Antiviral and Antibacterial Activities of N-(4-Substituted phenyl) Acetamide Derivatives Bearing 1,3,4-Oxadiazole Moiety

Article abstract of DOI:10.1002/cjoc.201600501

In this paper, a series of N-(4-substituted phenyl) acetamide derivatives bearing 1,3,4-oxadiazole moiety were synthesised. Preliminary bioassays revealed that these compounds not only exhibited favourable antiviral activities toward tobacco mosaic virus (TMV) but also demonstrated sustained inhibition activities against plant pathogenic bacteria, including Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Xanthomonas axonopodis pv. citri. Among the derivatives, TC₈and TC₂₀exerted the strongest curative activities against TMV, with half-maximal effective concentration (EC₅₀) values of 239.5 and 236.2 μg/mL, respectively, which were comparable to that of ningnanmycin (EC₅₀=273.2 μg/mL). Given their simple synthesis, the target compounds can serve as alternative antiviral candidates.

Full text of DOI:10.1002/cjoc.201600501

FULL PAPER
DOI: 10.1002/cjoc.201600501
Antiviral and Antibacterial Activities of N-(4-Substituted phenyl)
Acetamide Derivatives Bearing 1,3,4-Oxadiazole Moiety
Ling Chen,†,a Peiyi Wang,†,a Zhenxing Li,a Lei Zhou,a Zhibing Wu,a
Baoan Song,*,a and Song Yang*,a,b
a State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of
Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of
Guizhou University, Guiyang, Guizhou 550025, China
b College of Pharmacy, East China University of Science & Technology, Shanghai 550025, China
In this paper, a series of N-(4-substituted phenyl) acetamide derivatives bearing 1,3,4-oxadiazole moiety were
synthesised. Preliminary bioassays revealed that these compounds not only exhibited favourable antiviral activities
toward tobacco mosaic virus (TMV) but also demonstrated sustained inhibition activities against plant pathogenic
bacteria, including Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Xanthomonas axonopodis pv. cit-
ri. Among the derivatives, TC8 and TC20 exerted the strongest curative activities against TMV, with half-maximal
effective concentration (EC50) values of 239.5 and 236.2 µg/mL, respectively, which were comparable to that of
ningnanmycin (EC50＝273.2 µg/mL). Given their simple synthesis, the target compounds can serve as alternative
antiviral candidates.
Keywords 1,3,4-oxadiazole, acetamide, synthesis, antiviral, antibacterial
Introduction
nificant task.
Compounds with 1,3,4-oxadiazole scaffold exhibit a
Plant diseases caused by pathogenic viruses and
bacteria have attracted extensive attention because of
their significant threats towards agricultural products.[1-5]
Tobacco mosaic disease exhibits typical symptoms, such
as mosaic-like mottling and discoloration on the leaves;
this disease is mainly caused by the invasion of tobacco
mosaic virus (TMV) and can occur at all growth stages
of tobacco, thereby resulting in large economic losses
annually.[6-8] Some plant viral inhibitors (ribavirin and
ningnanmycin) have been used to combat TMV, but rare
chemicals can completely cure the infected plant tissues
or fully protect plants from infection under field condi-
tions.[9] Moreover, pathogenic bacteria can lead to vari-
ous diseases, such as rice bacterial leaf blight, tobacco
bacterial wilt and citrus bacterial canker, which are
caused by Xanthomonas oryzae pv. oryzae (Xoo), Ral-
stonia solanacearum (R. solanacearum), and Xan-
thomonas axonopodis pv. citri (Xac), respectively.[10-12]
Although some commercial bactericides had been em-
ployed to address these diseases, their poor efficiency,
high phytotoxicity, or bactericide resistance had been
paid more and more attention worldwide. Thus, explor-
ing and developing highly efficient antiviral and anti-
bacterial agents to manage plant diseases remain a sig-
wide range of biological activities, including antibacte-
rial, antifungal, antiviral and antitumour activities.[13-21]
Furthermore, our previous work verified that 1,3,4-oxa-
diazole derivatives displayed potent antibacterial and
anti-fungal activities and resulted in two antibacterial
candidates for commercialisation.[22-25] With their potent
bioactivity toward pathogenic microorganism, consid-
erable efforts have been exerted to explore and develop
alternative pesticide agents based on the scaffold of
1,3,4-oxadiazole.
An amide bond can modulate the physical properties
of a molecule, and bioactivities are often tuned by in-
troducing an amide bond into target compounds.[26] Re-
cently, some fungicides containing an amide bond have
been discovered and successfully commercialised; these
fungicides include boscalid, fluopicolide and salicylani-
lide. Hence, a series of N-(4-substituted phenyl) acet-
amide derivatives bearing 1,3,4-oxadiazole moiety were
designed by introducing an amide bond into 1,3,4-oxa-
diazole derivatives (Figure 1). Within these molecules,
an amide bond was placed at the 2-position of
1,3,4-oxadiazole. Moreover, the title compounds were
bioassayed against pathogenic virus (TMV) and patho-
genic bacteria (Xoo, R. solanacearum and Xac).
*
E-mail: jhzx.msm@gmail.com, songbaoan22@yahoo.com; Tel.: 0086-0851-88292171, Fax: 0086-0851-88292170
Received August 7, 2016; accepted October 7, 2016; published online December 20, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600501 or from the author.
The two authors contribute equally to this work.
†
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Chin. J. Chem. 2016, 34, 1236—1244

Antiviral and Antibacterial Activities of N-(4-Substituted phenyl) Acetamide Derivatives
Inhibition rate＝[(av local lesion no. of control (not
O
treated with compound)  av local lesion no. smeared
with drugs)/av local lesion no. of control (not treated
with compound)]×100%.
N
N
N
H
R1
S
O
Introducing
amide bond
Good bioactivity
In vitro antibacterial bioassay (turbidimeter test)
In our study, all the synthesized target compounds were
evaluated for their antibacterial activities against Xoo, R.
solanacearum, and Xac by the turbidimeter test in vitro.
Dimethylsulfoxide in sterile distilled water served as a
blank control, bismerthiazol and thiodiazole copper
served as positive controls. Approximately 40 μL of
solvent NB (1.5 g beef extract, 2.5 g peptone, 0.5 g
yeast powder, 5.0 g glucose, and 500 mL distilled water;
pH＝7.0－7.2) containing Xoo (R. solanacearum or
Xac), incubated on the phase of logarithmic growth, was
added to 5 mL of solvent NB containing the test com-
pounds and positive control. The inoculated test tubes
were incubated at (28±1) ℃ and continuously shaken
at 180 r/min for 24－48 h until the bacteria were incu-
bated on the logarithmic growth phase. The growth of the
cultures was monitored on a microplate reader by mea-
suring the optical density at 595 nm (OD595) given by
H
N
N
N
R1
S
R2
O
O
Target molecules with
tuned bioactivity?
Figure 1 Design strategy of the target compounds.
Experimental
Materials
Melting points were determined using an XT-4
binocular microscope (Beijing Tech Instrument Co.,
China) and left uncorrected. Elemental analysis was
performed using an Elemental Vario-III CHN analyzer.
NMR spectra were obtained by using a JEOL-ECX-500
apparatus. Chemical shifts were reported down field
from TMS with the solvent resonance as the internal
standard. Coupling constants (J) were reported in Hz
and referred to apparent peak multiplications. Mass
spectral studies were conducted on an Agilent 5973
organic mass spectrometer. The course of the reactions
was monitored by thin-layer chromatography analysis
on silica gel GF254. All reagents were analytical grade
or CP. All anhydrous solvents were dried and purified
according to standard techniques before use.
turbidity corrected values＝ODbacterial wiltODno bacterial wilt
,
and the inhibition rate I was calculated by I＝(CT)/C
×100%. C is the corrected turbidity values of bacterial
growth on untreated NB (blank control), and T is the
corrected turbidity values of bacterial growth on treated
NB. The experiment was repeated three times.
General synthesis protocols of target compounds
(TC1－TC30)
Antivir alactivity against TMV
The intermediate 2-bromo-N-(4-(substituted)-
phenyl)acetamide (5, 1.58 mmol) was added into a
mixture of 5-substituted-1,3,4-oxadiazole-2-thiol (3,
1.58 mmol) and K2CO3 (1.83 mmol) in the solvent
acetone, then the solution was stirred at room
temperature for 6 h. After that, the organic layer was
poured into ice-cold water to give precipitates, filtered,
and dried. Finally, the pure title compounds TC1－TC30
were obtained through recrystallization in methanol.
N-(4-Fluorophenyl)-2-((5-(4-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC1) A white solid,
Curative activity of the target compounds against
TMV in vivo Growing Nicotiana tabacum L. leaves
of the same age were selected. The leaves were inocu-
lated with TMV (concentration of 6×103 mg/mL) by
dipping and brushing the whole leaves, which had pre-
viously been scattered with silicon carbide. The leaves
were then washed with water after inoculation for 0.5 h.
The compound solution was smeared on the left side of
the leaves, and the solvent was smeared on the right side
as the control. The number of local lesions was counted
and recorded 3－4 d after inoculation. Three replicates
were set up for each.
Protection activity of the target compounds
against TMV in vivo The compound solutions were
smeared on the left side of the N. tabacum L. leaves,
and the solvents were smeared on the right side as the
control sample for growing N. tabacum L. leaves. After
12 h, crude TMV (concentration of 6×103 mg/mL)
was inoculated on whole leaves at the same concentra-
tion on each side of the leaves, which were previously
scattered with silicon carbide. After 0.5 h, the leaves
were washed with water and then dried. The number of
local lesions was recorded 3－4 d after inoculation.
Three replicates were used for each compound. The in-
hibitory rate of the compound was calculated according
to the following formula (“av” means average):
1
m.p. 199－200 ℃; yield 71%; H NMR (500 MHz,
DMSO-d6) δ: 10.48 (s, 1H), 7.92 (d, J＝6.7 Hz, 2H,
Ar-H), 7.62 (dd, J＝8.5, 1.6 Hz, 2H, Ar-H), 7.56 (d, J＝
6.5 Hz, 2H, NH-Ar-H), 7.13 (d, J＝15.8 Hz, 2H,
NH-Ar-H), 4.31 (s, 2H, CH2); 13C NMR (125 MHz,
DMSO-d6) δ: 165.3 (C＝O), [164.9, 164.2] (oxadiazol),
[159.7, 157.8, 137.3, 135.6, 130.1, 128.7, 122.4, 121.5
(d, J＝8.0 Hz), 116.0 (d, J＝11.5 Hz)] (aromatic), 37.3
(CH2); IR (KBr) vmax: 3282, 3050, 2930, 1684, 1671,
1546, 1508, 1476, 835, 809 cm1; MS (ESI) m/z: 364.1
([M＋H]＋).
N-(4-Chlorophenyl)-2-((5-(4-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC2) A white solid,
1
m.p. 197－198 ℃; yield 78%; H NMR (500 MHz,
DMSO-d6) δ: 10.57 (s, 1H, NH), 7.92 (d, J＝8.6 Hz, 2H,
Ar-H), 7.62 (d, J＝8.6 Hz, 2H, Ar-H), 7.58 (d, J＝8.9
Chin. J. Chem. 2016, 34, 1236—1244
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Chen et al.
FULL PAPER
Hz, 2H, NH-Ar-H), 7.35 (d, J＝8.9 Hz, 2H, NH-Ar-H),
4.32 (s, 2H, CH2); 13C NMR (125 MHz, DMSO-d6) δ:
165.6 (C＝O), [164.9, 164.2] (oxadiazol), [138.1, 137.3,
130.1, 129.3, 128.7, 127.8, 122.4, 121.2] (aromatic),
37.3 (CH2); IR (KBr) vmax: 3309, 3083, 2929, 1684,
1662, 1607, 1548, 1474, 837, 813 cm1; MS (ESI) m/z:
380.0 ([M＋H]＋).
oxadiazol-2-yl)thio)acetamides (TC7) A white solid,
m.p. 215－216 ℃; yield 60%; H NMR (500 MHz,
1
DMSO-d6) δ: 10.56 (s, 1H, NH), 7.91 (d, J＝6.2 Hz, 1H,
NH-Ar-H), 7.66 (d, J＝8.0 Hz, 1H, NH-Ar-H), 7.62－
7.58 (m, 1H, Ar-H), 7.52 (t, J＝8.4 Hz, 3H, Ar-H), 7.48
(d, J＝8.8 Hz, 2H, NH-Ar-H), 4.32 (s, 2H, CH2); 13C
NMR (125 MHz, DMSO-d6) δ: 165.5 (C＝O), [164.6,
163.7] (oxadiazol), [138.5, 133.9, 132.2 (d, J＝8.3 Hz),
131.7, 128.4, 122.6, 121.6, 115.8] (aromatic), 37.3
(CH2); IR (KBr) vmax: 3309, 3069, 2930, 1717, 1672,
1653, 1598, 1517, 1380, 1255, 829, 741 cm1; MS-ESI
(＋) m/z: 364.1 ([M＋H]＋).
N-(4-Bromophenyl)-2-((5-(4-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC3) A white solid,
1
m.p. 209－210 ℃; yield 87%; H NMR (500 MHz,
DMSO-d6) δ: 10.56 (s, 1H, NH), 7.93 (d, J＝8.6 Hz, 2H,
Ar-H), 7.62 (d, J＝8.6 Hz, 2H, NH-Ar-H), 7.52 (d, J＝
8.9 Hz, 2H, Ar-H), 7.48 (d, J＝9.0 Hz, 2H, NH-Ar-H),
4.32 (s, 2H, CH2); 13C NMR (125 MHz, DMSO-d6) δ:
165.6 (C＝O), [164.9, 164.2] (oxadiazol), [138.5, 137.3,
132.3, 130.2, 128.7, 122.4, 121.6, 115.9] (aromatic),
37.5 (CH2); IR (KBr) vmax: 3240, 3047, 2931, 1675,
1537, 1488, 1474, 1242, 838, 825 cm1. MS (ESI) m/z:
423.9 ([M＋H]＋).
N-(4-Chlorophenyl)-2-((5-(2-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC8) A white solid,
1
m.p. 168－169 ℃; yield 63%; H NMR (500 MHz,
DMSO-d6) δ: 10.58 (s, 1H, NH), 7.91 (d, J＝7.8 Hz, 1H,
NH-Ar-H), 7.66 (d, J＝8.0 Hz, 1H, NH-Ar-H), 7.60 (d,
J＝7.9 Hz, 1H, Ar-H), 7.58 (d, J＝8.8 Hz, 2H, Ar-H),
7.50 (t, J＝7.7 Hz, 1H, Ar-H), 7.35 (d, J＝8.6 Hz, 2H,
NH-Ar-H), 4.33 (s, 2H, CH2); 13C NMR (125 MHz,
DMSO-d6) δ: 165.5 (C＝O) [164.6, 163.8] (oxadiazol),
[138.1, 133.9, 132.2, 131.7, 129.3, 128.4, 127.8, 122.6,
121.2] (aromatic), 37.3 (CH2); IR (KBr) vmax: 3268,
3070, 2979, 1684, 1608, 1546, 1482, 1464, 1280, 1038,
817, 765 cm1; MS-ESI (＋) m/z: 380.0 ([M＋H]＋).
N-(4-Bromophenyl)-2-((5-(4-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC9) A white solid,
N-(4-p-Tolyl)-2-((5-(4-chlorophenyl)-1,3,4-oxadia-
zol-2-yl)thio)acetamides (TC4) A light yellow solid,
1
m.p. 207－209 ℃; yield 77%; H NMR (500 MHz,
DMSO-d6) δ: 10.37 (s, 1H, NH), 7.98 (d, J＝8.6 Hz, 2H,
Ar-H), 7.67 (d, J＝8.6 Hz, 2H, Ar-H), 7.48 (d, J＝8.4
Hz, 2H, NH-Ar-H), 7.14 (d, J＝8.3 Hz, 2H, NH-Ar-H),
4.34 (s, 2H, CH2), 2.25 (s, 3H, CH3); 13C NMR (125
MHz, DMSO-d6) δ: 165.1 (C ＝ O), [164.9, 164.3]
(oxadiazol), [137.3, 136.7, 133.2, 130.1, 129.8, 128.7,
122.4, 119.7] (aromatic), 37.4 (CH2), 21.0 (CH3); IR
(KBr) vmax: 3252, 3048, 2970, 2920, 1673, 1603, 1540,
1511, 1472, 1383, 1245, 844, 814 cm1; MS (ESI) m/z:
360.3 ([M＋H]＋).
1
m.p. 180－181 ℃; yield 60%; H NMR (500 MHz,
DMSO-d6) δ: 10.55 (s, 1H, NH), 7.91 (d, J＝6.3 Hz, 1H,
NH-Ar-H), 7.67 (d, J＝7.7 Hz, 1H, NH-Ar-H), 7.60 (t,
J＝7.0 Hz, 1H, Ar-H), 7.52 (t, J＝8.6 Hz, 3H, Ar-H),
7.48 (d, J＝8.9 Hz, 2H, NH-Ar-H), 4.33 (s, 2H, CH2);
13C NMR (125 MHz, DMSO-d6) δ: 165.5 (C＝O);
[164.5, 163.8] (oxadiazol), [138.6, 133.9, 132.3, 132.2,
131.7, 128.4, 122.7, 121.6, 115.8] (aromatic), 37.3
(CH2); IR (KBr) vmax: 3309, 3065, 2978, 1684, 1607,
1545, 1482, 1464, 1247, 1036, 815, 765 cm1; MS (ESI)
m/z: 424.0 ([M＋H]＋).
N-(4-p-Tolyl)-2-((5-(2-chlorophenyl)-1,3,4-oxadia-
zol-2-yl)thio)acetamides (TC10) A white solid, m.p.
122－123 ℃; yield 47%; 1H NMR (500 MHz,
DMSO-d6) δ: 10.33 (s, 1H, NH), 7.91 (d, J＝9.3 Hz, 1H,
NH-Ar-H), 7.67 (d, J＝8.0 Hz, 1H, NH-Ar-H), 7.60 (t,
J＝7.8 Hz, 1H, Ar-H), 7.50 (t, J＝7.5 Hz, 1H, Ar-H),
7.43 (d, J＝8.4 Hz, 2H, Ar-H ), 7.09 (d, J＝8.3 Hz, 2H,
NH-Ar-H), 4.31 (s, 2H, CH2), 2.22 (s, 3H, CH3); 13C
NMR (125 MHz, DMSO-d6) δ: 165.0 (C＝O), [164.7,
163.7] (oxadiazol), [136.7, 133.8, 133.2, 132.2, 131.7,
130.1, 129.8, 128.4, 122.7, 119.7] (aromatic), 37.3
(CH2), 21.0 (CH3); IR (KBr) vmax: 3272, 3132, 2923,
1688, 1653, 1610, 1554, 1507, 1399, 1204, 1171, 1036,
818, 764 cm1; MS (ESI) m/z: 360.1 ([M＋H]＋).
N-(4-Methoxyphenyl)-2-((5-(4-chlorophenyl)-
1,3,4-oxadiazol-2-yl)thio)acetamides (TC5) A white
1
solid, m.p. 210－212 ℃; yield 89%; H NMR (500
MHz, DMSO-d6) δ: 10.32 (s, 1H, NH), 7.95 (d, J＝8.6
Hz, 2H, Ar-H), 7.64 (d, J＝8.6 Hz, 2H, Ar-H), 7.49 (d,
J＝9.1 Hz, 2H, NH-Ar-H), 6.90 (d, J＝9.0 Hz, 2H,
NH-Ar-H ), 4.33 (s, 2H, CH2), 3.70 (s, 3H, OCH3); 13C
NMR (125 MHz, DMSO-d6) δ: 164.9 (C＝O), [164.8,
164.3] (oxadiazol), [156.0, 137.3, 132.3, 130.1, 128.70,
122.4, 121.2, 114.5] (aromatic), 55.7 (OCH3), 37.2
(CH2); IR (KBr) vmax: 3248, 3056, 2932, 2835, 1670,
1602, 1543, 1510, 1474, 1241, 846, 828 cm1; MS-ESI
(＋) m/z: 376.1 ([M＋K]＋).
N-(4-Nitrophenyl)-2-((5-(4-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC6) A light yellow
1
solid, m.p. 228－229 ℃; yield 58%; H NMR (500
MHz, DMSO-d6) δ: 11.03 (s, 1H, NH), 8.20 (d, J＝8.9
Hz, 2H, NH-Ar-H), 7.92 (d, J＝8.4 Hz, 2H, NH-Ar-H),
7.80 (d, J＝9.0 Hz, 2H, Ar-H), 7.61 (d, J＝8.4 Hz, 2H,
Ar-H), 4.39 (s, 2H, CH2); 13C NMR (125 MHz,
DMSO-d6) δ: 165.5 (C＝O), [165.00, 164.1] (oxadiazol),
[145.1, 143.0, 137.3, 130.2, 128.7, 125.7, 122.3, 119.5]
(aromatic), 37.4 (CH2); IR (KBr) vmax: 3363, 3111, 2928,
1707, 1604, 1536, 1507, 1470, 1248, 870, 836 cm1;
MS-ESI (＋) m/z: 391.2 ([M＋H]＋).
N-(4-Methoxyphenyl)-2-((5-(2-chlorophenyl)-
1,3,4-oxadiazol-2-yl)thio)acetamides (TC11) A white
1
solid, m.p. 150－152 ℃; yield 68%; H NMR (500
MHz, DMSO-d6) δ: 10.27 (s, 1H, NH), 7.92 (d, J＝7.8
Hz, 1H, Ar-H), 7.67 (d, J＝8.0 Hz, 1H, Ar-H), 7.62－
7.58 (m, 1H, Ar-H), 7.50 (t, J＝7.5 Hz, 1H, Ar-H), 7.45
N-(4-Fluorophenyl)-2-((5-(2-chlorophenyl)-1,3,4-
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Chin. J. Chem. 2016, 34, 1236—1244

Antiviral and Antibacterial Activities of N-(4-Substituted phenyl) Acetamide Derivatives
(d, J＝9.0 Hz, 2H, NH-Ar-H), 6.86 (d, J＝9.0 Hz, 2H,
NH-Ar-H), 4.29 (s, 2H), 4.29 (s, 2H, CH2), 3.68 (s, 3H,
OCH3); 13C NMR (125 MHz, DMSO-d6) δ: 164.7 (C＝
O), [164.6, 163.7] (oxadiazol), [156.0, 133.8, 132.3,
132.2, 131.7, 128.4, 121.2, 114.5] (aromatic), 55.7
(OCH3), 37.2 (CH2); IR (KBr) vmax: 3298, 3140, 3087,
1680, 1610, 1559, 1512, 1482, 1244, 1177, 1044, 835,
764 cm1; MS (ESI) m/z: 376.0 ([M＋H]＋).
(CH2); IR (KBr) vmax: 3312, 3030, 2926, 1659, 1589,
1525, 1488, 1396, 1202, 1183, 1080, 821, 791, 772, 718
cm1; MS (ESI) m/z: 424.0 ([M＋H]＋).
N-(o-Tolyl)-2-((5-(3-chlorophenyl)-1,3,4-oxadia-
zol-2-yl)thio)acetamides (TC16) A white solid, m.p.
150 － 152 ℃ ; yield 54%; 1H NMR (500 MHz,
DMSO-d6) δ: 10.34 (s, 1H, NH), 7.93－7.87 (m, 2H,
ArH ), 7.66 (d, J＝8.0 Hz, 1H, ArH), 7.57 (t, J＝7.9 Hz,
1H, ArH), 7.43 (d, J＝8.3 Hz, 2H, NH-Ar-H), 7.09 (d, J
＝8.2 Hz, 2H, NH-Ar-H), 4.31 (s, 2H, CH2), 2.21 (s, 3H,
CH3); 13C NMR (125 MHz, DMSO-d6) δ: 165.2 (C＝O),
[164.5, 136.7] (oxadiazol), [134.6, 133.2, 132.4, 132.0,
129.8, 126.4, 125.6, 125.4, 119.7] (aromatic), 37.3
(CH2), 21.0 (CH3); IR (KBr) vmax: 3264, 3020, 2930,
1688, 1654, 1554, 1463, 1380, 1201, 1170, 1078, 816,
719, 774, 716 cm1; MS (ESI) m/z: 360.1 ([M＋H]＋).
N-(4-Methoxyphenyl)-2-((5-(3-chlorophenyl)-1,3,
N-(4-Nitrophenyl)-2-((5-(4-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC12) A light
1
yellow solid, m.p. 218－220 ℃; yield 70%; H NMR
(500 MHz, DMSO-d6) δ: 11.03 (s, 1H, NH), 8.21 (d,
J＝9.2 Hz, 2H, NH-Ar-H), 7.91 (d, J＝6.2 Hz, 1H,
Ar-H), 7.80 (d, J＝9.2 Hz, 2H, NH-Ar-H), 7.66 (d, J＝
7.9 Hz, 1H, Ar-H), 7.59 (t, J＝6.9 Hz, 1H, Ar-H), 7.50
(t, J＝7.5 Hz, 1H, Ar-H), 4.40 (s, 2H, CH2); 13C NMR
(125 MHz, DMSO-d6) δ: 166.4 (C＝O), [164.5, 163.8]
(oxadiazol), [145.2, 143.3, 133.9, 132.2, 131.7, 128.4,
125.7, 122.6, 119.5] (aromatic), 37.4 (CH2); IR (KBr)
vmax: 3309, 3087, 2996, 1684, 1615, 1546, 1467, 1408,
1329, 1212, 1166, 1109, 857, 770, 753, 737 cm1; MS
(ESI) m/z: 391.2 ([M＋H]＋).
4-oxadiazol-2-yl)thio)acetamides (TC17)
A white
1
solid, m.p. 143－144 ℃; yield 48%; H NMR (500
MHz, DMSO-d6) δ:10.31 (s, 1H, NH), 7.96－7.87 (m,
2H, Ar-H), 7.67 (d, J＝8.0 Hz, 1H, Ar-H), 7.58 (t, J＝
7.9 Hz, 1H, Ar-H), 7.46 (d, J＝8.9 Hz, 2H, NH-Ar-H),
6.86 (d, J＝8.8 Hz, 2H, NH-Ar-H), 4.29 (s, 2H, CH2),
3.68 (s, 3H, OCH3); 13C NMR (125 MHz, DMSO-d6) δ:
164.9 (C＝O), [164.5, 156.0] (oxadiazol), [134.6, 132.4,
132.3, 132.0, 129.8, 127.6, 126.4, 125.6, 125.4, 121.2,
114.8, 114.6] (aromatic), 55.7 (OCH3), 37.2 (CH2); IR
(KBr) vmax: 3322, 3065, 2839, 1650, 1550, 1470, 1248,
1169, 1033, 833, 792, 775, 719 cm1; MS (ESI) m/z:
376.1 ([M＋H]＋).
N-(4-Fluorophenyl)-2-((5-(3-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC13) A white solid,
1
m.p. 136－138 ℃; yield 62%; H NMR (500 MHz,
DMSO-d6) δ: 10.54 (s, 1H, NH), 7.95 (s, 1H), 7.93 (d,
J＝7.8 Hz, 1H, Ar-H), 7.71 (d, J＝8.0 Hz, 1H, Ar-H),
7.64 (d, J＝3.8 Hz, 1H, Ar-H), 7.62 (d, J＝4.6 Hz, 2H,
NH-Ar-H), 7.18 (t, J＝8.9 Hz, 2H, NH-Ar-H), 4.37 (s,
13
2H, CH2); C NMR (125 MHz, DMSO-d6) δ: 165.4 (C
＝O), [164.5, 164.5] (oxadiazol), [135.6, 134.6, 132.4,
132.0, 126.4, 125.5 (d, J＝21.5 Hz), 121.5 (d, J＝8.1
Hz), 116.0 (d, J＝22.5 Hz)] (aromatic), 37.2 (CH2); IR
(KBr) vmax: 3285, 3075, 2975, 1658, 1546, 1510, 1478,
1409, 1215, 1169, 1080, 839, 805, 773, 724 cm1; MS
(ESI) m/z: 364.1 ([M＋H]＋).
N-(4-Nitrophenyl)-2-((5-(3-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC18) A light
yellow solid, m.p. 206－207 ℃; yield 77 %; H NMR
1
(500 MHz, DMSO-d6) δ: 11.03 (s, 1H, NH), 8.20 (d,
J＝9.1 Hz, 2H, NH-Ar-H), 7.87 (d, J＝7.5 Hz, 2H,
NH-Ar-H), 7.80 (d, J＝9.2 Hz, 2H, Ar-H), 7.63 (d, J＝
8.2 Hz, 1H, Ar-H), 7.57 (t, J＝7.9 Hz, 1H, Ar-H), 4.39
(s, 2H CH2); 13C NMR (125 MHz, DMSO-d6) δ: 166.6
(C＝O), [164.6, 164.3] (oxadiazol), [145.2, 143.1, 134.6,
132.4, 132.0, 126.4, 125.7, 125.6, 125.4, 119.5]
(aromatic), 37.4 (CH2); IR (KBr) vmax: 3326, 3074, 2837,
1700, 1570, 1556, 1507, 1332, 1253, 1171, 1109, 856,
792, 773, 721 cm1; MS (ESI) m/z: 391.2 ([M＋H]＋).
N-(4-Fluorophenyl)-2-((5-(4-chlorobenzyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC19) A white solid,
N-(4-Chlorophenyl)-2-((5-(3-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC14) A white solid,
1
m.p. 163－165 ℃; yield 74%; H NMR (500 MHz,
DMSO-d6) δ: 11.03 (s, 1H, NH), 8.21 (d, J＝8.6 Hz, 2H,
Ar-H), 7.92 (d, J＝8.0 Hz, 2HNH-Ar-H), 7.80 (d, J＝
8.4 Hz, 2H, NH-Ar-H), 7.62 (d, J＝8.0 Hz, 2H, Ar-H),
4.39 (s, 2H, CH2); 13C NMR (125 MHz, DMSO-d6) δ:
166.5 (C＝O), [165.0, 164.1] (oxadiazol), [145.2, 143.0,
137.3, 130.2, 128.7, 125.7, 122.3, 119.5] (aromatic),
37.4 (CH2); IR (KBr) vmax: 3313, 2974, 2926, 1660,
1594, 1520, 1407, 1202, 1183, 1080, 823, 791, 772, 718
cm1; MS (ESI) m/z: 380.0 ([M＋H]＋).
1
m.p. 129－130 ℃; yield 67%; H NMR (500 MHz,
DMSO-d6) δ: 10.41 (s, 1H, NH), 7.53 (dd, J＝9.1, 5.0
Hz, 2H, NH-Ar-H), 7.34 (d, J＝8.4 Hz, 2H, NH-Ar-H),
7.29 (d, J＝8.5 Hz, 2H, Ar-H), 7.13 (t, J＝8.9 Hz, 2H,
Ar-H), 4.23 (s, 2H, CH2), 4.20 (s, 2H, CH2); 13C NMR
(125 MHz, DMSO-d6) δ: 166.9 (C＝O), [165.2, 163.9]
(oxadiazol), [159.7, 157.7, 135.6, 133.7, 132.5, 131.4,
129.2, 121.4 (d, J＝8.0 Hz), 116.0 (d, J＝8.0 Hz)]
(aromatic), 37.1 (CH2), 30.5 (CH2); IR (KBr) vmax: 3309,
3094, 2837, 1676, 1588, 1480, 1410, 1168, 1092, 837,
808, 771, 695 cm1; MS (ESI) m/z: 378.1([M＋H]＋).
N-(4-Chlorophenyl)-2-((5-(4-chlorobenzyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC20) A white solid,
N-(4-Bromophenyl)-2-((5-(3-chlorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC15) A white solid,
1
m.p. 179－181 ℃; yield 53%; H NMR (500 MHz,
DMSO-d6) δ: 10.58 (s, 1H, NH), 7.92－7.87 (m, 2H,
Ar-H), 7.66 (d, J＝7.9 Hz, 1H, Ar-H), 7.57 (t, J＝7.9
Hz, 1H, Ar-H), 7.53 (d, J＝8.9 Hz, 2H, NH-Ar-H), 7.47
(d, J＝8.9 Hz, 2H, NH-Ar-H), 4.32 (s, 2H, CH2); 13C
NMR (125 MHz, DMSO-d6) δ: 165.7 (C＝O), [164.6,
164.4] (oxadiazol), [138.5, 134.6, 132.4, 132.3, 132.0,
126.4, 125.6, 125.4, 121.6, 115.9] (aromatic), 37.3
Chin. J. Chem. 2016, 34, 1236—1244
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1239

Chen et al.
FULL PAPER
1
m.p. 136－137 ℃; yield 80%; H NMR (500 MHz,
DMSO-d6) δ: 10.49 (s, 1H, NH), 7.54 (d, J＝8.3 Hz, 2H,
NH-Ar-H), 7.35 (d, J＝2.5 Hz, 2H, NH-Ar-H), 7.33 (d,
J＝2.0 Hz, 2H, Ar-H), 7.29 (d, J＝7.9 Hz, 2H, Ar-H),
4.23 (s, 2H, CH2), 4.21 (s, 2H, CH2); 13C NMR (125
MHz, DMSO-d6) δ: 166.9 (C ＝ O), [165.4, 163.8]
(oxadiazol), [138.1, 133.7, 132.5, 131.3, 129.3, 129.3,
127.8, 121.2] (aromatic), 37.1 (CH2), 30.5 (CH2); IR
(KBr) vmax: 3313, 3131, 2938, 1683, 1554, 1491, 1406,
1176, 1097, 1066, 823, 778 cm1; MS (ESI) m/z: 394.1
([M＋H]＋).
13C NMR (125 MHz, DMSO-d6) δ: 167.0 (C＝O),
[166.4, 163.7] (oxadiazol), [145.2, 143.0, 133.7, 132.5,
131.3, 129.2, 125.7, 119.4] (aromatic), 37.2 (CH2), 30.5
(CH2); IR (KBr) vmax: 3272, 3092, 2933, 1684, 1570,
1510, 1481, 1337, 1172, 1112, 858, 751 cm1; MS (ESI)
m/z: 405.3 ([M＋H]＋.
N-(4-(Fluorophenyl)-2-((5-(4-fluorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC25) A light
1
yellow solid, m.p. 217—218 ℃; yield 57%; H NMR
(500 MHz, DMSO-d6) δ: 11.03 (s, 1H, NH), 8.21 (d,
J＝9.0 Hz, 2H, Ar-H), 7.92 (d, J＝8.5 Hz, 2H, Ar-H),
7.80 (d, J＝9.0 Hz, 2H, NH-Ar-H), 7.62 (d, J＝8.3 Hz,
2H, NH-Ar-H), 4.32 (s, 2H, CH2); 13C NMR (125 MHz,
DMSO-d6) δ: 165.4 (C＝O); [164.9, 164.0] (oxadiazol),
[160.5, 135.6, 129.6 (d, J＝9.2 Hz), 128.6 (d, J＝9.1
Hz), 121.5 (d, J＝8.1 Hz), 119.2 (d, J＝7.7 Hz), 117.2
(dd, J＝22.4, 15.9 Hz), 116.4－115.9 (m) (aromatic)],
37.2 (CH2); IR (KBr) vmax: 3263, 3072, 2890, 1627,
1594, 1500, 1480, 1248, 843, 833, 776, 732 cm1; MS
(ESI) m/z: 348.2 ([M＋H]＋).
N-(4-Bromophenyl)-2-((5-(4-chlorobenzyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC21) A white solid,
m.p. 137—138 ℃; yield 92 %; H NMR (500 MHz,
1
DMSO-d6) δ: 10.48 (s, 1H, NH), 7.49 (d, J＝9.2 Hz, 2H,
NH-Ar-H), 7.47 (d, J＝9.2 Hz, 2H, NH-Ar-H), 7.34 (d,
J＝8.4 Hz, 2H, Ar-H), 7.28 (d, J＝8.5 Hz, 2H, Ar-H),
4.23 (s, 2H, CH2), 4.21 (s, 2H, CH2); 13C NMR (125
MHz, DMSO-d6) δ: 166.9 (C ＝ O), [165.5, 163.8]
(oxadiazol), [138.5, 133.7, 132.5, 132.2, 131.3, 129.2,
121.5, 115.8] (aromatic), 37.1 (CH2), 30.5 (CH2); IR
(KBr) vmax: 3316, 3126, 2938, 1684, 1550, 1490, 1473,
1179, 820, 778 cm1; MS (ESI) m/z: 438.3 ([M＋H]＋).
N-(p-Tolyl)-2-((5-(4-chlorobenzyl)-1,3,4-oxadia-
zol-2-yl)thio)acetamides (TC22) A white solid, m.p.
156 — 157 ℃ ; yield 97%; 1H NMR (500 MHz,
DMSO-d6) δ: 10.26 (s, 1H, NH), 7.40 (d, J＝7.4 Hz, 2H,
NH-Ar-H), 7.33 (d, J＝8.0 Hz, 2H, NH-Ar-H), 7.29 (d,
J＝8.1 Hz, 2H, Ar-H), 7.08 (d, J＝7.9 Hz, 2H, Ar-H),
4.23 (s, 2H, CH2), 4.20 (s, 2H, CH2), 2.22 (s, 3H, CH3);
13C NMR (125 MHz, DMSO-d6) δ: 166.8 (C＝O),
[165.0, 163.9] (oxadiazol), [136.7, 133.8, 133.2, 132.5,
131.3, 129.8, 129.2, 119.6] (aromatic), 37.2 (CH2), 30.5
(CH2), 21.0 (CH3); IR (KBr) vmax: 3317, 3133, 2939,
1681, 1554, 1491, 1473, 1380, 1173, 814, 719 cm1; MS
(ESI) m/z: 374.1 ([M＋H]＋).
N-(4-Chlorophenyl)-2-((5-(4-fluorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC26) A white solid,
m.p. 200－202 ℃; yield 61%; H NMR (500 MHz,
1
DMSO-d6) δ: 10.62 (s, 1H, NH), 8.02 (dd, J＝8.8, 5.4
Hz, 2H, Ar-H), 7.62 (d, J＝8.9 Hz, 2H, Ar-H), 7.44 (t,
J＝8.8 Hz, 2H, NH-Ar-H), 7.39 (d, J＝8.8 Hz, 2H,
NH-Ar-H), 4.36 (s, 2H, CH2); 13C NMR (125 MHz,
DMSO-d6) δ: 165.6 (C＝O), [165.0, 163.9] (oxadiazol),
[163.6, 138.1, 134.3, 133.7, 130.6, 129.6 (d, J＝8.7 Hz),
129.3, 127.8, 121.2, 120.2, 117.2 (d, J＝22.3 Hz)]
(aromatic), 37.3 (CH2); IR (KBr) vmax: 3309, 3077, 2860,
1663, 1605, 1546, 1500, 1489, 1238, 841, 814, 730, 624
cm1; MS (ESI) m/z: 364.0 ([M＋H]＋.
N-(4-Bromophenyl)-2-((5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl)thio)acetamides (TC27) A white
solid, m.p. 200－202 ℃; yield 66%; H NMR (500
1
N-(4-Methoxyphenyl)-2-((5-(4-chlorobenzyl)-
1,3,4-oxadiazol-2-yl)thio)acetamides (TC23) A white
solid, m.p. 138－139 ℃; yield 74%; H NMR (500
MHz, DMSO-d6) δ: 10.58 (s, 1H, NH), 7.98 (dd, J＝8.8,
5.4 Hz, 2H Ar-H), 7.51 (d, J＝8.9 Hz, 2H, Ar-H), 7.45
(d, J＝9.0 Hz, 2H, NH-Ar-H), 7.39 (t, J＝8.8 Hz, 2H,
Ar-H), 4.31 (s, 2H, CH2); 13C NMR (125 MHz,
DMSO-d6) δ: 165.7 (C＝O), [165.0, 163.9] (oxadiazol),
[163.6, 138.5, 132.3, 129.6 (d, J＝9.3 Hz), 121.6, 120.2,
117.2 (d, J＝22.3 Hz), 115.8] (aromatic), 37.3 (CH2); IR
(KBr) vmax: 3309, 3129, 2890, 1664, 1605, 1546, 1500,
1488, 1380, 1224, 841, 814, 730, 624 cm1; MS (ESI)
m/z: 407.9 ([M＋H]＋).
N-(p-Tolyl)-2-((5-(4-fluorophenyl)-1,3,4-oxadia-
zol-2-yl)thio)acetamides (TC28) A white solid, m.p.
172 － 173 ℃ ; yield 83%; 1H NMR (500 MHz,
DMSO-d6) δ: 10.32 (s, 1H, NH), 7.93 (t, J＝10.6 Hz,
2H, Ar-H), 7.62 (d, J＝8.5 Hz, 2H, NH-Ar-H), 7.41 (d,
J＝8.3 Hz, 2H, Ar-H), 7.09 (d, J＝8.2 Hz, 2H, Ar-H),
4.30 (s, 2H, CH2), 2.25 (s, 3H, CH3); 13C NMR (125
MHz, DMSO-d6) δ: 165.1 (C ＝ O), [164.9, 164.3]
(oxadiazol), [137.3, 136.7, 133.2, 130.1, 129.8, 128.7,
122.4, 119.7] (aromatic), 37.4 (CH2), 21.0 (CH3); IR
(KBr) vmax: 3249, 3043, 2925, 1673, 1607, 1540, 1534,
1501, 1380, 1229, 844, 812, 735, 622 cm1; MS (ESI)
1
MHz, DMSO-d6) δ: 10.19 (s, 1H, NH), 7.40 (d, J＝9.0
Hz, 2H, NH-Ar-H), 7.32 (d, J＝8.4 Hz, 2H, Ar-H), 7.27
(d, J＝8.5 Hz, 2H, Ar-H), 6.84 (d, J＝9.0 Hz, 2H,
NH-Ar-H), 4.24 (s, 2H, CH2), 4.16 (s, 2H, CH2), 3.67 (s,
3H, OCH3); 13C NMR (125 MHz, DMSO-d6) δ: 166.9
(C＝O), [164.8, 155.8] (oxadiazol), [133.8, 133.7, 132.5,
132.3, 131.3, 129.2, 121.2, 114.5] (aromatic), 55.7
(OCH3), 37.1 (CH2), 30.5 (CH2), 166.9, 164.8, 155.8,
133.8, 133.7, 132.5, 132.3, 131.3, 129.2, 121.2, 114.5,
55.7, 37.1, 30.5; IR (KBr) vmax: 3296, 3088, 2834, 1669,
1558, 1512, 1482, 1247, 1166, 823, 775 cm1; MS (ESI)
m/z: 390.1 ([M＋H]＋).
N-(4-Nitrophenyl)-2-((5-(4-chlorobenzyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC24) A light
1
yellow solid, m.p. 153－155 ℃; yield 61%; H NMR
(500 MHz, DMSO-d6) δ: 10.95 (s, 1H, NH), 8.21 (d,
J＝9.2 Hz, 2H, NH-Ar-H), 7.76 (d, J＝9.2 Hz, 2H,
NH-Ar-H), 7.33 (d, J＝6.4 Hz, 2H, Ar-H), 7.28 (d, J＝
8.5 Hz, 2H, Ar-H), 4.28 (s, 2H, CH2), 4.23 (s, 2H, CH2);
1240
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 1236—1244

Antiviral and Antibacterial Activities of N-(4-Substituted phenyl) Acetamide Derivatives
m/z: 344.1 ([M＋H]＋).
MHz, DMSO-d6) δ: 166.6 (C ＝ O), [165.6, 165.0]
N-(4-Methoxyphenyl)-2-((5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl)thio)acetamides (TC29) A white
solid, m.p. 188－189 ℃; yield 63%; H NMR (500
(oxadiazol), [163.8 (d, J＝21.3 Hz), 145.2, 143.1, 129.6
(d, J＝9.3 Hz), 125.7, 120.2, 119.5, 117.2 (d, J＝21.3
Hz)] (aromatic), 37.4 (CH2); IR (KBr) vmax: 3264, 3085,
2935, 1690, 1611, 1560, 1509, 1380, 1229, 849, 832,
754, 623 cm1; MS (ESI) m/z: 375.1 ([M＋H]＋).
1
MHz, DMSO-d6) δ: 10.28 (s, 1H, NH), 7.98 (d, J＝13.6
Hz, 2H, Ar-H), 7.45 (d, J＝8.8 Hz, 2H, Ar-H), 7.39 (t,
J＝8.7 Hz, 2H, NH-Ar-H), 6.86 (d, J＝8.8 Hz, 2H, NH-
Ar-H), 4.28 (s, 2H, CH2), 3.68 (s, 3H, CH3); 13C NMR
(125 MHz, DMSO-d6) δ: 165.6 (C＝O), [164.9, 164.0]
(oxadiazol), [159.7, 156.1, 132.3, 130.5, 129.8, 129.6 (d,
J＝9.1 Hz), 121.2 117.2 (d, J＝22.5 Hz), 114.7 (d, J＝
46.3 Hz)] (aromatic), 55.7 (OCH3), 37.3 (CH2); IR (KBr)
vmax: 3248, 3052, 2935, 1670, 1607, 1595, 1509, 1380,
1228, 849, 832, 735, 623 cm1; MS (ESI) m/z: 360.1
([M＋H]＋).
Results and Discussion
The synthetic route for the title compounds (TC1－
TC30) is illustrated in Scheme 1. The starting material
(substituted benzoic or benzyl carboxylic acid (1)) was
treated via esterification, hydrazidation, cyclisation and
acidification to provide an important intermediate,
namely, 5-substituted-1,3,4-oxadiazole-2-thiol (3).[27,28]
Another crucial intermediate (5) was synthesized
through the substitution reaction between 4-substituted
anilines and 2-bromoacetyl bromide under the base of
K2CO3 in dichloromethane. Finally, the title compounds
TC1－TC30 were obtained by incubating 3 and 5 in ac-
etone at room temperature for 6 h. All the target com-
N-(4-Nitrophenyl)-2-((5-(4-fluorophenyl)-1,3,4-
oxadiazol-2-yl)thio)acetamides (TC30) A light
1
yellow solid, m.p. 184－185 ℃; yield 62%; H NMR
(500 MHz, DMSO-d6) δ: 11.02 (s, 1H, NH), 8.21 (d,
J＝8.7 Hz, 2H, NH-Ar-H), 7.98 (dd, J＝8.0, 5.7 Hz, 2H,
NH-Ar-H), 7.80 (d, J＝9.2 Hz, 2H, Ar-H), 7.40 (t,
J＝8.8 Hz, 2H, Ar-H), 4.38 (s, 2H, CH2); 13C NMR (125
1
pounds were characterised by IR, H NMR, 13C NMR,
Scheme 1 Synthetic route of the title compounds (TC1－TC30)
N
N
(i) EtOH, 98%H2SO4
(i) KOH, CS2, EtOH
R1CONHNH2
R1COOH
R1
SH
(ii) NH2NH2 H2O
O
3
(ii) 5% HCl
H
1
2
N
N
K2CO3
N
R1
O
S
R2
O
Acetone
O
Br
H
N
Br
R2
TC1 - TC30
NH2
Br
K2CO3, dichloromethane
R2
O
4
5
TC1: R1 = 4-Cl-C6H4-
TC2: R1 = 4-Cl-C6H4-
TC3: R1 = 4-Cl-C6H4-
TC4: R1 = 4-Cl-C6H4-
TC5: R1 = 4-Cl-C6H4-
TC6: R1 = 4-Cl-C6H4-
TC7: R1 = 2-Cl-C6H4-
TC8: R1 = 2-Cl-C6H4-
TC9: R1 = 2-Cl-C6H4-
R2 = F
TC11: R1 = 2-Cl-C6H4-
TC12: R1 = 2-Cl-C6H4-
TC13: R1 = 3-Cl-C6H4-
TC14: R1 = 3-Cl-C6H4-
TC15: R1 = 3-Cl-C6H4-
TC16: R1 = 3-Cl-C6H4-
TC17: R1 = 3-Cl-C6H4-
TC18: R1 = 3-Cl-C6H4-
R2 = OCH3
R2 = NO2
R2 = F
TC21: R1 = 4-Cl-C6H4-CH2- R2 = Br
TC22: R1 = 4-Cl-C6H4-CH2- R2 = CH3
TC23: R1 = 4-Cl-C6H4-CH2- R2 = OCH3
TC24: R1 = 4-Cl-C6H4-CH2- R2 = NO2
R2 = Cl
R2 = Br
R2 = CH3
R2 = OCH3
R2 = NO2
R2 = F
R2 = Cl
R2 = Br
TC25: R1 = 4-F-C6H4-
TC26: R1 = 4-F-C6H4-
TC27: R1 = 4-F-C6H4-
TC28: R1 = 4-F-C6H4-
TC29: R1 = 4-F-C6H4-
TC30: R1 = 4-F-C6H4-
R2 = F
R2 = CH3
R2 = OCH3
R2 = NO2
R2 = Cl
R2 = Br
R2 = Cl
R2 = CH3
R2 = OCH3
R2 = NO2
R2 = Br
TC19: R1 = 4-Cl-C6H4CH2- R2 = F
TC20: R1 = 4-Cl-C6H4-CH2- R2 = Cl
TC10: R1 = 2-Cl-C6H4-
R2 = CH3
Table 1 Antiviral activities of the target compounds against tobacco mosaic virus (TMV) in vivo at 500 µg/mL
Compd
TC1
TC2
TC3
TC4
TC5
TC6
TC7
TC8
TC9
TC10
TC11
Curative activity/%
40.3±2.1
46.7±1.0
45.2±1.3
43.3±3.4
53.8±3.2
32.9±7.0
52.7±4.2
59.8±2.7
44.9±1.9
57.5±3.9
47.9±8.1
Protective activity/%
52.7±6.3
41.2±1.7
51.7±4.8
54.7±5.7
59.5±3.0
51.1±2.5
48.9±5.1
46.1±5.3
49.2±5.8
56.2±1.1
50.9±3.9
Compd
TC17
TC18
TC19
TC20
TC21
TC22
TC23
TC24
TC25
TC26
TC27
Curative activity/%
49.5±1.4
46.9±7.2
30.5±2.5
60.2±3.2
40.6±4.2
36.6±4.0
57.3±3.0
49.2±1.0
37.6±1.9
52.3±1.2
57.4±1.7
Protective activity/%
52.9±1.6
56.7 ±4.9
46.6±3.4
54.1±3.1
51.2±3.4
39.5±4.7
50.0±2.2
61.7±4.4
50.1±2.2
49.4±1.8
43.5±1.3
Chin. J. Chem. 2016, 34, 1236—1244
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chen et al.
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Continued
Compd
TC12
TC13
TC14
TC15
TC1
Curative activity/%
Protective activity/%
55.7±7.5
Compd
TC28
Curative activity/%
45.3±2.3
Protective activity/%
57.5±2.4
51.3±3.5
48.4±1.6
55.6±4.3
40.1±4.4
45.0±5.0
47.0±1.3
46.4±2.8
65.7±1.2
52.8±3.1
TC29
55.3±1.2
58.5±5.6
TC30
48.4±3.0
52.0±1.6
Ningnanmycin
57.9±1.4
47.7±6.0
Table 2 Half-maximal effective concentration (EC50) values of the curative activities of TC8, TC10, TC12, TC15, TC20, TC23, TC27 and
TC29 against TMV
Compd
TC8
R1
R2
Regression equation
y＝0.7154x＋3.2979
y＝0.6847x＋3.3197
y＝0.6646x＋3.3599
y＝0.6465x＋3.4134
y＝0.7493x＋3.2217
y＝0.6559x＋3.3971
y＝0.6030x＋3.5292
y＝0.7118x＋3.2633
y＝0.7221x＋3.2406
r2
EC50/(µg•mL1)
2-Cl-C6H4−
2-Cl-C6H4−
2-Cl-C6H4−
3-Cl-C6H4−
4-Cl-C6H4-CH2−
4-Cl-C6H4-CH2−
4-F-C6H4−
4-F-C6H4−
－
4-Cl
0.95 239.5±2.5
0.97 284.5±3.1
0.96 293.6±2.8
0.99 284.3±2.0
0.97 236.2±2.7
0.98 278.0±2.5
0.98 274.9±1.8
0.96 274.9±2.5
0.95 273.2±3.4
TC10
4-CH3
4-NO2
4-Br
TC12
TC15
TC20
4-Cl
TC23
4-OCH3
4-Br
TC27
TC29
4-OCH3
－
Ningnanmycin
and MS; NMR spectra are provided in the supplemen-
tary data.
The antiviral activities of the compounds (TC1－
TC30) toward TMV were investigated in vivo as previ-
ously described.[29] As shown in Table 1, most of the
target compounds showed acceptable curative and pro-
tective activities against TMV, with values ranging
within 40.1%－60.2% and 41.2%－61.7% at the con-
centration of 500 µg/mL, respectively. Among these
compounds, TC8 and TC20 exhibited favourable cura-
tive activities against TMV, with inhibition rates of
59.8% and 60.2%, respectively, which were slightly
higher than that of the positive control Ningnanmycin
(inhibition ratio, 57.9%). Moreover, the inhibition rates
of compounds TC10, TC12, TC23 and TC27 were 57.5%,
57.5%, 57.3% and 57.4%, respectively, which were also
comparable with that of ningnanmycin. All the title
compounds exhibited weaker protective activities than
ningnanmycin (protective activity, 65.7%).
The half-maximal effective concentration (EC50)
values of compounds TC8, TC10, TC12, TC15, TC20,
TC23, TC27 and TC29 for curative activity against TMV
were evaluated and listed in Table 2. Compounds TC8
and TC20 exerted stronger curative activity than ning-
nanmycin. The EC50 values of these compounds were
239.5 and 236.2 µg/mL, respectively, and that of ning-
nanmycin was 273.2 µg/mL. In addition, compounds
TC10, TC12, TC15, TC23, TC27 and TC29 showed com-
parable activities with ningnanmycin, and their EC50
values were 284.5, 293.6, 284.3, 278.0, 274.9, 274.9
and 273.2 µg/mL, respectively. These results revealed
that the kind of compounds could serve as applicable
and alternative antiviral candidates.
Figure 2 Comparison of curative activity of (TC1－TC30)
against TMV in vivo. NNM is Ningnanmycin.
The preliminary structure–activity relationship (SAR)
was elucidated in accordance with the curative effect
against TMV. From Figure 2, it was noted that the sub-
stituents on 5-position of 1,3,4-oxadiazole moiety or
arylamine had a great impact on the anti-TMV activity.
The result demonstrated that the electronic effect of
substituents on the arylamine did exert the effect toward
the bioactivity. For example, when R1 is 4-chlorophenyl,
a better electron-donating group (－OCH3, R2, 53.8%)
on the arylamine exhibited higher anti-TMV activity
than that of other electron-withdrawing groups (－F,
40.3%; －Cl, 46.7%; －Br, 45.2%; －NO2, 32.9%) or
a weaker electron-donating group (－CH3, 43.3%).
Moreover, the position of the substituent also affected
1242
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Chin. J. Chem. 2016, 34, 1236—1244

Antiviral and Antibacterial Activities of N-(4-Substituted phenyl) Acetamide Derivatives
the curative effect. When R2 is －F, －Cl, －CH3, or
－NO2, the order of activities of chloro-substituted
compounds followed 2-Cl-C6H4－＞3-Cl-C6H4－ (or
4-Cl-C6H4－). It was worth mentioning that the antivi-
rus activity was significantly enhanced when a soft
methylene group was placed within 4-Cl-C6H4－ and
1,3,4-oxadiazole moiety [46.7% for TC2 (without
－CH2－), 60.2% for TC20 (with －CH2－)]. Addition-
ally, different halogen groups also affected the anti-
TMV activity to acertain extent; for example, compared
with compounds TC19 (F, 30.5%), TC20 (Cl, 60.2%),
and TC21 (Br, 40.6%). In view of the above results, TC8
(R1 ＝ 4-Cl-C6H4 － , R2 ＝ Cl) and TC20 (R1 ＝
4-Cl-C6H4CH2－, R2＝Cl) exerted the strongest curative
activities against TMV than ningnanmycin, suggesting
that the two compounds could serve as potential plant
viral inhibitors against TMV.
their antibacterial activity, Gram-negative pathogenic
bacteria Xoo, R. solanacearum and Xac were screened.
In the present study, turbidimeter test was employed to
examine their antibacterial activities in vitro, and posi-
tive controls (bismerthiazol and thiodiazole copper)
were used for bioactivity comparison under the same
conditions.[30-33] As shown in Table 3, all the target
compounds exhibited certain inhibition effects against
the three bacteria at concentrations of 200 and 100
µg/mL. Among these compounds, TC16 and TC29 ex-
hibited favourable bioactivities against Xoo, with inhibi-
tion rates of 96.2% and 95.9% at the concentration of
200 µg/mL, respectively; these rates were higher than
that of the control agent bismerthiazol (56.1%). The
SAR on the anti-Xoo activity demonstrated that an elec-
tron-donating group (－OCH3, TC29, 95.9%) on the
arylamine exhibited higher antibacterial activity than
other electron-withdrawing groups (－F, TC25, 68.4%;
To determine whether these compounds can maintain
Table 3 Inhibition effect of the title compounds against Xoo, R. solanacearum, and Xac
Inhibition/%
Xoo
R. solanacearum
Xac
100 µg/mL
Compd.
200 µg/mL
68.3±9.5
69.1±2.1
62.4±7.7
62.7±9.8
25.3±7.2
46.4±4.8
39.5±8.8
72.6±3.1
34.7±4.6
72.4±9.3
13.8±3.1
43.5±2.7
58.9±4.5
53.4±9.1
36.5±6.8
96.2±4.1
66.3±7.6
68.5±4.8
28.2±4.8
62.1±1.5
21.4±3.0
67.1±3.7
－
100 µg/mL
14.5±4.8
27.4±3.9
36.6±6.8
51.8±9.5
17.5±9.0
21.9±4.7
23.0±5.0
38.6±2.8
8.8±1.4
25.4±3.5
6.8±4.0
19.4±0.8
42.7±3.8
27.3±9.6
16.2±6.3
14.3±4.8
27.3±3.9
36.1±6.8
12.3±3.4
17.5±9.0
12.4±4.7
23.4±5.0
38.3±2.8
8.5±1.4
25.1±3.5
6.8±4.0
19.2±0.8
42.4±3.8
27.6±9.6
0
200 µg/mL
100 µg/mL
19.3±5.2
9.5±3.3
200 µg/mL
77.5±7.3
35.7±2.3
52.4±9.1
55.3±6.1
38.7±8.3
68.8±5.3
43.4±6.4
0
TC1
39.4±5.9
17.6±4.4
19.8±4.9
22.9±5.0
25.3±7.2
10.1±0.6
31.6±6.2
49.4±6.9
30.7±7.7
57.3±5.1
32.3±3.1
27.5±3.0
47.7±4.2
32.4±4.9
20.7±6.0
46.3±7.6
24.1±4.7
76.5±5.6
29.6±6.0
30.7±5.9
19.8±2.7
45.9±5.0
26.6±5.5
19.3±7.2
37.5±5.3
30.6±5.5
10.4±6.5
26.6±2.4
51.2±4.0
12.3±2.7
－
18.5±7.2
32.8±7.8
26.2±1.8
40.0±2.1
29.8±1.6
38.3±2.2
35.5±3.4
0
TC2
TC3
14.4±5.1
9.8±7.4
TC4
TC5
17.3±9.0
4.4±0.4
TC6
TC7
11.6±2.9
28.5±5.4
4.9± 2.3
44.6±2.8
23.9±7.8
15.2±5.5
9.3±5.0
TC8
TC9
60.4±2.7
18.3±7.7
23.5±5.4
65.8±8.1
60.5±2.7
57.8±2.2
55.4±8.1
55.6±1.1
43.4±8.6
62.5±8.3
33.2±4.1
75.7±2.1
51.4±1.8
62.3±1.0
50.6±4.3
70.1±6.4
11.8±7.0
23.4±2.6
30.3±4.6
33.5±4.7
75.7±4.0
63.2±9.6
53.7±5.3
0
TC10
TC11
15.9±6.4
49.8±2.7
53.5±5.3
45.8±1.1
50.5±1.8
54.3±5.9
24.5±4.3
56.2±3.9
30.1±1.8
60.9±9.7
44.4±3.7
48.6±4.6
42.8±0.9
67.3±0.7
6.9±3.4
21.3±6.4
18.6±5.6
12.4±4.4
33.8±9.5
51.5±4.0
TC12
TC13
TC14
TC15
TC16
TC17
TC18
TC19
TC20
TC21
TC22
TC23
TC24
TC25
TC26
TC27
TC28
TC29
TC30
Bismerthiazol
Thiodiazole copper
28.0±2.5
11.1±0.9
37.3±7.0
21.4±7.3
31.8±1.7
18.4±4.0
10.5±3.6
6.2±5.9
25.5±6.6
11.4±8.6
6.4±5.9
80.3±6.0
68.4±8.6
59.4±7.1
63.5±8.2
63.7±6.0
95.9±9.0
11.2±6.5
56.1±7.3
15.6±6.8
18.2±4.9
9.3±6.0
11.7±5.9
30.9±7.4
11.5±6.0
49.3±5.4
－
－
－
92.5±2.7
52.3±4.9
51.4±2.4
22.7±2.6
－
－
Chin. J. Chem. 2016, 34, 1236—1244
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1243

Chen et al.
FULL PAPER
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We acknowledge the financial support of the Key
Technologies R&D Program (No. 2014BAD23B01),
National Natural Science Foundation of China (Nos.
21372052, 21662009), the Research Project of Chinese
Ministry
of
Education
(Nos.
213033A,
20135201110005), and Scientific Research Foundation
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1244
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 1236—1244