodin; synthesis; antiviral activity; tobacco
mosaic virus.
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Introduction
Plant diseases, caused by the tobacco mosaic virus (TMV),were found worldwide and
infected members of 9 plant families and at least 125 species, including tobacco, tomato, pepper,
cucumbers, and a number of ornamental flowers [1]. Therefore, TMV, known as a “plant
cancer”, is difficult to control. Ningnanmycin, as shown in Figure S 1 (Supplemental Materials),
is more effective in TMV. However, the use of Ningnanmycin for field trials is largely limited by
its unsatisfactory control efficiency [2].Therefore, it’s a significant challenge for the
development of a highly efficient, novel, and environmentally antiviral agent.
Emodin, an anthraquinone-based pigment and found in rhubarb, polygonumcuspidatum,
aloe, and other polygonaceae medicinal plants, is the most widely distributed one
hydroxyanthraquinones [3, 4]. Emodin shows wide range of pharmacological activities, such as
antibacterial, anti-inflammatory, anti-oxidation, antitumor, antivirus activities [5--9]. In the
agricultural field, emodin also shows good antifungal activity [9], antiviral activity [10], and
insecticidal activity [11]. Therefore, studies on the structure modification of emodin have
attracted a considerable attention.
1,3,4-Oxadiazole/Thiadiazole,a privileged structure, represents a key motif in heterocyclic
chemistry and occupies a prime place in medicinal chemistry due its competence to exhibit a
wide range of pharmacological activities. Recently, derivatives of 1,3,4-oxadiazole/thiadiazole
have been reported for their antibacterial [12, 13], antifungal [14--15], antiviral[16],
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inflammatory [17], antianxiety [18],and anti-tubercular activities [19]. In our previous work, we
have reported a series of 1,3,4-oxadiazole/thiadiazole derivatives which showed better
antibacterial [12--13], antifungal [14--15],antiviral activities [16].
Meanwhile, thioether groups are known to be associated with a wide range of biological
activities, such as antibacterial [20--22], antiviral [23, 24], antitumor [25], and other biological
activity. In recent years, study of this group has attracted growing attention from chemists and
biologists. In our previous studies, we have also designed and synthesized a variety of thioether
derivatives and evaluated for their antiviral activity, the results showed that these compounds
displayed excellent antiviral activity against TMV [26, 27].
In the present study, to aid the development of novel leading compounds with highly active
and readily available antiviral agents, we aim to introduce a 1,3,4-oxadiazole/ thiadiazole group
into the emodin group, using --SCH2-- group as a bridge, to build a novel family of bioactive
molecules. Herein, 14 novel thioether derivatives containing 1,3,4-oxadiazole/thiadiazole and
emodin moieties were designed and synthesized, the structures of the target compounds Y1--Y14
were confirmed by 1HNMR,13CNMR,IR, and MS (HREI) analysis. Bioassays identified that the
target compounds possessed moderate to good curative activity against TMV at the concentration
of 500 mg/L with the inhibition rates of 31.55%--54.62%. Especially, among the target
compounds, compounds Y2, Y8, and Y10 possessed appreciable curative activity in vivo, with
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the inhibition rates of 50.51%, 52.08% and 54.62%, respectively, which were similar to that of
Ningnanmycin (53.40%).
Results and Discussion
Chemistry
The synthetic route of the title compounds Y1--Y14 is illustrated in Scheme 1.
The intermediate 1 was obtained by the hydroxyl methylation of emodin; the reaction
mixture of emodin, (CH3)2SO4 and K2CO3was refluxed in acetone for 8 h and cooled down to
room temperature. Then the mixture was poured into water and separated to obtain intermediate
1. The intermediate 1 and NBS were refluxed, using AIBN as a catalyst, for 24 h. The mixture
was cooled down to room temperature and then poured into water and separated to obtain
intermediate 2. Meanwhile, intermediate 3 was prepared according to the reported methods
[12--13]. Finally, intermediates 2 and 3 were reacted in acetone for 2 h at room temperature and
the purified compounds were separated using thin chromatography (dichloromethane/ethyl
acetate, 25:3) to afford the target compounds Y1--Y14.
To optimize the reaction conditions for the preparation of the target compounds, the
synthesis of the target compound Y1 was used as the model reaction. The effect of different
reaction time, reaction temperature, and solvents on the yields of the target compounds was
determined and the results were summarized in Table S 1 (Supplemental Materials). As shown in
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Table S 1, the highest yield (68%) of the target compound Y1 was obtained under the following
optimal conditions: solvent, acetone; base, K2CO3; temperature, 25°C; and time, 2 h. The
structures of all target compounds Y1--Y14 were confirmed by 1H NMR, 13C NMR, IR, and
elemental analysis and physical and analytical data of the target compounds Y1-Y14 were shown
in Table S 2 (Supplemental Materials). From the spectral data of compounds Y1--Y14, the 1H
NMR spectrum showed two characteristic peaks near δ3.98 to 3.94 ppm for the Ar-OCH3 proton
and near δ4.67 to 4.50 ppm for the S--CH2--Ar proton. The IR spectrum of all the target
compounds showed broad absorption bands of around 3100 to 3020 cm−1 for Ar--H, and 2964 to
2914 cm−1 for CH2,C = O for in the range of 1675 to 1660 cm−1 and C = N for amide in the range
of 1600 to 1590 cm−1. As shown in Table S 2, the elemental analysis of all target compounds is
in good agreement with the theoretical data.
Antiviral activity
The antiviral activity against TMV of the target compoundsY1--Y14 was determined using
the half-leaf method [28--29]. As shown in Table S3, the bioassay results indicated that all of the
target compounds exhibited moderate to good anti-TMV activity at the concentration of 500
mg/L with the inhibition rates of 31.55%--54.62%. Among the target compounds, compounds
Y2, Y8 and Y10 exhibited better curative activity against TMV at 500 mg/L, with the inhibition
rates of 50.51%, 52.08% and 54.62%, respectively, which were similar to that of Ningnanmycin
(53.40%).
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Experimental
General methods
Emodin was purchased from Xi'an Jiatian Biological Technology Co. Ltd. Unless otherwise
stated, all reactants and reagents were purchased from commercial suppliers. The melting points
were determined on an XT-4 binocular microscope (Beijing Tech Instrument, China) and were
not corrected. Mass Spectra were recorded using LC-MS 1100/MSD spectrometer (Agilent,
USA). 1HNMR and 13C NMR(solvent CDCl3) spectral analyses were performed on a JEOL ECX
500 NMR spectrometer operated at 500 MHz for 1H NMR, 125 MHz for 13C NMR at room
temperature and TMS as the internal standard. Elements were analyzed with an Elemental
Vario-III CHN analyzer, and IR spectra were recorded in KBr on a Bruker VECTOR 22
spectrometer. Analytical thin layer chromatography (TLC) was performed on silica gel GF254.
General procedure for preparation of the target compounds Y1--Y14
To an oven-dried three-neck 50 mL round-bottom flask fitted with a magnetic stirring bar,
emodin (1.0 equiv.), (CH3)2SO4 (9.0 equiv.), K2CO3 (9.0 equiv.) and acetone (25 mL) was
added. The reaction mixture was refluxed for 8 h and cooled down to room temperature, then the
mixture was poured into water and separated the precipitate to obtain the intermediate 1. The
intermediate 1 (1.0 equiv.), NBS (1.16 equiv.) and acetone (25 mL) were slowly added a 50 mL
three-necked round-bottom flask. The reaction mixture was refluxed with AIBN as catalyst for
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24h and then cooled down to room temperature, then the solvent was poured into water and
separated to obtain the intermediate 2. Finally, the target compounds Y1--Y14 were synthesized
via condensation of intermediates 2 (1.0 equiv.), and 3 (1.0 equiv.), K2CO3 (3.0 equiv.) with KI
in acetone (25 mL) at the room temperature for 2h. The purified compounds were obtained from
column chromatography on silica gel.
Complete characterization of other compounds and sample 1H and 13C NMR spectra are
presented in the Supplemental Materials (Figure S 2 -- S 43)
Characterization of final compounds (Y10)
1,3,8-Trimethoxy-6-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)anthracene-9,10-dione
(Y10). Yield 82.3%, m.p. 181--182°C;1H NMR (500 MHz, CDCl3, ppm): δ 7.82 (s, 1H, Ar-H),
7.42 (s, 1H, Ar-H), 7.30 (s, 1H, Ar-H), 6.75 (s, 1H, Ar-H), 4.57 (s, 2H, S--CH2), 3.96 (s, 3H,
Ar--OCH3), 3.94 (s, 3H, Ar--OCH3), 3.94 (s, 3H, Ar--OCH3), 2.70 (s, 3H, S--C--CH3); 13C NMR
(125 MHz, CDCl3, ppm): δ183.9 (C = O), 181.5 (C = O), 165.7 (Ar--C = N), 163.9 (S--C--S),
163.8 (Ar--C), 161.8 (Ar--C), 159.9 (Ar--C), 142.7 (Ar--C), 136.3 (Ar--C), 134.9 (Ar--C), 123.1
(Ar--C), 119.4 (Ar--C), 119.0 (Ar--C), 118.3 (Ar--C), 105.4 (Ar--C), 102.0 (Ar--C), 56.7
(Ar--OCH3), 56.5 (Ar--OCH3), 55.9 (Ar--OCH3), 37.6 (Ar--CH2), 15.7 (S--C--CH3); IR (KBr,
cm--1) v 1669 (C = O str.), 1595 (C = N str.), 1250 (Ar--OCH3str.), 1070 (C--S str.), 1020 (N--N
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str.); MS m/z: 443 [M+H]+. Anal. Calcd for C21H18N2O5S2: C, 57.00; H, 4.10; N, 6.33; Found: C,
56.66; H, 4.50; N, 6.36.
Conclusion
In summary, we synthesized a series of novel thioether derivatives containing
1,3,4-oxadiazole/thiadiazole and emodin moieties, and the anti-TMV activity of the target
compounds Y1--Y14 were evaluated using the half-leaf method in vivo. The results of bioactivity
showed that most of synthesized compounds have a certain anti-TMV activity. In particular,
compounds Y2, Y8 and Y10 were found to possess appreciable curative activity against TMV at
the concentration of 500mg/L, with inhibitory rates of 50.51%, 52.08% and 54.62%,
respectively, which were similar to that of Ningnanmycin (53.40%). To the best of our
knowledge, this is the first report on the synthesis and antiviral activity of thioether derivatives
containing 1,3,4-oxadiazole/thiadiazole and emodin moieties.
Acknowledgements
This work was supported by the Natural Science Foundation of China (No. 21362004) and
the National Key Program for Basic Research (No. 2012CB722503).
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Scheme 1: The synthetic route of the target compoundsY1--Y14. a: (CH3)2SO4, K2CO3, acetone,
reflux, 8 h; b: NBS, AIBN, CCl4, reflux, 24 h; c: K2CO3, KI, acetone, 2 h.
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