Synthesis and bioactivities of novel thioether/sulfone derivatives containing 1,2,3-thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety

Article abstract of DOI:10.1016/j.bmcl.2013.08.107

A series of new thioether/sulfone compounds containing 1,2,3-thiadiazole and 1,3,4-oxadiazole/1,3,4-thiadiazole moiety were synthesized, the structures of all products were confirmed by IR, ¹H NMR, ¹³C NMR, and element analysis. Preliminary antifungal activity test showed that compound 8a exhibited moderate antifungal activity against Fusarium oxysporum at 50 μg/mL. Preliminary antiviral activity results showed that compounds 7a, 7c, 7d, 8a, and 9a displayed high antiviral activity against tobacco mosaic virus. The present work demonstrates that thioether/sulfone heterocyclic derivatives could be considered as new lead compounds for antiviral studies.

Full text of DOI:10.1016/j.bmcl.2013.08.107

Accepted Manuscript
Synthesis and bioactivities of novel thioether/sulfone derivatives containing
1,2,3-thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety
Wei-Ming Xu, Shi-Ze Li, Ming He, Song Yang, Xiang-Yang Li, Pei Li
PII:
S0960-894X(13)01056-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2013.08.107
BMCL 20845
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
10 April 2013
5 August 2013
28 August 2013
Please cite this article as: Xu, W-M., Li, S-Z., He, M., Yang, S., Li, X-Y., Li, P., Synthesis and bioactivities of novel
thioether/sulfone derivatives containing 1,2,3-thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety, Bioorganic &
Medicinal Chemistry Letters (2013), doi: http://dx.doi.org/10.1016/j.bmcl.2013.08.107
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Synthesis and bioactivities of novel thioether/sulfone derivatives containing
1,2,3-thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety
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Wei-Ming Xu*, Shi-Ze Li, Ming He, Song Yang*, Xiang-Yang Li, Pei Li
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Center for Research and Development of Fine Chemicals, 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, PR. China.
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* Author to whom correspondence should be addressed; E-Mail:
xuweiming2009@163.com; yngsdqj@126.com.
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Tel.: +86 851 829 2090; Fax: +86 851 362 2211.
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Abstract: A series of new thioether/sulfone compounds containing 1,2,3-thiadiazole
and 1,3,4-oxadiazole/1,3,4-thiadiazole moiety were synthesized, the structures of all
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products were confirmed by IR, H NMR, 13C NMR, and element analysis.
Preliminary antifungal activity test showed that compound 8a exhibited moderate
antifungal activity against F. oxysporum at 50 μg/mL. Preliminary antiviral activity
results showed that compounds 7a, 7c, 7d, 8a, and 9a displayed high antiviral activity
against tobacco mosaic virus. The present work demonstrates that thioether/sulfone
heterocyclic derivatives could be considered as new lead compounds for antiviral
studies.
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Keywords: synthesis; thioether/sulfone; heterocycle; antiviral activity;
Tobacco mosaic virus (TMV) is known to infect members of 9 plant families, and
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at least 125 individual species, including tobacco, tomato, pepper, cucumbers, and a
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Abbreviations used: IR, infra-red spectroscopy; H NMR, H nuclear magnetic resonance; 13C
NMR, 13C nuclear magnetic resonance; G. zeae, Gibberella zeae; F. oxysporum, Fusarium
oxysporum; C. mandshurica, Cytospora mandshurica.
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number of ornamental flowers. Plants infected by TMV are more susceptible to
damage by pests and pathogens, it is found that in certain fields 90-100% of the plants
show mosaic or leaf necrosis by harvesting time.1-3 There are fewer reagents that
registered and commercialized to control TMV in China, moreover, there are no
commercial antiviral reagent that can completely inhibit TMV once it does infect the
plants, actually, the cure rate only 30%-60% by common antiviral agents (e.g.,
ningnanmycin, virus A, and ribavirin).4 Because of the unsatisfactory cure rate and
economic loss of tobacco, much effort has been directed toward the development of
novel, potent, and structurally concise antiviral agents.
Most of the thioether/sulfone derivatives are known to be associated with a broad
spectrum of bioactivity, such as insecticidal, antifungal, and herbicidal in agrichemical.
5-7 In our previous work we had demonstrated antifungal and antibacterial activities of
a series of 2-substituted thioether/sulfone-5-substituted-1,3,4-thiadiazole/oxadiazole
derivatives, moreover, the structure and activity relationship study confirmed that
thioether/sulfone incorporated 1,3,4-oxadiazole/thiadiazole scaffold is an important
pharmacophore.8-10 The compounds bearing a 1,2,3-thiadiazole group possess
versatile biological activities, including fungicide activity, insecticide activity, and
herbicide activity.11-13 As an illustration of practical application, three of them had
already been commercialized in agrichemical: acibenzolar-S-methyl and tiadinil are
commercialized as antiviral, thidiazuron is used as a cotton defoliate
agrochemical.14-15 Modifications substituent group on 1,2,3-thiadiazole have been
performed, for example, in 2010, Fan et al. found that 4-methyl-1,2,3-thiadiazole
containing 1,2,4-ttriazolo[3,4-b][1,3,4] thiadiazoles derivatives have good antiviral
activity,16 and 4-methyl-1,2,3-thiadiazole-5-carboxylates derivatives has been
reported by Wang et al., which possesses good antiviral activity,17 in 2011, Fan et al.
reported that N-tert-butyl-N,N-diacylhydrazines containing 1,2,3-thiadiazoles
derivatives have good antiviral activities too.18
Nevertheless, literature reveals that there are no reports of a molecular scaffold
containing these important cores, fragment-based lead discovery has emerged as a
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more rational and focused approach for molecular modification and drug design. With
this view considering the biological significance of thioether/sulfone, oxadiazole, and
thiadiazole and as part of our program aimed at the discovery and development of
bioactive molecules, here we report the synthesis and biological activity of
thioether/sulfone with 1,2,3-thiadiazoles groups (as figure 1). The structure-activity
relationship (SAR) of these compounds was also discussed.
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(Figure 1)
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The synthetic route designed for the sulfone analogues 9 and 10 were
summarized in Scheme 1. 4-methyl-1,2,3-thiadiazole-5-carbohydrazide 4 was
synthesized from diethyl carbonate in four steps: hydrazidation, condensation,
cyclization, and hydrazidation by standard synthetic methods from commercially
available starting materials,19 5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole-
2-thiol 5 and 5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-thiadiazole-2-thiol 6 was easily
prepared by cyclization. Then, 5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole-
2-thiol 5 and the analogue 6 were converted to thioether derivatives 7 and 8 by a
thioetherification reaction with dimethyl(diethyl) sulfate or halide (RX).20 Treatment
of thioether 7 and 8 by KMnO4 afforded the heterocyclic sulfones 9 and 10, with good
yields.
(Scheme 1)
2-(4-methyl-1,2,3-thiadiazol-5-yl)-5-(methylthio)-1,3,4-oxadiazole(7a)
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White solid; mp 52-54˚C; yield 65.6%; H NMR (500 MHz, CDCl3) δ: 3.12 (s, 3H,
13
CH3), 3.45 (s, 3H, SCH3). C NMR (125 MHz, CDCl3) δ: 159.99, 157.75, 153.42,
131.58, 29.57, 14.32; Anal. Calcd for C6H6N4OS2: C 33.63, H 2.82, N 26.15; found: C
33.51, H 2.51, N 25.75.
2-(4-methyl-1,2,3-thiadiazol-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole (9a)
White solid; mp 132-134˚С; yield 70.5%; 1H NMR (500 MHz, CDCl3) δ: 3.12 (s, 3H,
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CH3), 3.56 (s, 3H, SO2CH3). 13C NMR (125 MHz, CDCl3) δ: 159.99, 157.75, 153.42,
131.58, 29.57, 14.32; IR (KBr, cm-1) ν: 2909, 1546, 1423, 676; Anal. Calcd for
C6H6N4O3S2: C 29.26, H 2.46, N 22.75; found: C 29.16, H 2.73, N 22.44.
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Inhibition effect of heterocyclic thioether/sulfone compounds on phytopathogenic
fungi was studied. Three fungi, representing typical fungi often occurring in the
Chinese agro-ecosystem, G. zeae, F. oxysporum and C. mandshurica, were chosen for
fungicide screening by the poison plate technique.9 The results were compared with
that of commercial agricultural fungicide Hymexazol (broad spectra fungicide), and
summarized in Table 1.
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(Table1)
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As indicated in Table 1, at the concentration of 50 µg/mL, some compounds
showed moderate antifungal activity against F. oxysporum, compound 8a had an
inhibition activity of 49.7% against F. oxysporum, compound 10a inhibited growth of
F. oxysporum at 45.0%, which is almost equal to commercial agricultural fungicide
Hymexazol(53%). However, the results indicated that all tested compounds had
inhibition activities below 21.7% against G. zeae; the inhibition of all the tested
compounds against C. mandshurica was less than 32.0%, which indicated that the title
compounds have low activity against to G. zeae and C. mandshurica.
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To make a judgment of the antiviral potency of the heterocyclic thioether/sulfone
bioactivities, the antiviral bioassay against TMV was assayed according to half-leaf
juice-robbing method, the commercially available plant virucide Ningnanmycin,
perhaps the most successful registered antiviral agent for plant, was used as the
reference,21 the antiviral results are listed in Table2.
(Table 2)
The results of activity against TMV in vivo indicated that (Table 2) most
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compounds showed a certain degree of inhibition activities against TMV. At the
concentration of 500 μg/mL, compounds 7a, 7c, 7d, 8a, and 9a had curative effect
against TMV at 54.1%, 48.4%, 47.1%, 48.3% and 46.8% respectively, which are
almost equal to that of Ningnanmycin; compounds 8d and 8f had an curative rate of
37.6% and 37.3%, respectively; the other compounds showed low curative effect
against TMW. 1,2,3-thiadiazole incorporating 1,3,4-oxadiazole derivatives such as
compounds 7a, 7c, 7d, and 9a showed potent antiviral activities against TMV.
However, slight lowering of activity was noticed with homologues of
1,2,3-thiadiazole incorporating 1,3,4-thiadiazole moiety (Table 2). Moreover,
oxidation of heterocyclic sulfides to their corresponding sulfones reduced the values
of antiviral activities slightly, such as compounds 7a, 7c, 7d, and 8a had higher
activities than those corresponding sulfones compounds 9a, 9c, 9d, and 10a.
Furthermore, it is worthwhile to note that the oxadiazole sulfones linked to less
sterically demanding R group has the best effect, amongst the title compounds, 7a (R
= methyl), 7d (R = ethyl) and 8a (R = ethyl) showed potent antiviral activities against
TMV being significantly higher than the rest (R = 2-fluorobenzyl, benzyl,
4-nitrobenzyl, etc.).
Additionally, some compounds were chosen for further evaluation of protection
and inactivation against TMV in vivo. The results in Table 2 indicate that some of the
tested compounds had good inactivation activity. Among these, compounds 7a and 7d
had inactivation rate of 90.3% and 85.5%, respectively, at 500 μg/mL, which were
almost equal to that of Ningnanmycin, and the other compounds showed lower
inactivation activity compere with Ningnanmycin. As for the protection activity, most
of them had lower activities than the positive control, only compound 7a stood out,
had protection activity of 52.8% at 500 μg/mL, which was equal to that of the positive
control, and the other compounds showed lower protection activity compare with
Ningnanmycin. These results indicated that some compounds had good potential of
anti-TMV bioactivity. There was observed no phytotoxicity to tobacco during the test
courses of experiment.
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Our studies only synthesized limited derivatives, to conclude the structure and
activity relationship, it deserves further synthetic studies and mode of action
determination at the molecular level. In addition, another new derivative of
1,2,3-thiadiazole had been synthesized in our group with good activity of antiviral.
The results of this study indicated that our idea of combination of thioether/sulfone
with 1,2,3-thiadiazole and other heterocycle is an interesting exploration.
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In conclusion, we have generated a number of thioether/sulfone compounds containing
1,2,3-thiadiazole and 1,3,4-oxadiazole/1,3,4-thiadiazole moiety, Preliminary antifungal
results indicated that the title compounds exhibited low to moderate antifungal
activities against F. oxysporum at 50 μg/mL, however, the antiviral activity results
showed that some of these synthesized compounds showed high antiviral activity
against tobacco mosaic virus in vivo. Further studies in order to improve the activity
profiles of the scaffolds are underway in the lab and will soon be communicated.
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Acknowledgments
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The authors wish to thank the National Natural Science Foundation of China
(21262009) and the National Key Technologies R&D Program of China
(2011BAE06B02) for the financial support.
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Supplementary Material
The synthesis, characterization and bioactivity test methods of title compounds are
available in supporting information.
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Table Legend
Table1 The antifungal activities of some title compounds at50 µg/mL
Table 2 The curative activities of some title compounds against TMV at 500 µg/mL
Figure Legend
Figure 1 Design strategy of the target compounds
Scheme Legend
Scheme 1 The synthetic route to title compounds
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Table 1
Inhibition rate (%)
X
compounds
R
G. zeae
F. oxysporum C. mandshurica
O
O
11.7±3.0
26.7±5.4
26.7±2.4
22.0±1.4
32.0±1.4
7a
7b
20.7±1.0
O
O
O
3.2±0.9
-3.0±0.8
-2.0±0.9
10.2±1.2
-0.8±2.3
0.0±2.3
3.5±0.8
-2.2±1.0
-4.5±1.5
7c
7d
7e
O
8.5±2.5
5.2±2.3
0.3±1.0
7f
-1.8±2.1
8.5±4.6
14.0±1.3
21.0±2.4
2.6±1.6
O
O
9a
9b
17.1±1.2
O
2.0±1.3
13.1±2.3
5.1±1.2
9c
O
S
4.8±0.7
8.7±2.3
9.0±1.2
9d
8a
21.7±3.0
49.7±5.4
22.0±1.4
S
8.5±4.6
5.0±0.9
3.0±0.8
60.0±1.2
21.0±2.4
45.0±3.3
33.1±2.9
53.0±2.9
17.1±1.2
-4.5±1.5
11.4±2.2
66.9±2.4
8b
S
10a
10b
S
Hymexazol
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Table 2
Compounds
7a
Curative Inactivation Protection
X
O
O
R
rate (%)
rate (%)
rate (%)
54.1
90.3
52.8
37.2
15.8
35.7
7b
O
O
O
48.4
47.1
35.9
56.4
85.5
-
37.5
46.4
-
7c
7d
7e
O
36.2
66.2
41.2
7f
O
O
46.8
31.4
76.8
61.4
44.8
21.4
9a
9b
O
S
S
S
33.1
48.3
32.6
37.6
43.1
82.9
-
13.1
44.0
-
9c
8a
8b
8d
52.3
32.3
S
21.2
41.3
25.5
8e
S
S
S
S
37.3
38.4
18.7
21.2
-
-
8f
62.5
-
34.7
-
10a
10b
10d
51.5
31.9
S
33.4
25.8
11.6
10e
10f
S
31.3
56.1
-
-
Ningnanmycin
92.5
59.3
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Figure 1
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1
Scheme 1
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3
Reagents and conditions: synthetic route to title compounds. (a) NH2NH2·H2O,
.
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5
6
7
8
CH3CH2OH; (b) CH3COCH2COOC2H5, CH2Cl2; (c) SOCl2; (d) CH3OH, NH2NH2
H2O; (e) for oxadiazoles KOH, CS2, C2H5OH, reflux; and then 5% HCl; (f) for
thiadiazole, KOH, CS2, C2H5OH, room temperature; and then ice-bath for 0-5 ˚С; (g)
NaOH, H2O, RX; (h) KMnO4, CH3COOH;
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