Synthesis and biological activities of benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety

Article abstract of DOI:10.1080/10426507.2018.1539992

A series of benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety were designed, synthesized and evaluated for their antibacterial, antifungal and antiviral activities. The bioassay results indicated that most of target compounds showed good antiviral activities against tobacco mosaic virus (TMV) and antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solanacearum (Rs). Especially, the anti-Xoo effect of title compounds 5k (N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(2-tolyl)-1,3,4-thiadiazol-2-yl)thio)acetamide) and the anti-Rs effect of title compounds 5a (N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(4-(trifluorom ethyl)phenyl)-1,3,4-thiadiazol-2-yl)thio)acetmide) respectively reached 52.4% and 71.6% at 100 μg/mL, which are superior to that of bismerthiazol (32.0% and 52.3%). In addition, the protective and inactivation activities of title compound 5i (N-(5-methoxybenzo [d]thiazol-2-yl)-2-((5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)thio)acetamide) against TMV were 79.5% and 88.3%, respectively, which are better than that of ningnanmycin (76.4% and 86.8%). The above research showed that benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety may be used as potential molecular templates in searching for highly-efficient antiviral and antibacterial agents.

Full text of DOI:10.1080/10426507.2018.1539992

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 biological activities of benzothiazole
derivatives bearing a 1,3,4-thiadiazole moiety
Xu Tang, Zhongbo Wang, Xinmin Zhong, Xiaobin Wang, Lijuan Chen, Ming He
& Wei Xue
To cite this article: Xu Tang, Zhongbo Wang, Xinmin Zhong, Xiaobin Wang, Lijuan Chen, Ming
He & Wei Xue (2018): Synthesis and biological activities of benzothiazole derivatives bearing
a 1,3,4-thiadiazole moiety, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2018.1539992
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2018.1539992
Synthesis and biological activities of benzothiazole derivatives
bearing a 1,3,4-thiadiazole moiety
Xu Tanga, Zhongbo Wanga, Xinmin Zhonga, Xiaobin Wangb, Lijuan Chena, Ming Hea, and Wei Xuea
aState Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering Key Laboratory of Green Pesticide and Agricultural
b
Bioengineering Ministry of Education, Center for Research and Development of Fine Chemicals Guizhou University, Guiyang, China; College
of Sciences, Nanjing Agricultural University, Nanjing, China
ABSTRACT
ARTICLE HISTORY
Received 27 August 2018
Accepted 21 October 2018
A series of benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety were designed, synthesized
and evaluated for their antibacterial, antifungal and antiviral activities. The bioassay results indi-
cated that most of target compounds showed good antiviral activities against tobacco mosaic
virus (TMV) and antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia
solanacearum (Rs). Especially, the anti-Xoo effect of title compounds 5k (N-(5-methoxybenzo[d]-
thiazol-2-yl)-2-((5-(2-tolyl)-1,3,4-thiadiazol-2-yl)thio)acetamide) and the anti-Rs effect of title com-
pounds 5a (N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(4-(trifluorom ethyl)phenyl)-1,3,4-thiadiazol-2-
yl)thio)acetmide) respectively reached 52.4% and 71.6% at 100 µg/mL, which are superior to that
of bismerthiazol (32.0% and 52.3%). In addition, the protective and inactivation activities of title
compound 5i (N-(5-methoxybenzo [d]thiazol-2-yl)-2-((5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)thio)ace-
tamide) against TMV were 79.5% and 88.3%, respectively, which are better than that of ningnan-
mycin (76.4% and 86.8%). The above research showed that benzothiazole derivatives bearing a
1,3,4-thiadiazole moiety may be used as potential molecular templates in searching for highly-effi-
cient antiviral and antibacterial agents.
KEYWORDS
Benzothiazole; 1,3,4-
thiadiazole; antibacterial
activity; antifungal activity;
antiviral activity
GRAPHICAL ABSTRACT
Introduction
pesticides, such as bismerthiazol, thiodiazole copper, ning-
nanmycin, carbendazol and so on, not only lead to the
development of pathogens resistance, but also result in a
harmful influence on the environment and non-target
organisms. Therefore, the discoveries for novel lead com-
pounds with potent agricultural bioactivities are very impor-
tant in the field of agricultural chemistries.
Benzothiazole derivatives are privileged heterocyclic com-
pounds that play key roles in a search for novel medicines
and agrochemicals due to their broad-spectrum bioactiv-
ities,[7] such as antifungal,[8] antibacterial,[9] hemostatic,[10]
anticancer,[11] antiviral,[12] herbicidal,[13] anti-inflamma-
tory[14] and anti-diabetic activities.[15] In the last decades,
some representative benzothiazole derivatives, such as bena-
zolin, benthiavalicarb -isopropyl and dufulin, were devel-
oped as commercial agrochemicals that promoted the rapid
development of agriculture around the world. In our pre-
vious studies, a series of benzothiazole derivatives bearing a
oxime ether,[16] phosphonate[17] or cyanoacrylate[18] group
Agricultural diseases caused by pathogenic bacteria, viruses
and fungi are regarded as the “plant killers” that can result
in the significant losses in agricultural output by causing
necrotic lesions on leaves, stems or fruits.[1,2] As demaging
agricultural bacterial diseases, rice bacterial leaf blight and
ralstonia solanacearum, which were respectively caused by
Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solana-
cearum (Rs), are extremely difficult to manage in agricul-
tural production.[3,4] Meanwhile, tobacco mosaic virus
(TMV) is a classical pathogenic virus that can infects at least
125 agricultural crops including tobacco, tomato, pepper,
potato, cucumber and so on.[5,6] Furthermore, wheat scab,
apple rot and capsicum wilt, which are respectively caused
by Fusarium graminearum (Fg), Oxytetracycline hydrochlor-
ide (Oh) and Capsicum wilt (Cw), are severe fungal diseases
that are extremely difficult to manage in agricultural pro-
duction and affect the qualities and outputs of agricultural
products. However, long-term uses of existing traditional were reported for their desirable agricultural bioactivities.
CONTACT Wei Xue
wxue@gzu.edu.cn
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article can be accessed on the publisher's website https://doi.org/10.1080/10426507.2018.1539992.
ß 2018 Taylor & Francis Group, LLC

2
X. TANG ET AL.
Scheme 1. Synthetic route of the title compounds.
In addition, 1,3,4-thiadiazole is a pivotal sulfurated frag- IR and elemental analyses. In the 1H NMR spectra, the
ment that exists in bioactive compounds with anticancer,[19]
absorption peaks at 9.04-6.95 ppm reveal the existence of
antinociceptive,[20] anxiolytic,[21] antiviral,[22] anticonvul-
aromatic protons of title compounds. At the same time,
sant,[23] antibacterial[24] or antifungal[25] activity. Recently,
the
characteristic
singlets
at
13.44–12.58
and
pharmacological studies on 1,3,4-thiadiazole derivatives
demonstrated that the sulfurated heterocycles had tremen-
dous application foregrounds in the development of novel
agricultural bactericides and virucides. In our preious works,
series of 1,3,4-thiadiazole derivatives bearing sulfone,[3] 1,4-
pentadiene-3-one[26] and myricetin[27] scaffolds were found
to exhibit obvious bioactivities against plant pathogenic bac-
teria and viruses. In order to continue our studies on
searching for novel effective agrichemicals with new action
mechanisms, a 1,3,4-thiadiazole group was introduced into
the 2-position of benzothiazole nucleus to build a new
molecular structure with potent biological activities. Thus, a
series of benzothiazole derivatives bearing a 1,3,4-thiadiazole
moiety were designed, synthesized (Scheme 1) and evaluated
for their antibacterial, antifungal and antiviral activities in
this work.
4.46–3.77 ppm are attributed to the absorptions of –NH–
and –CH2– groups, respectively. The chemical shifts at
166.35–157.45 and 38.43–36.08 ppm in the 13C NMR
spectra confirm the existences of C = O and –CH2– frag-
ments, respectively. In the IR spectra, signals at
1765–1667 and 1597–1547 cm−1 are allocated to the char-
acteristic vibrations of C = O and C = N– fragments,
respectively. In addition, the tested values of elemental
analyses are consistent with the calculated values of
title compounds.
Antifungal and antibacterial activities in vitro
The antifungal effects of target compounds 5a–5o against
Fg, Oh and Cw were evaluated at 50 µg/mL by a mycelial
growth rate method.[32,33] The commercial fungicide carben-
dazol was tested as a positive control under the same condi-
tions, and the results are summarized in Table S1
(Supplemental Materials). As shown in Table S1, the anti-
fungal effects against Fg, Oh and Cw ranged 13.6–26.2%, 7.
7–26.3% and 11.4–31.8%, respectively, which are inferior to
that of carbendazol (100.0%, 100.0% and 100.0%).
The antibacterial effects of target compounds against Xoo
and Rs were also evaluated at 100 µg/mL by a turbidimeter
test.[34,35] The commercial bactericide thiadiazole-copper
was tested as a positive control under the same conditions,
and the antibacterial bioassay results are shown in Table S1
(Supplemental Materials). Table S1 indicated that some tar-
get compounds exhibited considerable antibacterial effects
against Xoo and Rs. Particularly, the anti-Xoo effects of
compounds 5d, 5e, 5f, 5k, 5l and 5m at 100 µg/mL were 41.
2%, 42.7%, 32.7%, 52.4%, 42.3% and 38.7%, respectively,
which are superior to that of bismerthiazol (32.0%). At the
same time, the title compounds 5a, 5f, 5h and 5m exhibited
obvious anti-Rs effects at 100 µg/mL, with corresponding
inhibition rates of 71.6%, 64.7%, 66.5% and 65.3%, respec-
Results and discussion
Chemistry
The synthestic route to title compounds N-(benzo[d]thiazol-
2-yl)-2-((5-phenyl- 1,3,4-thiadiazol-2-yl)thio) acetamide
derivatives (5a–5o) was described in Scheme 1. According to
the reported methods described in the reported litera-
tures,[28,29] the key intermediates 3 (substituted 1,3,4-thiadia-
zole-2-thiols) was synthesized by three steps including
esterification, amidation and cyclization reactions.
Intermediates 4 (substituted 2-chloro-N-(benzo[d]thiazol-2-
yl)acetamides) were prepared by a substitution reaction of
benzo[d]thiazol-2-amine derivatives with chloroacetyl chlor-
ide in chloroform.[30,31] Finally, the substituted 1,3,4-thiadia-
zole-2-thiol (3) was reacted with substituted 2-chloro-N-
(benzo[d]thiazol-2-yl)acetamide (4) in water under 70 °C for
3 h to obtain a benzothiazole derivatives bearing a 1,3,4-thia-
diazole moiety (5) with a good yield.
A series of benzothiazole derivatives bearing a 1,3,4-
1
thiadiazole moiety were identified by H NMR, 13C NMR, tively, which are better than that of bismerthiazol (52.3%).

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Structure-activity relationships of antibacterial activities
better inactivation activities than their corresponding cura-
tive and protection activities as showed in Table S2
(Supplemental Materials). Second, the 4-NO2Ph, 2,4-di-ClPh
and 4-FPh groups on the R1 position greatly improved the
inactivation activities of title compounds against TMV. For
instance, the inactivation activities of target compounds 5b
(R1=4-NO2Ph, R2=5-NO2) and 5i (R1=4-NO2Ph, R2=5-
OMe), 5c (R1=2,4-diClPh, R2=5-NO2) and 5j (R1=2,4-
diClPh, R2=5-OMe), 5f (R1=4-FPh, R2=5-NO2) and 5m
(R1=4-FPh, R2=5-OMe) were 87.4% and 88.3%, 87.5% and
88.3%, 87.1% and 87.6%, respectively, which are better than
that of the other substituent groups. Third, when R2 was
substituted with a 5-OMe group, the corresponding com-
pound 5i has better inactivation effect against TMV than
those compounds bearing a 5-NO2 (5b) or 7-Me (5o) group.
Finally, when R1 was substituted by a 2,4-diCl group, the
obtained compounds exhibited better protection and inacti-
vation activities against TMV. For instance, the protection
and inactivation effects of target compounds 5c (R1=2,4-
diClPh, R2=5-NO2) and 5j (R1=2,4-diClPh, R2=5-OMe) were
77.3% and 87.5%, 78.3% and 88.3%, respectively, which are
better than that of ningnanmycin (76.4% and 86.8%).
Table S1 (Supplemental Materials) showed that the changes
of substituted groups could greatly effect the inhibition
effects against plant bacteria, and some structure activity
relationships analyses were discussed as below. First, the 4-
CF3Ph and 4-FPh groups on the R1 position are favorable
for the anti-Rs acvitities of target compounds. For example,
the 4-FPh and 4-CF3Ph moieties on the R1 position were
advantageous for their antibacterial activities against Rs. For
instance, compounds 5a (R1=4-CF3Ph, R2=5NO2), 5f (R1=4-
FPh, R2=5-NO2), 5h (R1=4-CF3Ph, R2=5-OMe) and 5m
(R1= 4-FPh, R2=5-OMe) exhibited important anti-Rs effects
at 100 µg/mL, with corresponding inhibition rates of 71.6%,
64.7%, 66.5% and 65.3%, respectively, which are better than
that of the other substituent groups. At the same time, the
2-MePh, 2-MeOPh and 4-FPh groups on the R1 position are
favorable for the anti-Xoo acvitities of target compounds.
For example, the anti-Xoo effects of compounds 5d (R1=2-
MePh, R2=5-NO2) and 5k (R1=2-MePh, 5-OMe), 5e (R1=2-
MeOPh, R2=5-NO2) and 5l (R1=2-MeOPh, R2=5-OMe), 5f
(R1=4-FPh, 5-NO2) and 5m (R1=4-FPh, 5-OMe) at 100 µg/
mL ranged from 32.7% to 52.4%, which are better than that
of thiadiazole-copper (32.0%). Furthermore, when R2 was
substituted by a 5-OMe group, the obtained compounds
exhibited better antibacterial effects against Xoo and Rs. For
instance, the anti-Xoo and anti-Rs effects of title compound
5i (R2=5-OMe, R1=4-NO2) were 26.9% and 25.1%, respec-
tively, which are better than that of title compounds 5b
(R2=5-NO2, R1=4-NO2, 0.0% and 8.7%) and 5o (R2=7-Me,
R1=4-NO2, 7.3% and 6.2%).
Experimental
General methods
All reagents and solvents purchased from Chinese Chemical
Reagent Company are analytical or chemical pure. Melting
points of synthesized compounds were measured by a
uncorrected XT-4 Binocular Microscope (Beijing Tech.
Instrument, China). Using DMSO-d6 as the solvent and
TMS as an internal standard, a JEOL-ECX 500 NMR spec-
Antiviral activities against TMV in vitro
1
trometer (JEOL, Japan) were used to record the H and 13C
The antiviral effects of target compounds 5a–5o against NMR spectra of target compounds. The IR spectra were
TMV in vivo were evaluated by a half leaf blight spot measured by
a
Bruker VECTOR 22 spectrometer
method,[36,37] and are shown in Table S2 (Supplemental (SHIMADZU, Japan) using a KBr disk. The elemental analy-
Materials). The commercial viricide ningnanmycin was ses were measured by an Elementar Vario-III CHN Analyser
tested as a positive control under the same conditions. The (Elementar, German). The Supplemental Materials contains
1
results from Table S 2 demonstrate that the curative, protec- sample H and 13C NMR spectra and IR spectra of products
tion and inactivation activities ranged 40.1–54.6%, 5 (Figures S1–S45).
72.3–79.5% and 82.4–88.3%, respectively. Among them, tar-
get compounds 5h, 5i, 5j, 5k, 5l and 5n showed protective
activities against tobacco mosaic virus (TMV), with corre-
Synthesis of target compounds 5a-5o
sponding inhibition rates of 78.3%, 79.5%, 78.3%, 78.3%,
78.9% and 78.5%, respectively, which are superior to ning-
nanmycin (76.4%). At the same time, the inactivation activ-
ities of target compounds 5b, 5c, 5f, 5i, 5j, 5k and 5m were
87.4%, 87.5%, 87.1%, 88.3%, 88.3%, 87.2% and 87.6%,
respectively, which are better than those of ningnanmy-
cin (86.8%).
According to the reported methods described in the
reported literatures,[29,30] the key intermediates 3 (substi-
tuted 1,3,4-thiadiazole-2-thiols) was synthesized by three
steps including esterification, amidation and cyclization
reactions. Intermediates 4 (substituted 2-chloro-N-(ben-
zo[d]thiazol-2-yl)acetamides) were prepared by a substitu-
tion reaction of benzo[d]thiazol-2-amine derivatives with
chloroacetyl chloride in chloroform.[31,32] A mixture of a
intermediate
3
(20 mmol) and potassium hydroxide
Structure-activity relationships of antiviral activities
(20 mmol) in the water (20 mL) was stirred at room temper-
Table S2 (Supplemental Materials) indicated that the anti- ature for 10 min. Then, substituted 2-chloro-N-(benzo[d]-
TMV activities of target compounds were greatly affected by thiazol-2-yl) acetamide (20 mmol) was added to the above
structural variations of benzothiazole derivatives bearing a 1, solution and stirred at 70 °C for 3 h. After the reaction was
3,4-thiadiazole moiety. First, all title compounds exhibited finished, the solvent was filtered, and the obtained crude

4
X. TANG ET AL.
product was purified by recrystallization form a mixture of benzothiazole-5-C), 143.70 (s, benzothiazole-8-C), 133.99
methanol and dichloromethane (V:V = 1:1) to produce title
compounds 5a–5o.
(s, Ar-4-C), 132.77 (s, Ar-2-C), 129.42 (s, Ar-1-C), 122.38
(s, Ar-3-C), 121.37 (s, Ar-5-C), 120.14 (s, Ar-6-C), 119.69
(s, benzothiazole-7-C), 117.60 (s, benzothiazole-6-C),
109.95 (s, benzothiazole-4-C), 36.25 (s, -SCH2-); IR (KBr,
cm−1) ν: 3460, 3184, 2963, 1684 (C = O), 1558 (C = N),
1523, 1473, 1398, 1375, 1261, 1153, 1065, 979, 825, 748;
Anal. calc. for C17H9Cl2N5O3S3: C, 40.97; H, 1.82; N,
14.05; Found: C, 40.66; H, 1.83; N, 14.17.
N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(4-(trifluoromethyl)-
phenyl)-1,3,4-thiadiazol-2-yl)thio)acetmide (5a)
Yellow solid, yield: 81%, m.p: 219–222 °C; 1H NMR
(500 MHz, DMSO-d6) δ 13.15 (s, 1H, –NH–), 9.01 (d,
J = 2.4 Hz, 1H, benzothiazole-4-H), 8.25 (dd, J = 9.0,
2.4 Hz, 1H, benzothiazole-6-H), 8.00–7.96 (m, 2H, benzo-
thiazole-7-H, Ar-2-H), 7.89 (d, J = 9.0 Hz, 1H, Ar-6-H),
7.40–7.36 (m, 2H, Ar-3,5-2H), 4.47 (s, 2H, –SCH2–); 13C
NMR (126 MHz, DMSO-d6) δ 167.40 (s, benzothiazole-2-
C), 167.07 (s, thiadiazole-2-C), 166.28 (s, C = O), 157.35
(s, thiadiazole-5-C), 148.12 (s, benzothiazole-9-C), 133.42
(s, benzothiazole-5-C), 131.65 (s, benzothiazole-8-C),
131.36 (s, Ar-1-C), 130.53 (s, Ar-4-C), 128.86 (s, Ar-2-C),
127.25 (s, Ar-6-C), 126.94 (s, Ar-3-C), 125.41(s, Ar-5-C),
124.25 (s, benzothiazole-7-C), 123.25 (s, benzothiazole -6-
C), 119.72 (s, benzothiazole-4-C), 37.49 (s, -CH2-); IR
(KBr, cm−1) ν: 3460, 3167, 3003, 1688 (C = O), 1558
(C = N), 1394, 1327, 1259, 1261, 1062, 1029, 831, 942, 750,
704, 663; Anal. calc. for C18H13F3N5O4S2: C, 43.46; H,
2.03; N, 14.03; Found: C, 43.79; H, 2.01; N, 13.97.
N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(o-tolyl)-1,3,4-thiadia-
zol-2-yl)thio)acetamide (5d)
Yellow solid, yield: 81%, m.p: 226–228 °C; 1H NMR
(500 MHz, DMSO-d6) δ 13.19 (s, 1H, –NH–), 9.04 (s, 1H,
benzothiazole-4-H), 8.26 (d, J = 8.9 Hz, 1H, benzothiazole
-6-H), 7.90 (d, J = 8.9 Hz, 1H, benzothiazole-7-H), 7.61 (d,
J = 7.6 Hz, 1H, Ar-6-H), 7.46-7.36 (m, 2H, Ar-4,5-2H), 7.31
(t, J = 7.2 Hz, 1H, Ar-3-H), 4.51 (d, J = 21.5 Hz, 2H,
–SCH2–), 2.44 (s, 3H, –CH3); 13C NMR (126 MHz, DMSO-
d6) δ 167.35 (s, benzothiazole-2-C), 164.65 (s, thiadiazole-2-
C), 163.22 (s, C = O), 157.37 (s, thiadiazole-5-C), 154.90 (s,
benzothiazole-9-C), 148.12 (s, benzothiazole-5-C), 132.87 (s,
benzothiazole-8-C), 131.64 (s, Ar-1-C), 130.51 (s, Ar-2-C),
127.61 (s, Ar-3-C), 127.24 (s, Ar-4-C), 124.22 (s, Ar-5,6-2C),
120.31 (s, benzothiazole-7-C), 119.72 (s, benzothiazole-6-C),
116.88 (s, benzothiazole-4-C), 37.30 (s, –CH2–), 18.49 (s,
–CH3); IR (KBr, cm−1) ν: 3191, 3055, 2917, 1695 (C = O),
1574 (C = N), 1447, 1374, 1297, 1283, 1164, 1085, 977, 905,
834, 797; Anal. calc. for C18H13N5O3S3: C, 48.74; H, 2.95; N,
15.79; Found: C, 48.68; H, 2.96; N, 15.73.
N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(4-nitrophenyl)-1,3,4-
thiadiazol-2-yl)thio)acetamide (5b)
Red solid, yield: 76%, m.p: >250 °C; 1H NMR (500 MHz,
DMSO-d6) δ 13.16 (s, 1H, –NH–), 9.03 (dd, J = 9.4, 2.4 Hz,
1H, benzothiazole-6-H), 8.37–8.33 (m, 2H, benzothiazole-
4,7-2H), 8.25 (dd, J = 8.9, 2.4 Hz, 1H, Ar-3-H), 8.19-8.15 (m,
2H, Ar-5,6-2H), 7.89 (dd, J = 8.9, 4.0 Hz, 1H, Ar-3-H), 4.53
(s, 2H, -SCH2-); 13C NMR (126 MHz, DMSO-d6) δ 168.77
(s, benzothiazole-2-C), 167.71 (s, thiadiazole-2-C), 165.25 (s,
C = O), 165.08 (s, thiadiazole-5-C), 163.26 (s, benzothiazole-
9-C), 154.34 (s, benzothiazole-5-C), 143.30 (s, Ar-4-C),
132.87 (s, Ar-1-C), 130.47 (d, J = 8.8 Hz, Ar-2-C), 126.39 (s,
Ar-6-C), 122.21 (s, Ar-3-C), 120.94 (s, Ar-5-C), 119.40 (s,
benzothiazole-7-C, benzothiazole-6-C), 117.22 (s, benzothia-
zole-6-C), 117.04 (s, benzothiazole-4-C), 38.20 (s, –CH2–);
IR (KBr, cm−1) ν: 3300, 3081, 2933, 1693 (C = O), 1574
(C = N), 1518, 1492, 1346, 1288 1149, 1079, 982, 904, 853;
Anal. calc. for C17H10N6O5S3: C, 43.03; H, 2.12; N, 17.71;
Found: C, 43.27; H, 2.11; N, 17.74.
N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(2-methoxyphenyl)-
1,3,4-thiadiazol-2-yl)thio) acetamide (5e)
Yellow solid, yield: 83%, m.p: 204–206 °C; 1H NMR
(500 MHz, DMSO-d6) δ 13.44–12.84 (s, 1H, –NH–), 9.03 (t,
J = 5.4 Hz, 1H, benzothiazole-4-H), 8.25 (dt, J = 14.2, 7.1 Hz,
1H, benzothiazole-6-H), 8.18 (dd, J = 7.9, 1.7 Hz, 1H, benzo-
thiazole-7-H), 7.91 (t, J = 11.4 Hz, 1H, Ar-6-H), 7.58–7.47
(m, 1H, Ar-4-H), 7.30-7.19 (m, 1H, Ar-5-H), 7.15–7.05 (m,
1H, Ar-3-H), 4.55–4.31 (m, 2H, –SCH2–), 3.96 (d,
J = 18.0 Hz, 3H, –OCH3); 13C NMR (126 MHz, DMSO-d6) δ
167.32 (s, benzothiazole-2-C), 165.03 (s, thiadiazole-2-C),
162.43 (s, C = O), 157.39 (s, thiadiazole-5-C), 155.92 (s, ben-
zothiazole -9-C), 148.12 (s, Ar-2-C), 133.25 (s, benzothia-
zole-5-C), 131.64 (s, benzothiazole-8-C), 130.50 (s, Ar-1-C),
127.74 (s, Ar-4-C), 127.24 (s, Ar-6-C), 124.22 (s, benzothia-
zole-7-C), 121.79 (s, Ar-5-C), 119.72 (s, benzothiazole-6-C),
118.35 (s, benzothiazole-4-C), 113.01 (s, Ar-3-C), 56.69 (s,
–OCH3), 37.28 (s, -SCH2-); IR (KBr, cm−1) ν: 3420, 3365,
3327, 3930, 1684 (C = O), 1570 (C = N), 1548, 1474, 1435,
1395, 1261, 1166, 1059, 1030, 829; Anal. calc. for
C18H13N5O4S3: C, 47.05; H, 2.85;N, 15.24; Found: C, 47.17;
N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(2,4-dichlorophenyl)-
1,3,4-thiadiazol-2-yl)thio)acetamide (5c)
Yellow solid, yield: 80%, m.p: 246–247 °C; 1H NMR
(500 MHz, DMSO-d6) δ 13.32 -12.91 (m, 1H, –NH–), 8.99
(s, 1H, benzothiazole-4-H), 8.24 (d, J = 8.9 Hz, 1H, benzo-
thiazole-6-H), 8.09 (d, J = 8.5 Hz, 1H, benzothiazole-7-H),
7.86 (d, J = 9.7 Hz, 2H, Ar-3,6-2H), 7.60 (d, J = 8.6 Hz,
1 H, Ar-5-H), 4.51 (s, 2H, –SCH2–); 13C NMR (126 MHz,
DMSO-d6) δ 167.79 (s, benzothiazole-2-C), 165.23 (s,
thiadiazole-2-C), 163.75 (s, C = O), 162.89 (s, thiadiazole-
5-C), 156.64 (s, benzothiazole-9-C), 153.93 (s, H, 2.83; N, 15.29.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(4-fluorophenyl)-1,3,4- 1332, 1319, 1275, 1199, 1172, 1097, 1026, 819, 810; Anal.
thiadiazol-2-yl)thio) acetamide (5f)
calc. for C19H13F3N4O2S3: C, 47.29; H, 2.72; N, 11.61;
Found: C, 47.18; H, 2.71; N, 11.53.
Yellow solid, yield: 84%, m.p: 214–217 °C; 1H NMR
(500 MHz, DMSO-d6) δ 8.94 (d, J = 2.3 Hz, 1H, benzothia-
zole-4-H), 8.22 (dd, J = 2.4 Hz, 1H, benzothiazole-6-H),
7.95–7.89 (m, 2H, benzothiazole-7-H, Ar-2-H), 7.82 (d,
J = 9.0 Hz, 1 H, Ar-6-H), 7.38–7.32 (m, 2H, Ar-3,5-2H), 4.47
(s, 2H, –SCH2–); 13C NMR (126 MHz, DMSO-d6) δ 168.06
(s, benzothiazole-2-C), 167.20 (s, thiadiazole-2-C), 165.08 (s,
C = O), 157.40 (s, thiadiazole-5-C), 148.13 (s, Ar-4-C),
137.04 (s, benzothiazole-9-C), 132.14 (s, benzothiazole-5-C),
131.65 (s, benzothiazole-8-C), 131.21 (s, Ar-1,2-2C), 131.01
(s, Ar-6-C), 130.52 (s, benzothiazole-7-C), 128.86 (s, benzo-
thiazole-6-C), 127.18 (S, benzothiazole-4-C), 124.23 (s, Ar-3-
C), 119.72 (s, Ar-5-C), 37.32 (s, -CH2-); IR (KBr, cm−1) ν:
3213, 3094, 2959, 1682 (C = O), 1573 (C = N), 1466, 1338,
1258, 1168, 1164, 1085, 1020, 847, 799; Anal. calc. for
C17H10FN5O3S3: C, 45.63; H, 2.25; N, 15.65; Found: C,
45.54; H, 2.27; N,15.63.
N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(4-nitrophenyl)-
1,3,4-thiadiazol-2-yl)thio)acetamide (5i)
1
Yellow solid, yield: 77%, m.p: >250 °C; H NMR (500 MHz,
DMSO-d6) δ 12.65 (s, 1H, –NH–), 8.33 (d, J = 8.7 Hz, 2 H,
Ar-3,5-2H), 8.14 (d, J = 8.7 Hz, 2 H, Ar-2,6-2H), 7.59 (dd,
J = 48.0, 5.5 Hz, 2H, benzothiazole-4,7-2H), 7.01 (dd, J = 8.7,
2.4 Hz, 1H, benzothiazole-6-H), 4.49 (d, J = 15.6 Hz, 2H,
–OCH3), 3.77 (s, 3H, –SCH2–); 13C NMR (126 MHz,
DMSO-d6) δ 166.69 (s, benzothiazole-2-C), 166.03 (s, thia-
diazole -2-C), 163.14 (s, C = O), 156.83 (s, thiadiazole-5-C),
156.07 (s, benzothiazole-9-C), 143.14 (s, benzothiazole-5-C),
138.03 (s, Ar-4-C), 133.35 (s, Ar-1-C), 132.26 (s, Ar-2-C),
132.08 (s, Ar-6-C), 129.17 (s, Ar-3-C), 126.97 (s, Ar-5-C),
122.62 (s, benzothiazole-8-C), 121.89 (s, benzothiazole-7-C),
115.64 (s, benzothiazole-6-C), 105.32 (s, benzothiazole-4-C),
56.19 (s, -OCH3), 36.09 (s, -CH2-); IR (KBr, cm−1) ν: 3481,
3196, 3080, 2995, 1690 (C = O), 1558 (C = N), 1464, 1437,
1406, 1368, 1258, 1173, 1065; Anal. calc. for C18H13N5O4S3:
C, 47.05; H, 2.85; N, 15.21; Found: C, 47.09; H, 2.84;
N, 15.18.
N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(2-hydroxyphenyl)-
1,3,4-thiadiazol-2-yl)thio) acetamide (5g)
Yellow solid, yield: 81%, m.p: >250 °C; H NMR (500 MHz,
DMSO-d6) δ 13.12 (s, 1H, –NH–), 11.22 (s, 1H, –OH), 9.04
(dd, J = 9.8, 2.4 Hz, 1H, benzothiazole-4-H), 8.28–8.17 (m,
1H, benzothiazole-6-H), 8.10 (dd, J = 7.9, 1.4 Hz, 1H, benzo-
thiazole -7-H), 7.90 (dd, J = 8.9, 4.1 Hz, 1H, Ar-6-H), 7.37
(ddd, J = 15.5, 4.6 Hz, 1H, Ar-4-H), 7.07–6.91 (m, 2 H, Ar-
3,5-2H), 4.50 (d, J = 15.9 Hz, 2H, –SCH2); 13C NMR
1
N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(2,4-dichloro-
phenyl)-1,3,4-thiadiazol-2-yl)thio) acetamide (5j)
White solid, yield: 80%, m.p: 202–204 °C; 1H NMR
(500 MHz, DMSO-d6) δ 12.76 – 12.46 (m, 1H, –NH–), 8.16-
8.02 (m, 1H, benzothiazole-4-H), 7.93-7.79 (m, 1H, benzo-
thiazole -7-H), 7.72-7.45 (m, 3H, Ar-3,5,6-3H), 7.01 (dd,
J = 8.9, 2.5 Hz, 1H, benzothiazole-6-H), 4.44 (d, J = 42.2 Hz,
2H, –OCH3), 3.79 (d, J = 15.3 Hz, 3H, –SCH2); 13C NMR
(126 MHz, DMSO-d6)
δ 169.04 (s, benzothiazole-2-C),
167.67 (s, thiadiazole-2-C), 165.59 (s, C = O), 165.24 (s, thia-
diazole-5-C), 163.26 (s, Ar-5-C), 154.51 (s, benzothiazole-9-
C), 143.17 (s, benzothiazole-5-C), 132.92 (s, benzothiazole-8-
C), 130.48 (d, J = 8.7 Hz, Ar-4,6-2C), 126.41 (s, Ar-1-C),
122.17 (s, Ar-3,5-2C), 120.80 (s, benzothiazole-7-C), 119.32
(s, benzothiazole-6-C), 117.14 (d, J = 22.2 Hz, benzothiazole-
4-C), 38.43 (s, -CH2-); IR (KBr, cm−1) ν: 3186, 3089, 2998,
1682 (C = O), 1551 (C = N), 1434, 1393, 1314, 1282, 1168,
1030, 982, 823; Anal. calc. for C17H11N5O4S3: C, 45.83; H,
2.49; N, 15.72; Found: C, 45.84; H, 2.47; N, 15.76.
(126 MHz, DMSO-d6)
δ 166.88 (s, benzothiazole-2-C),
164.62(s, thiadiazole-2-C), 163.23 (s, C = O), 157.82 (s, thia-
diazole-5-C), 157.30(s, benzothiazole-9-C), 148.12(s, benzo-
thiazole-5-C), 134.20(s, Ar-1-C), 131.64(s, Ar-4-C), 130.58
(s, Ar-2-C), 127.26 (s, Ar-3-C), 124.28 (s, Ar-6-C), 121.24 (s,
Ar-5-C), 119.74 (s, benzothiazole-8-C), 113.17 (d, benzothia-
zole-6,7-2C), 112.31(s, benzothiazole-4-C), 56.48 (s, -OCH3),
36.03 (s, -CH2-); IR (KBr, cm−1) ν: 3443, 3183, 2992, 1682
(C = O), 1558 (C = N), 1472, 1383, 1348, 1253, 1157, 1054,
1036, 806; Anal. calc. for C18H12Cl2N4O3S3: C, 44.72; H,
2.50; N, 11.59; Found: C, 44.48; H, 2.51; N, 11.55.
N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(4-(trifluorome-
thyl)phenyl)-1,3,4-thiadiazol-2-yl)thio)acetamide (5h)
White solid, yield: 81%, m.p: >250 °C; H NMR (500 MHz,
1
DMSO-d6) δ 12.61 (s, 1H, –NH–), 8.08 (s, 2H, benzothia-
zole-4,7-2H), 7.87 (s, 2H, Ar-3,5-2H), 7.71–7.44 (m, 2H, Ar-
2,6-2H), 7.12–6.90 (m, 1H, benzothiazole-6-H), 4.49 (s, 2H,
–SCH2–), 3.77 (s, 3H, –OCH3); 13C NMR (126 MHz,
DMSO-d6) δ 170.24 (s, benzothiazole-2-C), 167.19 (s, thia-
diazole-2-C), 166.35 (s, C = O), 165.13 (s, thiadiazole-5-C),
157.20 (s, benzothiazole-5-C), 148.08 (s, benzothiazole-9-C),
136.81 (s, Ar-1-C), 132.42 (s, Ar-4-C), 131.67 (s, Ar-2-C),
131.34 (d, J = 11.9 Hz, Ar-6-C), 130.55 (s, Ar-3-C), 129.27 (s,
Ar-5-C), 127.27 (s, benzothiazole-7-C), 124.28 (d,
J = 11.6 Hz, benzothiazole-6-C), 119.74 (d, J = 7.8 Hz, benzo-
N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(o-tolyl)-1,3,4-thia-
diazol-2-yl)thio)acetamide (5k)
White solid, yield: 82%, m.p: 199–201 °C; 1H NMR
(500 MHz, DMSO-d6) δ 12.68 (d, J = 37.5 Hz, 1H, –NH–),
7.67–7.59 (m, 2H, benzothiazole-4,7-2H), 7.54 (t, J = 4.4 Hz,
1H, Ar-6-H), 7.41 (ddd, J = 15.2, 10.7, 4.1 Hz, 2H, Ar-4,5-
2H), 7.31 (dd, J = 14.2, 6.7 Hz, 1H, Ar-3-H), 7.00 (dt, J = 9.5,
4.7 Hz, 1H, benzothiazole-6-H), 4.49 (d, J = 14.8 Hz, 2H,
-SCH2-), 3.77 (s, 3H, –OCH3); 13C NMR (126 MHz,
thiazole-4-C), 43.02 (s, –OCH3), 37.32 (s, -CH2-); IR (KBr, DMSO-d6) δ 167.32 (s, benzothiazole-2-C), 165.03 (s, thia-
cm−1) ν: 3196, 3184, 3086, 1682 (C = O), 1610 (C = N), 1470, diazole-2-C), 162.44 (s, C = O), 157.40 (s, thiadiazole-5-C),

6
X. TANG ET AL.
155.94 (s, benzothiazole-5-C), 148.13 (s, benzothiazole-9-C), N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(2-hydroxy-
phenyl)-1,3,4-thiadiazol-2-yl)thio) acetamide (5n)
133.25 (s, Ar-1-C), 131.65 (s, Ar-2-C), 130.51 (s, Ar-3-C),
127.75 (s, Ar-4-C), 127.24 (s, Ar-6-C), 124.22 (s, Ar-5-C), White solid, yield: 82%, m.p: 234–236 °C; H NMR (500 MHz,
1
DMSO-d6) δ 12.58 (s, 1H, –NH–), 11.23 (s, 1H, –OH), 8.16-
8.06 (m, 1H, benzothiazole-4-H), 7.63 (d, J = 8.8 Hz, 1H, ben-
zothiazole-7-H), 7.53 (d, J = 2.5 Hz, 1H, Ar-6-H), 7.38-7.32 (m,
1 H, Ar-4-H), 7.04–6.98 (m, 2H, Ar-3,5-2H), 6.98-6.92 (m,
1 H, benzothiazole-6-H), 4.42 (d, J = 12.2 Hz, 2H, -SCH2-), 3.77
(d, J = 4.8 Hz, 3H, –OCH3); 13C NMR (126 MHz, DMSO-d6)
δ 167.32 (s, benzothiazole-2-C), 165.03 (s, thiadiazole-2-C),
162.43 (s, C = O), 157.39 (s, thiadiazole-5-C), 155.92 (s, benzo-
thiazole-5-C), 148.12 (s, Ar-2-C), 133.25 (s, benzothiazole-9-C),
131.64 (s, Ar-4-C), 130.50 (s, Ar-6-C), 127.74 (s, Ar-1-C),
127.24 (s, benzothiazole-8-C), 124.22 (s, Ar-5-C), 121.79 (s,
benzothiazole -7-C), 119.72 (s, Ar-3-C), 118.35 (s, benzothia-
zole-6-C), 113.01 (s, benzothiazole -4-C), 56.69 (s, -OCH3),
37.28 (s, -CH2-); IR (KBr, cm−1) ν: 3480, 3184, 3078, 1684
(C = O), 1558 (C = N), 1474, 1458, 1398, 1261, 1153, 1065, 826;
Anal. calc. for C17H11N5O4S3: C, 50.22; H, 3.28; N, 13.01;
Found: C, 50.18; H, 3.27; N, 13.05.
121.80 (s, benzothiazole-8-C), 119.72 (s, benzothiazole-7-C),
118.36 (s, benzothiazole-6-C), 113.02 (s, benzothiazole-4-C),
56.69 (s, –OCH3), 37.29 (s, –CH2–); IR (KBr, cm−1) ν: 3461,
3061, 2959, 1703 (C = O), 1576 (C = N), 1449, 1348, 1298,
1271, 1246, 1151, 984, 888, 773, 747; Anal. calc. For
C19H16N4O2S3: C, 53.35; H, 3.76; N, 13.27; Found: C, 53.32;
H, 3.74; N, 13.29.
N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(2-methoxy-
phenyl)-1,3,4-thiadiazol-2-yl)thio)acetamide (5l)
White solid, yield: 84%, m.p: >250 °C; 1H NMR (500 MHz,
DMSO-d6) δ 12.69 (s, 1H, –NH–), 8.27 (dd, J = 7.9, 1.6 Hz,
1H, benzothiazole-4-H), 7.70 (t, J = 6.9 Hz, 1H, benzothiazole-
7-H), 7.63-7.57 (m, 2H, Ar-4,6-2H), 7.32 (d, J = 8.3 Hz, 1H,
Ar-5-H), 7.18 (t, J = 7.8 Hz, 1H, Ar-3-H), 7.08 (dd, J = 8.8,
2.6 Hz, 1H, benzothiazole-6-H), 4.53 (d, J = 17.5 Hz, 2H,
–CH2–), 4.02 (s, 3H, –OCH3), 3.84 (s, 3H, –OCH3); 13C
NMR (126 MHz, DMSO-d6) δ 167.49 (s, benzothiazole-2-C),
165.45 (s, thiadiazole-2-C), 159.55 (s, C = O), 158.74 (s, thiadia-
zole-5-C), 156.25 (s, benzothiazole-5-C), 152.38 (s, Ar-2-C),
150.68 (s, benzothiazole-9-C), 145.73 (s, Ar-4-C), 137.22 (s,
Ar-6-C), 129.52 (s, benzothiazole-8-C), 129.08 (s, Ar-1-C),
128.11 (s, benzothiazole-7-C), 118.38 (s, Ar-5-C), 107.62 (s,
Ar-3-C), 101.46 (d, benzothiazole-4,6-2C), 56.76 (s, –OCH3),
56.55 (s, –OCH3), 38.05 (s, -CH2-); IR (KBr, cm−1) ν: 3480,
3169, 2988, 1676 (C = O), 1558 (C = N), 1393, 1304, 1219,
1161, 1065, 1047, 980, 818; Anal. calc. for C19H16N4O3S3: C,
51.33; H, 3.63; N, 12.60; Found: C, 51.42; H, 3.64; N, 12.71.
N-(7-methylbenzo[d]thiazol-2-yl)-2-((5-(4-nitrophenyl)-
1,3,4-thiadiazol-2-yl)thio)acetamide (5o)
White solid, yield: 84%, m.p: 204–206 °C; 1H NMR
(500 MHz, DMSO-d6) δ 12.88 (s, 1H, –NH–), 8.00-7.94 (m,
2H, Ar-3,5-2H), 7.76 (d, J = 7.7 Hz, 1H, benzothiazole -4-H),
7.40–7.33 (m, 2H, Ar-2,6-2H), 7.25-7.16 (m, 2H, benzothia-
zole-5,6-2H), 4.42 (s, 2H, –SCH2–), 2.54 (s, 3H, -CH3); 13C
NMR (126 MHz, DMSO-d6) δ 166.88 (s, benzothiazole-2-C),
165.17 (s, thiadiazole-2-C), 162.97 (s, C = O), 157.29 (s, thia-
diazole-5-C), 156.63 (s, benzothiazole-9-C), 148.11 (s, Ar-4-
C), 133.99 (s, Ar-1-C), 131.65 (s, benzothiazole-7-C), 130.55
(s, Ar-2-C), 129.45 (s, Ar-6-C), 127.26 (s, Ar-3-C), 124.28 (s,
Ar-5-C), 120.12 (s, benzothiazole-8-C), 119.74 (s, benzothia-
zole-6-C), 117.58 (s, benzothiazole-5-C), 109.96 (s, benzo-
thiazole-4-C), 36.08 (s, –SCH2–), 18.48 (s, –CH3); IR (KBr,
cm−1) ν: 3460, 3196, 3086, 1670 (C = O), 1557 (C = N), 1522,
1472, 1458, 1396, 1362, 1348, 1265, 1163, 1062,860, 808,
707; Anal. calc. for C18H12Cl2N4OS3: C, 46.25; H, 2.59; N,
11.99; Found: C, 46.42; H, 2.58; N, 12.02.
N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(4-fluorophenyl)-
1,3,4-thiadiazol-2-yl)thio) acetamide (5m)
Yellow solid, yield: 84%, m.p: 238–240 °C; 1H NMR
(500 MHz, DMSO-d6) δ12.60 (s, 1H, –NH–), 7.95–7.90 (m,
2H, benzothiazole-4,7-2H), 7.63 (d, J = 8.8 Hz, 1H, Ar-2-H),
7.53 (d, J = 2.6 Hz, 1H, Ar-6-H), 7.35 (ddd, J = 9.8, 2.6 Hz,
2H, Ar-3,5-2H), 7.03-6.98 (m, 1H, benzothiazole-6-H), 4.46
(s, 2H, –SCH2–), 3.77 (s, 3H, –OCH3); 13C NMR
Conclusion
A series of benzothiazole derivatives bearing a 1,3,4-thiadia-
zole moiety were designed, synthesized, and structures of all
1
(126 MHz, DMSO-d6)
δ 167.34 (s, benzothiazole-4-C),
title compounds were identified by H NMR, 13C NMR, IR
162.44 (s, thiadiazole-2-C), 157.45 (s, C = O), 155.94 (s, thia-
diazole-5-C), 148.14(s, Ar-4-C), 133.25 (s, benzothiazole-9-
C), 131.66 (s, benzothiazole-5-C), 130.49 (d, Ar-1,2-2C),
127.75 (s, Ar-6-C), 127.22 (s, benzothiazole-8-C), 124.20 (s,
benzothiazole-7-C), 121.80 (s, benzothiazole-6-C), 119.71 (s,
Ar-3-C), 118.38 (s, Ar-5-C), 113.03 (s, benzothiazole-4-C),
56.70 (s, -OCH3), 37.33 (s, -SCH2-); IR (KBr, cm−1) ν: 3452,
3187, 3077, 1681 (C = O), 1559 (C = N), 1465, 1371, 1309,
1255, 1237, 1121, 1070, 983, 836, 814; Anal. calc. for
C18H13FN4O2S3: C, 49.89; H, 3.03; N, 12.75; Found: C,
49.76; H, 3.04; N, 12.74.
and elemental analyses. At the same time, the results of bio-
logical assays indicated that most of target compounds
showed good antiviral activities against TMV and antibacte-
rial activities against Xoo and Rs. Especially, the anti-Xoo
effects of title compounds 5d, 5e, 5f, 5k, 5l and 5m reached
38.7–52.4% at 100 µg/mL, and the anti-Rs effects of title
compounds 5a, 5f, 5h and 5m ranged 64.7–71.6% at 100 µg/
mL, which are superior to that of bismerthiazol (32.0% and
52.3%). In addition, the protective and inactivation activities
of title compound 5i against TMV was 79.5% and 88.3%,
respectively, which are better than those that of

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
Sulfur Silicon Relat. Elem. 2017, 193, 1–8. doi:10.1080/
10.10426507.2017.1395878.
ningnanmycin (76.4% and 86.8%). Further studies on the
antiviral and antibacterial mechanism are cur-
rently underway.
[12] Shaikh, F. M.; Patel, N. B.; Sanna, G.; Busonera, B.; Colla, P. L.;
Rajani, D. P. Synthesis of Some New 2-Amino-6-Thiocyanato
Benzothiazole Derivatives Bearing 2,4-Thiazolidinediones and
Screening of Their in Vitro Antimicrobial, Antitubercular and
Antiviral Activities. Med. Chem. Res. 2015, 24, 3129–3142. doi:
10.1007/s00044-015-1358-0.
[13] Huang, T.; Sun, J.; An, L.; Zhang, L.; Han, C. Synthesis and
Herbicidal Evaluation of Novel Benzothiazole Derivatives as
Potential Inhibitors of d1 Protease. Bioorg. Med. Chem. Lett.
2016, 26, 1854–1859. doi:10.1016/j.bmcl.2016.01.087.
[14] Tariq, S.; Alam, O.; Amir, M. Synthesis, anti-Inflammatory,
p38α MAP Kinase Inhibitory Activities and Molecular Docking
Studies of Quinoxaline Derivatives Containing Triazole Moiety.
Arch. Pharm. Res. 2018, 351, 3–4. doi:10.1016/j.bioorg.
2017.12.003.
Acknowledgement
The authors gratefully acknowledge grants from the National Key
Research and Development Program of China (No. 2017YFD0200506), the
National Nature Science Foundation of China (No. 21867003), the Major
Program of Innovation Research Team of Educational Commission of
Guizhou Province (No. 2016113), the Science and Technology Platform
for Talent of Guizhou Province (No. 20165608) and the Science and
Technology Project of Guizhou Province (No. 20172956).
References
[15] Bhutani, R.; Pathak, D. P.; Kapoor, G.; Husain, A.; Kant, R.;
Iqbal, M. A. Synthesis, Molecular Modelling Studies and ADME
Prediction of Benzothiazole Clubbed oxadiazole-Mannich Bases,
and Evaluation of Their anti-Diabetic Activity through in Vivo
Model. Bioorg. Chem. 2018, 77, 6–15. doi:10.1016/j.bioorg.
2017.12.037.
[16] Pandey, V. K.; Pathak, L. P.; M.; Yadav, A. S.; Mishra, S. K.
Synthesis and anti-TMV Activity of 7-Aralkyl-2-Phenyl-3-
(Phthalimidomethyl/2-Phenyl-3- Ethyl-4-Oxo-(3H)Quinazolinyl)-
1,3,4-Thiadiazole[3,2-a]-s-Triazine-5(6H,7H)-Thi Ones. Chin. J.
Org. Chem. 2007, 26, 702–706. doi:10.1016/j.carres.2007.03.009.
[17] Valasani, K. R.; Hu, G.; Chaney, M. O.; Yan, S. S. Structure-
Based Design and Synthesis of Benzothiazole Phosphonate
Analogues with Inhibitors of Human Abad-aβ for Treatment of
Alzheimer's Disease. Chem. Biol. Drug. Des. 2013, 81, 238–249.
doi:10.1111/cbdd.12068.
[1] Li, B.; Liu, B.; Shan, C.; Ibrahim, M.; Lou, Y.; Wang, Y.; Xie,
G.; Li, H-y.; Sun, G. Antibacterial Activity of Two Chitosan
Solutions and Their Effect on Rice Bacterial Leaf Blight and
Leaf Streak. Pest Manag. Sci. 2013, 69, 312–320. doi:10.1002/
ps.3399.
[2] Graham, J. H.; Gottwald, T. R.; Cubero, J.; Achor, A. D.
Xanthomonas axonopodis pv. citri: factors Affecting Successful
Eradication of Citrus Canker. Mol. Plant Pathol. 2004, 5, 1–15.
doi:10.1046/J.1364-3703.2003.00197.X.
[3] Li, P.; Shi, L.; Yang, X.; Yang, L.; Chen, X. W.; Wu, F.; Shi,
Q. C.; Xu, W. M.; He, M.; Hu, D. Y.; Song, B. A. Design,
Synthesis, and Antibacterial Activity against Rice Bacterial Leaf
Blight and Leaf Streak of 2,5-Substituted- 1,3,4- Oxadiazole/
Thiadiazole Sulfone Derivative. Bioorg. Med. Chem. Lett. 2014,
24, 1677–1680. doi:10.1016/j.bmcl.2014.02.060.
[18] Zhang, L. H.; Hu, X.; Yang, D.; Fan, S.; Wei, H. Synthesis and
[4] Chen, Y.; Yang, X.; Gu, C. Y.; Zhang, A. F.; Zhang, Y.; Wang,
W. X.; Gao, T. C.; Yao, J.; Yuan, S. K. Activity of a Novel
Bactericide, Zinc Thiazole against Xanthomonas oryzae pv. ory-
zae in Anhui Province of China. Ann. Appl. Biol. 2015, 166,
129–131. doi:10.1111/aab.12170.
[5] Zhao, W. G.; Wang, J. G.; Li, Z. M.; Yang, Z. Synthesis and
Antiviral Activity against Tobacco Mosaic Virus and 3D-QSAR
of Alpha-Substituted-1,2,3- Thiadiazoleacetamides. Bioorg. Med.
Antiviral
Activityof(E)-3-(4-or6-Methylbenzo[d]Thiazol-2-yl-
Amino)-2-Cyano-3-(Methylthio) Acrylate Derivatives. Chin. J.
Org. Chem. 2011, 31, 1419–1424. doi:10.1016/j.carres.
2011.31.001.
[19] Flefel, E. M.; El-Sayed, W. A.; Mohamed, A. M.; El-Sofany,
W. I.; Awad, H. M. Synthesis and Anticancer Activity of New
1-Thia-4-Azaspiro[4.5]Decane,
Their
Derived
Thiazolopyrimidine and 1,3,4-Thiadiazole Thioglycosides.
Molecules 2017, 22, 170–182. doi:10.3390/molecules22010170.
[20] Can, O. D.; Altintop, M. D.; Ozkay, U. D.; Ucel, U. I.; Doğruer,
B.; Kaplancikli, Z. A. Synthesis of Thiadiazole Derivatives
Bearing Hydrazone Moieties and Evaluation of Their
Pharmacological Effects on Anxiety, Depression, and
Nociception Parameters in Mice. Arch. Pharm. Res. 2012, 35,
659–669. doi:10.1007/s12272-012-0410-6.
Chem.
j.bmcl.2006.05.043.
[6] Su, B.; Cai, C. L.; Deng, M.; Wang, Q. M. Spatial Configuration
and Three-Dimensional Conformation Directed Design,
Lett.
2006,
16,
6107–6109.
doi:10.1016/
Synthesis,
Antiviral
Activity,
and
Structure–Activity
Relationships of Phenanthroindolizidine Analogues. J. Agric.
Food Chem. 2016, 64, 2039–2041. doi:10.1021/acs.jafc.5b06112.
[7] Abdou, W. M.; Khidre, M. D.; Shaddy, A. A. Microwave
Promoted Synthesis and Anticological Screening of β-
Aminobisphosphonates-Based Benzothiazole Motif against
Human Breast and Colon Cancer Diseases. Chem. Pap. 2018,
72, 2753–2768. doi:10.1007/s11696-018-0505-8.
[8] Zhao, S. Z.; Zhao, L. Y.; Zhang, X. Q.; Liu, C. C.; Hao, C. Z.;
Xie, H. L.; Sun, B.; Zhao, D. M.; Chen, M. S. Design, Synthesis,
and Structure-Activity Relationship Studies of Benzothiazole
Derivatives as Antifungal Agents. Eur. J. Med. Chem. 2016, 123,
514–522. doi:10.1016/j.ejmech.2016.07.067.
[21] Clerici, F.; Pocar, D.; Guido, M.; Loche, A.; Perlini, V.; Brufani,
M.
Synthesis
of
2-Amino-5-Sulfanyl-1,3,4-Thiadiazole
Derivatives and Evaluation of Their Antidepressant and
Anxiolytic Activity. J. Med. Chem. 2001, 44, 931–936. doi:
10.1021/jm001027w.
[22] 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. Bioorg. Med. Chem. Lett. 2013, 23, 5821–5824. doi:
10.1016/j.bmcl.2013.08.107.
[9] Singh, M.; Singh, S. K.; Gangwar, M.; Nath, G.; Singh, S. K.
Design, Synthesis and Mode of Action of Some Benzothiazole
Derivatives Bearing an Amide Moiety as Antibacterial Agents.
RSC Adv. 2014, 4, 19013–19023. doi:10.1039/C4 RA02649G.
[10] Nong, W. Q.; Zhao, A. R.; Wei, J. R.; Cheng, H.; Luo, X.; Lin,
C. W. Synthesis of a Series of Benzothiazole Amide Derivatives
and Their Biological Evaluation as Potent Hemostatic Agents.
RSC Adv. 2018, 8, 6231–6241. doi:10.1039/c7ra13397a.
[23] Rajak, H.; Deshmukh, R.; Aggarwal, N.; Kashaw, S.; Kharya,
M. D.; Mishra, P. Synthesis of Novel 2,5-Disubstituted 1,3,4-
Thiadiazoles for Their Potential Anticonvulsant Activity: phar-
macophoric Model Studies. Arch. Pharm. Chem. Life. Sci. 2009,
342, 453–461. doi:10.1002/ardp.200800213.
[24] Li, P.; Shi, L.; Gao, M.-N.; Yang, X.; Xue, W.; Jin, L.-H.; Hu,
D.-Y.; Song, B.-A. Antibacterial Activities against Rice Bacterial
Leaf Blight and Tomato Bacterial Wilt of 2-Mercapto -5-
Substituted-1,3,4-Oxadiazole/Thiadiazole Derivatives. Bioorg.
Med. Chem. Lett. 2015, 25, 481–484. doi:10.1016/j.bmcl.2014.
12.038.
[11] Osmaniye, D.; Levent, S.; Ardıç, C. M.; Özlem, A.; Özkay, Y.;
Kaplancıklı, Z. A. Synthesis and Anticancer Activity of Some
Novel Benzothiazole-Thiazolidine Derivatives. Phosphorus,

8
X. TANG ET AL.
[25] Liu, F.; Luo, X. Q.; Song, B. A.; Bhadury, P. S.; Yang, S.; Jin, [32] Chen, M.; Chen, L.; Zhu, X.; Wang, X.; Li, Q.; Zhang, J.; Lu,
D.; Xue, W. Synthesis and Biological Activities of cyclanoneO-
(2-(3-Aryl-4- Amino-4H-1,2,4 -Triazol-3-yl)Thio)Acetyl)Oxime
Derivatives. Phosphorus, Sulfur Silicon Relat. Elem. 2017, 192,
1259–1263. doi:10.1080/10426507.2017.1315419.
L. H. Synthesis and Antifungal Activity of Novel Sulfoxide
Derivatives Containing Trimethoxyphenyl Substituted 1,3,4-
Thiadiazole and 1,3,4-Oxadiazole Moiety. Bioorg. Med. Chem.
Lett. 2008, 16, 3632–3640. doi:10.1016/j.bmc.2008.02.006.
[26] Yu, H.; Han, Y.; Ding, Y.; Xie, D.; Hu, D.; Li, P.; Li, X. Design,
Synthesis, and Antiviral Activity of Novel Rutin Derivatives
Containing 1, 4-Pentadien-3-One Moiety. Eur. J. Med. Chem.
2015, 92, 732–737. doi:10.1016/j.ejmech.2015.01.017.
[27] Zhong, X. M.; Wang, X. B.; Chen, L. J.; Ruan, X. H.; Li, Q.;
Zhang, J. P. Synthesis and Biological Activity of Myricetin
Derivatives Containing 1,3,4- Thiadiazole Scaffold. Chem. Cent.
J. 2017, 11, 106. doi:10.1186/s13065-017-0336-7.
[28] Saha, A.; Kumar, R.; Kumar, R.; Devakumar, C. Green
Synthesis of 5-Substituted- 1,3,4- Thiadiazole-2-Thiols as New
Potent Nitrification Inhibitors. J. Heterocyclic Chem. 2010, 47,
838–845. doi:10.1002/jhet.345.
[29] Omar, Y. M.; Abdu-Allah, H. M.; Abdel-Moty, S. Synthesis,
Biological Evaluation and Docking Study of 1,3,4-Thiadiazole-
Thiazolidinone Hybrids as anti-Inflammatory Agents with Dual
Inhibition of COX-2 and 15-LOX. Russ. J. Bioorg. Chem. 2018,
80, 461–471. doi:10.1016/j.bioorg. 2018.06.036.
[30] Balijapalli, U.; Udayadasan, S.; Panyam Muralidharan, V.;
Sukumarapillai, D. K.; Shanmugam, E.; Paduthapillai Gopal, A.;
S. Rathore, R.; Kulathu Iyer, S. An Insight into the
Photophysical Properties of Amide Hydrogen Bonded n-
(Benzo[d]Thiazol-2-yl) Acetamide Crystals. Spectrochim. Acta.
A 2017, 173, 572–577. doi:10.1016/j.saa.2016.10.007.
[31] Sharma, P. C.; Kumar, R.; Chaudhary, M.; Sharma, A.; Rajak,
H. Synthesis and Biological Evaluation of Novel Benzothiazole
Clubbed Fluoroquinolone Derivatives. J. Enzyme Inhib. Med.
Chem. 2013, 28, 1–10. doi:10.3109/14756366.2011.611943.
[33] Wang, X.; Ren, Z.; Wang, M.; Chen, M.; Lu, A.; Si, W.; Yang,
C. Design and Synthesis of Novel 3-(Thiophen-2-yl)-1,5-
Dihydro-2H-Pyrrol-2-One Derivatives Bearing
a Hydrazone
Moiety as Potential Fungicides. Chem. Cent. J. 2018, 12, 83.
doi:10.1186/s13065-018-0452-z.
[34] Wang, X.; Li, P.; Li, Z.; Yin, J.; He, M.; Xue, W.; Chen, Z.;
Song, B. A. Synthesis and Bioactivity Evaluation of Novel
Arylimines
Containing
a
3-Aminoethyl-2-
[(p-
Trifluoromethoxy)Anilino]-4(3H)-Quinazolinone Moiety. J.
Agric. Food Chem. 2013, 61, 9575–9582. doi:10.1021/jf403193q.
Epub 2013 Sep 30.
[35] Wang, P. Y.; Zhou, L.; Zhou, J.; Wu, Z. B.; Xue, W.; Song, B. A.;
Yang, S. Synthesis and Antibacterial Activity of Pyridinium-
Tailored 2,5-Substituted-1,3,4- Oxadiazole Thioether/Sulfoxide/
Sulfone Derivatives. Bioorg. Med. Chem. Lett. 2016, 26, 1214–1217.
doi:10.1016/j.bmcl.2016.01.0290.
[36] Long, C.; Li, P.; Chen, M. H.; Dong, L.; Hu, D. Y.; Song, B. A.
Synthesis, anti-Tobacco Mosaic Virus and Cucumber Mosaic
Virus Activity, and 3D-QSAR Study of Novel 1,4-Pentadien-3-
One Derivatives Containing 4-Thioquina Zoline Moiety. Eur. J.
Med. Chem. 2015, 102, 639–647. doi:10.1016/j.ejmech.2015.
08.029.
[37] Gan, X. H.; Hu, D. Y.; Li, P.; Wu, J.; Chen, X. W.; Xue, W.;
Song, B. A. Design, Synthesis,Antiviral Activity and Three-
Dimensional Quantitative Structure– Activityrelationship Study
of Novel 1,4-Pentadien-3-One Derivatives Containing the 1,3,4-
Oxadiazole Moiety. Pest Manag. Sci. 2016, 72, 534–543. doi:
10.1002/ps. 4018.