Design, Synthesis, Antiviral Activities of Novel Phosphonate Derivatives Containing Quinazoline Based on Chalone Motif

Article abstract of DOI:10.1002/jhet.2849

Based on the structure of natural product chalone, a series of novel phosphonate derivatives were designed and synthesized through 1,4-hydrophosphinylation of α,β-unsaturated carbonyl compounds. Their structures were characterized by IR, NMR, MS, and elemental analysis. The antiviral activities against cucumber mosaic virus were evaluated for the first time. The bioassay results indicated that most compounds exhibited good protective activities, low curative activities, and weak inactive activities. The antiviral protective activities of compounds C2 and C5 were 55.1% and 56.8%, respectively, which are slightly higher than those of the commercial Ningnanmyin (49.3%) and Dufulin (53.1%). Moreover, compounds C2 and C9 exhibited moderate curative activities (42.6% and 46.6%). Therefore, the basic motif of C1 can be used as a new lead structure for developing antivirus agents.

Full text of DOI:10.1002/jhet.2849

Month 2017
Design, Synthesis, Antiviral Activities of Novel Phosphonate Derivatives
Containing Quinazoline Based on Chalone Motif
a,b †
a†
a
a
a
a
Guo-Ping Zhang, * Jian-Ke Pan, Jian Zhang, Zeng-Xue Wu, Deng-Yue Liu, and Lei Zhao
a
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, China
b
Department of Chemistry, Huaibei Normal University, Huaibei 235000, China
*
E-mail: hbzgp-1@163.com
Guo-Ping Zhang and Jian-Ke Pan contributed equally to this study.
†
Additional Supporting Information may be found in the online version of this article.
Received July 31, 2016
DOI 10.1002/jhet.2849
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Based on the structure of natural product chalone, a series of novel phosphonate derivatives were
designed and synthesized through 1,4-hydrophosphinylation of α,β-unsaturated carbonyl compounds. Their
structures were characterized by IR, NMR, MS, and elemental analysis. The antiviral activities against
cucumber mosaic virus were evaluated for the first time. The bioassay results indicated that most compounds
exhibited good protective activities, low curative activities, and weak inactive activities. The antiviral
protective activities of compounds C2 and C5 were 55.1% and 56.8%, respectively, which are slightly
higher than those of the commercial Ningnanmyin (49.3%) and Dufulin (53.1%). Moreover, compounds
C2 and C9 exhibited moderate curative activities (42.6% and 46.6%). Therefore, the basic motif of C1
can be used as a new lead structure for developing antivirus agents.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
and antimalarial [10]. In our previous study, a series of
chalcone derivatives with heterocycle were designed and
synthesized, exhibiting moderate to good anti-plant viral
activity in vivo [11–14]. These findings inspire us to
further modify chalcone motif.
Plant viruses, also named “plant cancer,” have caused
severe economic losses to agriculture worldwide [1].
Among them, cucumber mosaic virus (CMV), a member
of the family Bromoviridae, is a major agronomic threat
that infects more than 1000 plant species [2]. At present,
the commercial antiviral agent such as ningnanmycin and
dufulin displayed 30–60% in vivo curative effect at
In addition, phosphonates and their phosphonic
derivatives
possess
intriguing
biological
and
pharmacological properties, which have been mainly
focused on antibiotic activity [15], antibacterial activity
[16], enzyme inhibitors [17], and herbicides [18], and can
be used as inhibitors of renin [19] or HIV proteases [20].
Moreover, phosphonate derivatives were also found to
exhibit good antiviral activities against plant virus [21].
In our previous study, a series of phosphonates with
heterocycle [22], thiourea [23], cyanoacrylate [24], and
amide [25], respectively, were designed and synthesized,
exhibiting moderate to good antiviral activity in vivo.
Meanwhile, quinazolin-4(3H)-one is a heterocycle moiety
exhibiting extensive biological activities such as
antifungal [26], antibacterial [27], and antitumor [28].
5
00 μg/mL against CMV [3]. Because of poor field
efficacy and huge economic loss, it is still necessary to
the development of economically viable antiviral
chemicals for application in agriculture.
Natural products have been demonstrated to be used as
ideal lead structure to develop agrochemicals, due to its
good compatibility, biodegradability and low toxicity [4].
It is well known that chalcone is the precursor of
flavonoids and isoflavonoids, which possesses promising
biological activities such as antifungal [5], anticancer [6],
anti-retroviral [7], anti-inflammatory [8], antioxidant [9],
©
2017 Wiley Periodicals, Inc.

G.-P. Zhang, J.-K. Pan, J. Zhang, Z.-X. Wu, D.-Y. Liu, and L. Zhao
Vol 000
Moreover, we also found that quinazoline derivatives
Table 1
[29,30] possessed excellent antiviral activities in vivo.
Optimized reaction condition of 1,4-addition.
Herein, a series of novel phosphonate derivatives
a
b
Entry
Base
Solvent
Time (h)
Yield (%)
containing quinazoline were designed and synthesized
through 1,4-addition reactions of diethyl phosphite to
chalone. Their antiviral activities in vivo against CMV
were subsequently evaluated, and preliminary structure–
activity relationship of these compounds against CMV
was discussed.
1
2
3
4
5
6
7
KOH
NaOEt
THF
THF
THF
THF
Toluene
DMSO
DMF
12
12
12
12
12
12
12
5
17
48
55
10
25
0
NaNH
NaH
NaH
NaH
NaH
2
a
Reaction conditions: B1 (1 mmol), diethyl phosphite (1.5 mmol), base
(
1.5 mmol), solvent (5 mL), r.t, 12 h;
Isolated yields.
RESULTS AND DISCUSSION
b
Synthesis and spectroscopy. The synthesis procedures
for intermediates A, B, and target compound C were
shown in Scheme 1. Intermediate A was synthesized
referring to the literature [31] with mainly optimized
reaction condition (Scheme 1). The method can
efficiently obtain to compound A in 96% yield after THF
solvent instead of ethanol without adding few drops of
conc. HCl. Intermediate B can be synthesized classically
by Claisene-Schmidt condensation between compound A
and aromatic aldehyde employing potassium hydroxide
as catalyst [31].
Target compound C were synthesized through 1,4-
hydrophosphinylation of α,β-unsaturated carbonyl
compounds. The reaction base had a great influence on
the reaction yield in our experiment. As shown in
Table 1, the hydrophosphonylation reaction of chalcones
derivatives containing quinazoline B1 with diethyl
phosphite was chosen as a model reaction to optimize
reaction conditions. In initial studies, different bases were
screened in THF as the solvent (5 mL) in room
temperature for 12 h (Table 1, entry 1–4), When the
reaction was carried out with NaH as the base, it could
afford the product C1 in good yield (Table 1, entry 4).
The effects of solvents were then evaluated by using NaH
as the base (Table 1, entry 4–7). THF (Table 1, entry 4)
was found to be an optimal solvent, giving C1 in a good
yield (up to 55%). With the optimized reaction conditions
in hand, the target compounds C1–C14 were synthesized.
1
Compound C were identified by melting point,
H
13
31
NMR, C NMR, P NMR, IR, elemental analyses, and
MS spectra. In H NMR, the CH-P proton appeared at δ
1
3.44–4.96 as m or d, the NH proton appeared at δ
13
10.02–10.04 as a singlet. In the C NMR spectra of
compound C, the typical carbon resonance at δ
195.1–195.7 was indicative of a carbonyl group (C═O).
31
In the P NMR spectra of compound C, the typical
phosphorus resonance at δ 25.80–28.90 was indicative of
a phosphorus group. The IR spectra of compound C
À1
showed bands at 1670–1683 cm for C═O stretching.
Scheme 1. The synthetic routes of the title compound C.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Design, Synthesis, and Antiviral Activity
Antivirus activities. The antiviral activities of the target
compounds C1–C14 against CMV were assayed. The
commercial agent ningnanmycin and dufulin were used
as controls. Results of the bioassay shown in Table 2
indicated that the title compounds exhibited good
protective activities, low curative activities, and weak
inactive activities in vivo against CMV. Among them,
compounds C2 and C5 showed good protective activities
against CMV at 500 μg/mL, with the inhibition rates of
protective activities against CMV. When the group at
meta or para positions is a bromine moiety, C5 and C7
also exhibited good protective activities against CMV.
However, when the group at ortho or para position is a
chlorine moiety, C3, C6, and C8 showed poor anti-CMV
activities. Accidentally, compound C9 with chlorine
moiety exhibited good an-CMV activity mainly for the
influence of fluoride group. Meanwhile, C10–C14 with
heterocycle moiety exhibited good activity against CMV.
In short, the presence of fluorine, bromine, or heterocycle
groups could improve the antiviral activity of the
compound more than that of other groups.
In summary, a series of novel phosphonates containing
quinazoline based on chalone motif have been
synthesized via 1,4-addition reaction in moderate yields
and structurally confirmed. Bioassay results showed that
the title compounds exhibited good protective activities,
low curative activities, and weak inactive activities
in vivo against CMV. Among them, C2 and C9 also
exhibited moderate curative activity. Moreover, C2 and
C5 exhibited slightly high protective activities than that
of the controls. Therefore, the basic motif of C1 can be
used as a leading compound for further structural
optimization to develop a potential antivirus agent.
5
5.1% and 56.8%, respectively, which were slightly
higher than that of ningnanmycin (49.3%) and similar to
that of dufulin (53.1%); Meanwhile, compounds C1, C7,
C9, C10, C11, C12, C13, and C14 exhibited the similar
protective activities against CMV (48.0%, 52.1%, 48.7%,
4
7.8%, 48.1%, 47.4%, 51.2%, and 51.8%, respectively)
to that of ningnanmycin. Moreover, compounds C3, C4,
and C6 exhibited weak protective activities in vivo
against CMV (10.7%, 9.3%, and 12.2%, respectively).
Among them, compounds C2 and C9 showed moderate
curative activities. However, other compounds exhibited
weak curative activities and inactive activities.
To further investigate the action of introducing
phosphonate moiety on title compounds, the title
compounds C1, C2, and C5 (48.0%, 55.1%, and 56.8%)
with typically high protective activities were selected and
were compared with those of the accordingly
intermediates B1, B2, and B5 (17.7%, 12.2%, and 25.6%,
respectively). The results indicated that the introduction of
phosphonate moiety can effectively improve the antiviral
activity of title compounds. Meanwhile, the group at the
phenyl ring (R) of the title compounds greatly affects the
in vivo anti-CMV protective activity. When the group at
ortho position is a fluorine moiety, C2 exhibits good
EXPERIMENTAL
Materials and methods. Nuclear magnetic resonance
spectra were recorded on a JEOL ECX-500 spectrometer
(JEOL, Tokyo, Japan). Infrared spectra were recorded on
Bruker VECTOR 22 spectrometer (Bruker, Karlsruhe,
Germany) using KBr disks. The electron impact (EI) mass
Table 2
In vivo antivirus activity data of title compounds at 500 μg/mL.
a
a
a
Compd.
R
Curative effect (%)
Protective effect (%)
Inactive effect (%)
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C
6
H
5
33.8 ± 2.3
40.5 ± 1.5
15.8 ± 0.5
15.0 ± 0.8
14.7 ± 0.9
26.0 ± 0.9
10.9 ± 1.2
29.6 ± 1.8
46.6 ± 2.0
6.1 ± 0.7
17.8 ± 0.6
8.8 ± 1.0
14.9 ± 1.4
11.6 ± 1.7
51.2 ± 1.8
52.4 ± 1.2
48.0 ± 2.0
55.1 ± 2.3
10.7 ± 1.6
9.3 ± 2.7
11.5 ± 1.4
21.0 ± 0.9
15.9 ± 1.0
26.2 ± 1.8
35.9 ± 3.5
22.4 ± 2.2
14.3 ± 0.7
15.7 ± 1.1
25.9 ± 3.7
19.4 ± 0.5
13.3 ± 3.2
15.9 ± 0.8
21.5 ± 1.2
22.5 ± 1.9
73.2 ± 2.1
78.4 ± 0.7
2-FC
2-ClC
2-CF
3-BrC
4-ClC
4-BrC
2,6-Cl
2-F-6-ClC
2-thiophene
2-furan
2-pyridine
3-pyridine
4-pyridine
6
H
4
6
H
4
3
C
6
H
4
6
H
4
56.8 ± 2.6
12.2 ± 3.0
52.1 ± 1.9
33.4 ± 2.1
48.7 ± 1.9
47.8 ± 2.5
48.1 ± 1.0
47.4 ± 1.4
51.2 ± 2.3
51.8 ± 3.0
49.3 ± 2.5
53.1 ± 1.6
6
H
4
6
H
4
2
C
6
H
3
6
H
3
C14
Control
Dufulin
b
c
a
Average of three replicates.
Ningnanmycin was used as the control.
b
c
Dufulin was also used as the control.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G.-P. Zhang, J.-K. Pan, J. Zhang, Z.-X. Wu, D.-Y. Liu, and L. Zhao
Vol 000
spectra were recorded on a Finnigan Mat SSQ 7000
70 eV) mass spectrometer (Blue Lion Biotech, LLC,
(s), 126.72 (d, J = 5.0 Hz), 125.85 (s), 123.63 (s), 121.41
19
(
(s), 115.91 (s); F NMR (471 MHz, DMSO-d ) δ
6
Snoqualmie, WA, USA). Silica gel GF254-coated glass
plates (Branch Qingdao Haiyang Chemical Co., Qingdao,
China) were used for thin-layer chromatography under
detection at 254 nm. Silica gel 200–300 mesh (Branch
Qingdao Haiyang Chemical Co., Qingdao, China) was
applied to column chromatography. Unless otherwise
stated, all reagents were purchased from Aladdin
Chemicals Co. (Aladdin, Shanghai, China) and used with-
out further purification. All solvents used in the reactions
were distilled from appropriate drying agents prior to use.
À57.21 (s). HRMS (ES) m/z for C H F N O
24
16 3 3
+
[M + Na] Calcd. 442.1137. Found: 442.1129.
B8: The compound was obtained in 76.7% yield as
1
yellowish solid; mp 192–194°C. H NMR (500 MHz,
DMSO-d ) δ 10.07 (s, 1H, NH), 8.70 (s, 1H, quinazoline-
6
2-H), 8.59 (d, J = 8.2 Hz, 1H, quinazoline-8-H), 8.14
(dd, J = 36.4, 8.8 Hz, 4H, CH = CH + Ar-H), 7.89–7.78
(m, 3H, Ar-H), 7.70–7.61 (m, 2H, Ar-H), 7.55 (d,
J = 8.1 Hz, 2H, Ar-H), 7.38 (t, J = 8.1 Hz,1H, Ar-H);
13
C NMR (126 MHz, DMSO-d ) δ 187.78 (s), 157.94
6
(s), 154.66 (s), 150.39 (s), 145.05 (s), 136.72 (s),
General synthetic procedure.
According to the
literature [32], methyl anthranilate was treated with
HCONH2 in the presence of HCOOH and then
chlorinated to obtain 4-chloroquinazoline.
134.67 (s), 133.86 (s), 132.75 (s), 131.98 (s), 131.45
(s), 131.02 (s), 130.16 (s), 129.64 (s), 128.48 (s),
1
27.13 (s), 123.64 (s), 121.47 (s), 115.91 (s). HRMS
+
Preparation of intermediate N-(4-acetyl-phenyl)-quinazolin-
(ES) m/z for
C H15Cl N O [M + Na] Calcd.
23 2 3
4
-amine (A).
Referring to the literature [31] by a
modified method, to a solution of 4-chloroquinazoline
mmol) in 10 mL THF was added 4-
442.0485. Found: 442.0481.
B9: The compound was obtained in 85.3% yield as
light-brown solid; mp 224–226°C. H NMR (500 MHz,
1
(
3
aminoacetophenone (3 mmol) (Scheme 1). The mixture
was stirred under reflux for 2 h with TLC monitoring.
The reaction mixture was filtered and washed with THF,
the filter cake is compound A as a pale yellowish solid
DMSO-d ) δ 10.07 (s, 1H, NH), 8.69 (s, 1H, quinazoline-
6
2-H), 8.59 (d, J = 8.2 Hz, 1H, quinazoline-8-H), 8.17 (d,
J = 8.4 Hz, 2H, CH = CH), 8.08 (d, J = 8.7 Hz, 2H,
Ar-H), 7.88–7.73 (m, 4H, Ar-H), 7.64 (t, J = 7.4 Hz, 1H,
Ar-H), 7.50–7.38 (m, 2H, Ar-H), 7.34 (t, J = 10.0 Hz,
3
2
(0.72 g, yield 91%), mp 256–257°C (lit mp 255–257°C).
13
Preparation of intermediate substituted chalcones derivatives
1H, Ar-H); C NMR (126 MHz, DMSO-d ) δ 187.94
6
with quinazoline (B). Referring to the literature [31] with
minor improvement, a mixture of A (1 mmol) and
aromatic aldehydes (1 mmol) was stirred in ethanol
(s), 162.78 (s), 160.76 (s), 157.94 (s), 154.66 (s),
150.37 (s), 144.99 (s), 135.58 (d, J = 4.7 Hz), 133.85
(s), 133.09 (s), 132.47 (d, J = 10.6 Hz), 132.08 (s),
130.05 (s), 129.16 (d, J = 12.0 Hz), 128.46 (s), 127.12
(s), 126.80 (s), 123.65 (s), 122.00 (d, J = 14.4 Hz),
(30 mL) and water (1 mL) and then KOH (1 mmol)
added to it. The mixture was kept overnight at room
temperature and then it was poured onto crushed ice,
stirred, and acidified with dilute HCl (pH = 1.0). The
solid separated was filtered and recrystallized from
ethanol to obtain the intermediates B. Among them,
characterization data of new compounds are given as
follows:
19
121.47 (s), 115.99 (d, J = 10.0 Hz);
F NMR
(471 MHz, DMSO-d ) δ À107.80 (s). HRMS (ES) m/z
6
+
for C H ClFN O [M + Na] Calcd. 426.0780. Found:
23
15
3
426.0772.
B10: The compound was obtained in 92.2% yield as
1
yellowish solid; mp 253–255°C. H NMR (500 MHz,
B1: yellow solid, yield 78%; B2: yellow solid, yield
DMSO-d ) δ 10.05 (s, 1H, NH), 8.70 (s, 1H, quinazoline-
6
8
7
1%; B3: yellow solid, yield 79%; B5: yellow oil, yield
1%; B6: yellow solid, yield 81%; B7: yellow solid,
2-H), 8.60 (d, J = 8.3 Hz, 1H, quinazoline-8-H), 8.14 (q,
J = 2.3 Hz, 4H, CH = CH + Ar-H), 7.90–7.86 (m, 2H,
Ar-H), 7.82 (d, J = 8.1 Hz, 1H, Ar-H), 7.75 (d,
J = 5.0 Hz, 1H, Ar-H), 7.68–7.65 (m, 2H, Ar-H), 7.59 (d,
J = 15.3 Hz, 1H, thiophene-3-H), 7.17 (dd, J = 5.0,
yield 79%.
B4: The compound was obtained in 88.2% yield as
1
yellowish solid; mp more than 300°C. H NMR
13
(500 MHz, DMSO-d ) δ 10.08 (s, 1H, NH), 8.71 (s, 1H,
3.6 Hz, 1H, thiophene-4-H); C NMR (126 MHz,
6
quinazoline-2-H), 8.60 (d, J = 8.2 Hz, 1H, quinazoline-
DMSO-d ) δ 187.57 (s), 157.99 (s), 154.74 (s), 150.40
6
8
8
-H), 8.31 (d, J = 7.8 Hz, 1H, Ar-H), 8.20 (dd, J = 25.1,
.9 Hz, 4H, CH = CH + Ar-H), 8.04 (d, J = 15.3 Hz, 1H,
(s), 144.54 (s), 140.43 (s), 136.64 (s), 133.88 (s),
133.17 (s), 132.65 (s), 130.77 (s), 129.90 (s), 129.25
(s), 128.50 (s), 127.14 (s), 123.64 (s), 121.46 (s), 120.91
(s), 115.90 (s). HRMS (ES) m/z for C H N OS
Ar-H), 7.95 (dd, J = 15.4, 2.1 Hz, 1H, Ar-H), 7.88 (t,
J = 7.6 Hz, 1H, Ar-H), 7.84–7.74 (m, 3H, Ar-H),
21 15 3
1
3
+
7
.70–7.61 (m, 2H, Ar-H);
C NMR (126 MHz,
[M + Na] Calcd. 380.0829. Found: 380.0821.
DMSO-d ) δ 187.71 (s), 157.98 (s), 154.72 (s), 150.41
B11: The compound was obtained in 87.2% yield as
yellowish solid; mp 232–235°C. H NMR (500 MHz,
6
1
(
s), 144.97 (s), 137.70 (s), 133.91 (s), 133.54 (d,
J = 4.8 Hz), 132.21 (s), 130.94 (s), 130.31 (s), 129.29
s), 128.51 (s), 128.12 (s), 127.89 (s), 127.18 (s), 126.81
DMSO-d ) δ 10.05 (s, 1H, NH), 8.71 (s, 1H, quinazoline-
6
(
2-H), 8.60 (d, J = 8.2 Hz, 1H, quinazoline-8-H), 8.14 (q,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Design, Synthesis, and Antiviral Activity
J = 8.9 Hz, 4H, CH = CH + Ar-H), 7.92–7.84 (m, 2H,
Ar-H ), 7.82 (d, J = 8.3 Hz, 1H, Ar-H), 7.67
General procedure for the synthesis of the target
compound C. To a solution of compound B (1 mmol)
and diethyl phosphite (1.5 mmol) in 5 mL THF was
added NaH (1 mmol) (Scheme 1). The mixture was
stirred at room temperature with TLC monitoring. The
reaction mixture was poured into water (20 mL) and
extracted with dichloromethane (20 mL × 3). The
dichloromethane solution was dried with anhydrous
(t, J = 7.6 Hz, 1H, Ar-H), 7.60–7.51 (m, 2H, Ar-H), 7.08
(
d, J = 3.4 Hz, 1H, furan-3-H), 6.67 (dd, J = 3.4, 1.8 Hz,
1
3
1
1
1
H, furan-4-H); C NMR (126 MHz, DMSO-d ) δ
6
87.54 (s), 157.98 (s), 154.74 (s), 151.81 (s), 150.40 (s),
46.61 (s), 144.54 (s), 133.89 (s), 132.68 (s), 130.45
(
(
(
s), 129.83 (s), 128.50 (s), 127.16 (s), 123.63 (s), 121.47
s), 119.29 (s), 117.29 (s), 115.89 (s), 113.65 (s). HRMS
Na SO4 and evaporated in vacuum. The residue was
2
+
ES) m/z for C H N O [M + Na] Calcd. 364.1056.
purified by silica gel column eluted with methanol-
ethyl acetate (V∶V = 1∶100) to obtain the target
compound C. Their characterization data of compound
C are given as follows (their spectra data seen in
Supporting Information).
21 15 3 2
Found: 364.1048.
B12: The compound was obtained in 91.4% yield as
1
yellowish solid; mp 265–267°C. H NMR (500 MHz,
DMSO-d ) δ 10.07 (s, 1H, NH), 8.71 (s, 1H, quinazoline-
6
C1: The compound was obtained in 56.7% yield as
2-H), 8.66 (d, J = 8.3 Hz, 1H, quinazoline-8-H), 8.60 (d,
1
J = 8.3 Hz, 1H, pyridine-6-H), 8.24–8.05 (m, 5H,
CH = CH + Ar-H), 7.93–7.76 (m, 4H, Ar-H), 7.74–7.61
yellowish solid; mp 169–170°C. H NMR (500 MHz,
DMSO-d ) δ: 10.03 (s, 1H, NH), 8.68 (s, 1 H,
6
1
3
quinazoline-2-H), 8.61–8.51 (m, 1H, quinazoline-8-H),
8.14–8.04 (m, 2 H, Ar-H), 8.03–7.93 (m, 2 H, Ar-H),
(
(
(
m, 2H, Ar-H), 7.45–7.34 (m, 1H, Ar-H); C NMR
126 MHz, DMSO-d ) δ 188.31 (s), 157.97 (s), 154.72
s), 153.47 (s), 150.56 (s), 150.40 (s), 144.82 (s),
6
7
4
.92–7.59 (m, 3 H, Ar-H), 7.41–7.08 (m, 5 H, Ar-H),
.02–3.90 (m, 2 H,CH CO), 3.88–3.66 (m, 4 H, 2
1
42.96 (s), 137.73 (s), 133.87 (s), 132.47 (s), 130.08
2
(
(
s), 128.50 (s), 127.14 (s), 125.69 (s), 125.42 (s), 125.26
CH
O), 3.58–3.45 (m, 1 H, CHP), 1.15 (t, J = 7.00 Hz, 3
2
13
H, CH ), 1.01 (t, J = 7.10 Hz, 3 H, CH ); C NMR
s), 123.64 (s), 121.49 (s), 115.90 (s). HRMS (ES) m/z for
3
3
+
(126 MHz, DMSO-d ) δ: 195.7, 158.0, 154.7, 150.4,
C H N O [M + Na] Calcd. 375.1217. Found: 375.1221.
6
22 16 4
B13: The compound was obtained in 93.2% yield as
yellowish solid; mp 263–265°C. H NMR (500 MHz,
144.7, 136.9, 133.9, 131.5, 129.7, 129.5, 128.7, 128.5,
1
1
1
27.4, 127.1, 123.6, 121.3, 115.8, 62.5, 62.2, 38.6, 38.3,
31
6.7, 16.2; P NMR (202 MHz, DMSO-d ) δ: 28.90; IR
DMSO-d ) δ 10.06 (s, 1H, NH), 9.01 (d, J = 2.1 Hz, 1H,
6
6
À1
pyridine-2-H), 8.71 (s, 1H, quinazoline-2-H), 8.63–8.51
(KBr, cm ) ν: 3315, 1673, 1233, 1179, 1051; Anal.
Calcd. for C H N O P: C, 66.25; H, 5.77; N, 8.58;
(m, 2H, quinazoline-8-H+ pyridine-6-H), 8.34 (d,
27 28 3 4
J = 8.0 Hz, 1H, Ar-H ), 8.20 (dd, J = 27.5, 8.9 Hz, 4H,
CH = CH+ Ar-H), 8.10 (d, J = 15.7 Hz, 1H, Ar-H), 7.88
Found: C, 66.45; H, 5.63; N, 8.51; MS (ESI) m/z: 490.2
([M + H] ), 512.2 ([M + Na] ).
+
+
C2: The compound was obtained in 55.6% yield as
(t, J = 7.6 Hz, 1H, Ar-H), 7.82 (d, J = 8.3 Hz, 1H,
1
Ar-H), 7.74 (d, J = 15.7 Hz, 1H, Ar-H), 7.67 (t,
J = 7.6 Hz, 1H, Ar-H), 7.47 (dd, J = 7.9, 4.8 Hz, 1H,
yellowish solid; mp 143–145°C. H NMR (500 MHz,
DMSO-d ) δ: 10.04 (s, 1 H, NH), 8.68 (s, 1 H,
6
13
quinazoline-2-H), 8.58 (d, J = 7.9 Hz, 1 H, quinazoline-
8-H), 8.23–8.04 (m, 2 H, Ar-H), 8.05–7.93 (m, 2 H,
Ar-H), 7.94–7.60 (m, 3 H, Ar-H), 7.55–6.99 (m, 4 H,
Ar-H), 4.13 (d, J = 10.10 Hz, 1 H, Ar-H, CHP),
Ar-H); C NMR (126 MHz, DMSO-d ) δ 187.85 (s),
6
1
57.99 (s), 154.74 (s), 151.44 (s), 150.85 (s), 150.41
(
(
s), 144.78 (s), 140.40 (s), 135.61 (s), 133.90 (s), 132.48
s), 131.20 (s), 130.20 (s), 128.52 (s), 127.17 (s),
1
24.48 (s), 124.46 (s), 123.63 (s), 121.41 (s), 115.90 (s).
4.04–3.92 (m, 2 H, CH
CH O), 1.17 (t, J = 7.0 Hz, 3 H, CH
3
2
CO), 3.92–3.71 (m, 4 H, 2
+
HRMS (ES) m/z for C H N O [M + Na] Calcd.
3
2
), 1.03 (t,
2
2 16 4
13
J
=
7
.
0
H
z
,
3
H
,
C
H
)
;
C
N
M
R
(
1
2
6
M
H
z
,
D
M
S
O
-
d
)
75.1217. Found: 375.1213.
B14: The compound was obtained in 95.1% yield as
3
6
δ 195.3, 158.0, 154.7, 150.4, 144.7, 133.9, 131.3, 130.0,
1
yellowish solid; mp more than 300°C. H NMR
500 MHz, DMSO-d ) δ 10.08 (s, 1H, NH), 8.72 (s, 1H,
129.6, 128.5, 127.2, 123.6, 121.3, 115.7, 62.6, 62.4,
3
1
3
7.7, 30.4, 16.7,16.6; P NMR (202 MHz, DMSO-d ) δ:
(
6
6
19
quinazoline-2-H), 8.65 (d, J = 6.0 Hz, 2H, pyridine-
27.80; F NMR (471 MHz, DMSO-d
(KBr, cm ) ν:3313, 1683, 1238, 1184, 1044; Anal.
6
) δ: À116.4; IR
À1
2
8
1
,6-2H), 8.60 (d, J = 8.2 Hz, 1H, quinazoline-8-H),
.27–8.13 (m, 5H, CH = CH + Ar-H), 7.89 (t, J = 7.5 Hz,
H, Ar-H), 7.85–7.78 (m, 3H, Ar-H), 7.72–7.60 (m, 2H,
Calcd. for C H FN O P: C, 63.90; H, 5.36; N, 8.28;
27 27
3 4
Found: C, 63.76; H, 5.23; N, 8.17; MS (ESI) m/z: 508.2
+
+
13
Ar-H). C NMR (126 MHz, DMSO-d ) δ 187.97 (s),
1
1
([M + H] ), 530.2 ([M + Na] ).
6
C3: The compound was obtained in 63.5% yield as
57.99 (s), 154.73 (s), 150.90 (s), 150.41 (s), 144.97 (s),
42.50 (s), 140.92 (s), 133.94 (s), 132.25 (s), 130.32
1
yellowish solid; mp 175–177°C. H NMR (500 MHz,
(
(
s), 128.52 (s), 127.20 (s), 126.96 (s), 123.63 (s), 123.03
DMSO-d ) δ: 10.02 (s, 1 H, NH), 8.68 (s, 1 H,
quinazoline-2-H), 8.57 (d, J = 8.20 Hz, 1 H, quinazoline-
8-H), 8.07 (t, J = 11.61 Hz, 2 H, Ar-H), 7.98 (d,
6
s), 121.42 (s), 115.90 (s). HRMS (ES) m/z for
+
C H N O [M + Na] Calcd. 375.1217. Found: 375.1209.
22 16 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G.-P. Zhang, J.-K. Pan, J. Zhang, Z.-X. Wu, D.-Y. Liu, and L. Zhao
Vol 000
J = 8.80 Hz, 2 H, Ar-H), 7.91–7.50 (m, 4 H, Ar-H),
.47–7.07 (m, 3 H, Ar-H), 4.39 (d, J = 9.80 Hz, 1 H,
7.92–7.58 (m, 3 H, Ar-H), 7.51–7.23 (m, 4 H, Ar-H),
7
4.02–3.91 (m, 2 H, CH CO), 3.91–3.71 (m, 4 H, 2
2
CHP), 4.07–3.92 (m, 2 H, CH CO), 3.89–3.48 (m, 4 H, 2
CH O), 3.52–3.54 (m, 1 H, CHP), 1.16 (t, J = 7.01 Hz, 3
2
2
13
CH O), 1.18 (t, J = 7.01 Hz, 3 H, CH ), 1.01 (t,
H, CH ), 1.04 (t, J = 7.01 Hz, 3 H, CH ); C NMR
2
3
3
3
1
3
J = 7.01 Hz, 3 H, CH3);
C NMR (126 MHz,
(126 MHz, DMSO-d ) δ: 195.5, 158.0, 154.7, 150.4,
6
DMSO-d ) δ: 195.4, 158.0, 154.7, 150.4, 144.7, 134.9,
144.7, 136.1, 133.9, 132.1, 131.5, 131.4, 129.6, 128.6,
6
1
33.9, 131.3, 130.0, 129.8, 129.6, 129.0, 128.5, 127.6,
27.2, 123.6, 121.3, 62.6, 62.5, 35.7, 34.6, 16.8, 16.5;
128.4, 127.2, 123.6, 121.3, 62.6, 62.3, 39.1, 38.1, 16.8,
31
1
16.6; P NMR (202 MHz, DMSO-d ) δ: 28.30; IR (KBr,
6
31
À1
P NMR (202 MHz, DMSO-d ) δ: 27.80; IR (KBr,
cm ) ν: 3327, 1676, 1235, 1176, 1043; Anal. Calcd. for
6
À1
cm ) ν: 3285, 1681, 1234, 1177, 1053; Anal. Calcd. for
C H ClN O P: C, 61.89; H, 5.19; N, 8.02; Found: C,
27
27
3 4
C H ClN O P: C, 61.89; H, 5.19; N, 8.02; Found: C,
61.97; H, 5.31; N, 8.17; MS (ESI) m/z: 524.2
([M + H] ), 546.2 ([M + Na] ).
27
27
3 4
+
+
6
1.95; H, 5.36; N, 8.11; MS (ESI) m/z: 524.2
+
+
([M + H] ), 546.1 ([M + Na] ).
C7: The compound was obtained in 46.9% yield as
1
C4: The compound was obtained in 55.6% yield as
yellowish solid; mp 174–176°C. H NMR (500 MHz,
1
yellowish solid; mp 179–181°C. H NMR (500 MHz,
DMSO-d ) δ: 10.03 (s, 1H, NH), 8.68 (s, 1H,
6
DMSO-d ) δ: 10.03 (s, 1 H, NH), 8.68 (s, 1 H,
quinazoline-2-H), 8.58 (d, J = 8.21 Hz, 1 H, quinazoline-
quinazoline-2-H), 8.62–8.50 (m, 1H, quinazoline-2-H),
8.16–8.04 (m, 2H, Ar-H), 8.04–7.93 (m, 2H, Ar-H),
7.92–7.58 (m, 3H, Ar-H), 7.54–7.27 (m, 4H, Ar-H),
4.01–3.92 (m, 2H, CH CO), 3.91–3.69 (m, 4H, 2 CH O),
6
8
-H), 8.09 (d, J = 8.5 Hz, 2 H, Ar-H), 7.98 (d,
J = 8.6 Hz, 2 H, Ar-H), 7.84 (m, 3 H, Ar-H), 7.74–7.55
m, 3 H, Ar-H), 7.54–7.30 (m, 1 H, Ar-H), 4.31–4.12 (m,
H, CHP), 4.07–3.88 (m, 2 H, CH CO), 3.85–3.47 (m, 4
2
2
(
1
3.58–3.44 (m, 1H, CHP), 1.16 (t, J = 7.01 Hz, 3 H,
13
CH ), 1.05 (t, J = 7.01 Hz, 3 H, CH ); C NMR
2
3
3
H, 2 CH O), 1.14 (t, J = 7.00 Hz, 3 H, CH ), 0.92 (t,
(126 MHz, DMSO-d ) δ: 195.5, 158.0, 154.7, 150.4
144.7, 136.6, 133.9, 131.9, 131.5, 129.6, 128.5, 127.2,
2
3
6
1
3
J = 7.00 Hz, 3 H, CH3);
C NMR (126 MHz,
DMSO-d ) δ 195.1, 158.0, 154.7, 150.4, 144.7, 136.3,
123.6, 121.3, 120.6, 62.6, 62.4, 39.7, 38.1, 16.8, 16.6;
6
31
1
33.9, 132.9, 131.3, 131.0, 129.6, 128.5, 128.0, 127.1,
P NMR (202 MHz, DMSO-d ) δ: 28.10; IR (KBr,
6
À1
1
23.6, 121.3, 115.9, 62.7, 62.5, 35.4, 34.4, 16.7, 16.39;
cm ) ν: 3329, 1674, 1234, 1178, 1042; Anal. Calcd. for
31
P NMR (202 MHz, DMSO-d ) δ: 27.40; IR (KBr,
C H BrN O P: C, 57.05; H, 4.79; N, 7.39; Found: C,
6
27 27
3 4
À1
cm ) ν: 3336, 1676, 1235, 1177, 1050; Anal. Calcd. for
57.11; H, 4.71; N, 7.36; MS (ESI) m/z: 570.1
+
+
C H F N O P: C, 60.32; H, 4.88; N, 7.54; Found: C,
([M + H] ), 592.1 ([M + Na] ).
28 27 3 3 4
6
0.19; H, 4.95; N, 7.67; MS (ESI) m/z: 558.2
C8: The compound was obtained in 55.2% yield as
yellowish solid; mp 164–166°C. H NMR (500 MHz,
+
+
1
([M + H] ), 580.2 ([M + Na] ).
C5: The compound was obtained in 49.3% yield as
yellowish solid; mp 96–98°C. H NMR (500 MHz,
DMSO-d ) δ: 10.03 (s, 1H, NH), 8.68 (s, H, quinazoline-
6
1
2-H), 8.57 (d, J = 8.20 Hz, H, quinazoline-8-H), 8.10 (d,
J = 8.80 Hz, H, Ar-H), 7.97 (d, J = 8.80 Hz, 2 H, Ar-H),
7.90–7.58 (m, 3 H, Ar-H), 7.55–7.16 (m, 3 H, Ar-H),
DMSO-d ) δ: 10.04 (s, 1 H, NH), 8.68 (s, 1 H,
6
quinazoline-2-H), 8.58 (d, J = 8.20 Hz, 1 H, quinazoline-
8
-H), 8.09 (d, J = 8.90 Hz, 2 H, Ar-H), 8.00 (d,
4.96 (m, 1 H, CHP), 4.10–3.97 (m, 4 H, 2 CH O),
2
J = 8.90 Hz, 2 H, Ar-H), 7.91–7.52 (m, 4 H, Ar-H),
3.96–3.83 (m, 2 H, CH CO), 1.18 (t, J = 7.0 Hz, 3 H,
2
13
7
3
1
.49–7.15 (m, 3 H, Ar-H), 4.04–3.92 (m, 2 H, CH CO),
CH ), 1.05 (t, J = 7.0 Hz, 3 H, CH ); C NMR
2
3
3
.92–3.73 (m, 4 H, 2 CH O), 3.61–3.44 (m, 1 H, CHP),
(126 MHz, DMSO-d ) δ: 195.4, 158.0, 154.7, 150.4,
2
6
.16 (t, J = 7.01 Hz, 3 H, CH ), 1.04 (t, J = 7.01 Hz, 3
144.7, 137.3, 135.3, 133.9, 133.4, 131.1, 130.6, 129.8,
3
13
H, CH3); C NMR (126 MHz, DMSO-d ) δ: 195.5,
129.4, 128.5, 127.1, 123.6, 121.4, 115.9, 62.5, 62.4,
6
31
1
1
1
58.0, 154.7, 150.4, 144.7, 140.0, 133.9, 132.4, 131.3,
37.5, 35.6, 16.8, 16.5; P NMR (202 MHz, DMSO-d6)
À1
30.7, 130.3, 129.6, 128.8, 128.5, 127.2, 123. 6, 121.9,
δ: 26.20; IR (KBr, cm ) ν: 3311, 1673, 1233, 1179,
31
21.3, 115.8, 62.6, 62.4, 39.3, 38.2, 16.6,16.7; P NMR
1051; Anal. Calcd. for C H Cl N O P: C, 58.08; H,
27
26
2 3 4
À1
(202 MHz, DMSO-d ) δ: 28.10; IR (KBr, cm ) ν: 3318,
4.69; N, 7.53; Found: C, 58.17; H, 4.54; N, 7.46; MS
6
+
+
1
676, 1234, 1182, 1042; Anal. Calcd. for
(ESI) m/z: 558.2 ([M + H] ), 580.1 ([M + Na] ).
C H BrN O P: C, 57.05; H, 4.79; N, 7.39; Found: C,
C9: The compound was obtained in 53.7% yield as
yellowish solid; mp 167–169°C. H NMR (500 MHz,
27
27
3 4
1
5
7.18; H, 4.87; N, 7.25; MS (ESI) m/z: 570.2
+
+
(
[M + H] ), 592.1 ([M + Na] ).
DMSO-d ) δ: 10.04 (s, 1H, NH), 8.68 (s, 1 H,
6
C6: The compound was obtained in 51.5% yield as
yellowish solid; mp 166–168°C. H NMR (500 MHz,
quinazoline-2-H), 8.58 (d, J = 8.01 Hz, 1 H, quinazoline-
8-H), 8.10 (d, J = 8.90 Hz, 2 H, Ar-H), 7.96 (d,
J = 8.84 Hz, 2 H, Ar-H), 7.91–7.59 (m, 3 H, Ar-H),
7.41–6.96 (m, 3 H, Ar-H), 4.51–4.55 (m, 1 H, CHP),
1
DMSO-d ) δ: 10.03 (s, 1 H, NH), 8.68 (s, 1 H,
6
quinazoline-2-H), 8.61–8.52 (m, 1 H, quinazoline-8-H),
8
.16–8.04 (m, 2 H, Ar-H), 8.03–7.94 (m, 2 H, Ar-H),
4.07–3.96 (m, 2 H, CH CO), 3.95–3.64 (m, 4 H, 2
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Design, Synthesis, and Antiviral Activity
1
3
CH O), 1.17 (t, J = 7.00 Hz, 3 H, CH ), 1.07 (t,
(t, J = 7.01 Hz, 3 H, CH3); C NMR (126 MHz,
2
3
1
3
J = 7.00 Hz, 3 H, CH3);
C NMR (126 MHz,
DMSO-d ) δ: 195.8, 158.0, 154.7, 150.4, 149.15,
6
DMSO-d ) δ: 195.5, 158.0, 154.7, 150.4, 144.8, 133.9,
144.6, 136.7, 133.9, 131.5, 129.4, 128.5, 127.1, 125.4,
6
31
1
1
31.1, 130.0, 129.4, 128.5, 127.2, 126.1, 123.6, 121.4,
123.6, 122.5, 121.4, 115.9, 62.4, 42.0, 36.6, 16.7;
P
3
1
15.9, 62.7, 62.5, 37.0, 33.7, 16.8, 16.6; P NMR
NMR (202 MHz, DMSO-d ) δ: 27.70; IR (KBr,
6
À1
À1
(
202 MHz, DMSO-d ) δ: 26.30; IR (KBr, cm ) ν: 3279,
cm )ν: 3316, 1670, 1234, 1181, 1051; Anal. Calcd.
6
1
672, 1245, 1176, 1058; Anal. Calcd. for
for C H N O P: C, 63.67; H, 5.55; N, 11.42; Found:
2
6 27 4 4
C H ClFN O P: C, 59.84; H, 4.84; N, 7.75; Found: C,
C, 63.48; H, 5.69; N, 11.51; MS (ESI) m/z: 491.2
([M + H] ), 513.2 ([M + Na] ).
27
26
3 4
+
+
5
9.61; H, 4.75; N, 7.70; MS (ESI) m/z: 542.2
+
+
([M + H] ), 564.2 ([M + Na] ).
C13: The compound was obtained in 52.9% yield as
1
C10: The compound was obtained in 55.1% yield as
yellowish solid; mp 86–88°C. H NMR (500 MHz,
1
yellowish solid; mp 156–158°C. H NMR (500 MHz,
DMSO-d ) δ: 10.04 (s, 1 H, NH), 8.68 (s, 1 H,
6
DMSO-d ) δ: 10.04 (s, 1H, NH), 8.69 (s, 1 H,
quinazoline-2-H), 8.58 (d, J = 8.40 Hz, 1 H, quinazoline-
quinazoline-2-H), 8.62–8.32 (m, 3 H, quinazoline-8-
H + pyridine-2,6-2H), 8.14–8.04 (m, 2 H, Ar-H),
8.02–7.96 (m, 2 H, Ar-H), 7.91–7.74 (m, 3 H, Ar-H),
6
8
-H), 8.10 (d, J = 8.80 Hz, 2 H, Ar-H), 8.00 (d,
J = 8.90 Hz, 2 H, Ar-H), 7.93–7.58 (m, 3 H, Ar-H),
.44–6.80 (m, 3 H, thiophene-H), 4.13 (d, J = 9.7 Hz, 1
7.71–7.18 (m, 2 H, Ar-H), 4.05–3.94 (m, 2 H, CH CO),
2
7
3.93–3.76 (m, 4 H, 2 CH O), 3.66–3.52 (m, 1 H, CHP),
2
H, CHP), 4.04–3.79 (m, 4 H, 2 CH O), 3.76–3.43 (m, 2
1.16 (t, J = 7.01 Hz, 3 H, CH ), 1.05 (t, J = 7.01 Hz, 3H,
2
3
13
H, CH CO), 1.23–1.13 (t, J = 7.01 Hz, 3 H, CH ), 1.10
CH3); C NMR (126 MHz, DMSO-d ) δ 195.4, 158.0,
2
3
6
1
3
(
t, J = 7.01 Hz, 3 H, CH3); C NMR (126 MHz,
154.7, 150.9, 150.4, 148.5, 136.7, 133.9, 133.0, 131.3,
DMSO-d ) δ: 195.2, 158.0, 154.7, 150.4, 144.8, 138.9,
129.6, 128.5, 127.1, 123.8, 123.6, 121.3, 115.9, 62.7,
6
31
1
1
33.9, 131.3, 129.6, 128.5, 127.2, 127.1, 125.5, 123.6,
62.5, 37.8, 36.2, 16.8, 16.6; P NMR (202 MHz,
31
À1
21.4, 115.9, 62.8, 62.5, 35.1, 34.0, 16.8, 16.7; P NMR
DMSO-d ) δ 27.75; IR (KBr, cm ) ν: 3305, 1679, 1233,
6
À1
(
202 MHz, DMSO-d ) δ: 26.80; IR (KBr, cm ) ν: 3313,
1179, 1049; Anal. Calcd. for C H N O P: C, 63.67; H,
6
26 27 4 4
1
678, 1236, 1177, 1046; Anal. Calcd. for
5.55; N, 11.42; Found: C, 63.52; H, 5.76; N, 11.47; MS
(ESI) m/z: 491.2 ([M + H] ), 513.2 ([M + Na] ).
+
+
C H N O PS: C, 60.60; H, 5.29; N, 8.48; Found: C,
25 26 3 4
6
0.71; H, 5.42; N, 8.41; MS (ESI) m/z: 496.2
C14: The compound was obtained in 47.0% yield as
yellowish solid; mp 173–175°C. H NMR (500 MHz,
+
+
1
([M + H] ), 518.1 ([M + Na] ).
C11: The compound was obtained in 57.0% yield as
yellowish solid; mp 172–174°C. H NMR (500 MHz,
DMSO-d ) δ: 10.03 (s, 1 H, NH), 8.68 (s, 1 H,
6
1
quinazoline-2-H), 8.57 (d, J = 8.2 Hz, 1 H, quinazoline-
8-H), 8.45 (d, J = 5.8 Hz, 2 H, pyridine-2,6–2 H), 8.09
(d, J = 8.91 Hz, 2 H, Ar-H), 8.00 (d, J = 8.82 Hz, 2 H,
Ar-H), 7.92–7.58 (m, 3 H, Ar-H), 7.49–7.31 (m, 2
DMSO-d ) δ: 10.04 (s, 1H, NH), 8.69 (s, 1 H,
6
quinazoline-2-H), 8.58 (d, J = 8.0 Hz, 1 H, quinazoline-
-H), 8.19–8.06 (m, 2 H, Ar-H), 8.05–7.96 (m, 2 H,
8
Ar-H), 7.94–7.62 (m, 3 H, Ar-H), 7.57–7.41 (m, 1 H,
furan-H), 6.45–6.20 (m, 2 H, furan-H), 4.05–3.79 (m, 4
H, 2 CH O), 3.77–3.64 (m, 2 H, CH CO), 3.51–3.38 (m,
H, Ar-H), 4.05–3.94 (m, 2 H, CH CO), 3.94–3.79 (m, 4
2
H, 2 CH O), 3.64–3.51 (m, 1 H, CHP), 1.16 (t,
2
J = 7.01 Hz, 3 H, CH ), 1.07 (t, J = 7.01 Hz, 3 H, CH );
2
2
3
3
13
1
H, CHP), 1.18 (t, J = 7.01 Hz, 3 H, CH ), 1.12 (t,
C NMR (126 MHz, DMSO-d ) δ: 195.3, 158.0, 154.7,
3
6
1
3
J = 7.01 Hz, 3 H, CH3);
C NMR (126 MHz,
150.4, 149.8, 146.4, 144.8, 133.9, 131.3, 129.6, 128.5,
127.1, 125.0, 123.6, 121.3, 115.9, 62.8, 62.6, 38.3, 37.5,
DMSO-d ) δ: 195.2, 158.0, 154.7, 150.3, 144.8, 142.7,
6
3
1
1
1
33.9, 131.2, 129.6, 128.5, 127.2, 123.6, 121.4, 115.8,
16.8, 16.6; P NMR (202 MHz, DMSO-d ) δ: 27.30; IR
6
3
1
À1
11.3, 108.0, 62.7, 62.4, 36.7, 32.7, 16.8; P NMR
(KBr, cm ) ν: 3323, 1676, 1239, 1181, 1046; Anal.
À1
(202 MHz, DMSO-d ) δ: 25.80; IR (KBr, cm ) ν: 3311,
Calcd. for C H N O P: C, 63.67; H, 5.55; N, 11.42;
6
26 27 4 4
1
680, 1239, 1178, 1043; Anal. Calcd. for C H N O P:
Found: C, 63.83; H, 5.47; N, 11.28; MS (ESI) m/z: 491.2
([M + H] ), 513.2 ([M + Na] ).
2
5 26 3 5
+
+
C, 62.63; H, 5.47; N, 8.76; Found: C, 62.79; H, 5.51; N,
8
+
+
.70; MS (ESI) m/z: 480.2 ([M + H] ), 502.2 ([M + Na] ).
The in vivo antivirus activity assay. Using the Scott’s
method [33], cucumber mosaic virus was purified. The
biological activity of the title compounds against CMV
were evaluated using a half-leaf method according to the
previous references [34]. At first, growing Nicotiana
tabacum L. leaves of the same age were selected. All of
the leaves were previously scattered with silicon carbide.
General procedure for curative effects of compound C is
illustrated as follows: purified virus smeared both sides of
the leaves after inoculation for 0.5 h, the compound
C12: The compound was obtained in 50.0% yield as
1
yellowish solid; mp 187–189°C. H NMR (500 MHz,
DMSO-d ) δ: 10.03 (s, 1 H, NH), 8.68 (s, 1 H,
quinazoline-2-H), 8.62–8.52 (m, 1 H, quinazoline-8-H),
8
Ar-H), 8.04–7.94 (m, 2 H, Ar-H), 7.93–7.56 (m, 4
H, Ar-H), 7.50–7.11 (m, 2 H, Ar-H), 4.26–4.00 (m, 2
H, CH CO), 4.00–3.82 (m, 4 H, 2 CH O), 3.54–3.36
6
.46–8.31 (m, 1 H, pyridine-6-H), 8.22–8.05 (m, 2 H,
2
2
(m, 1 H, CHP), 1.15 (t, J = 7.01 Hz, 3 H, CH ), 1.10
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G.-P. Zhang, J.-K. Pan, J. Zhang, Z.-X. Wu, D.-Y. Liu, and L. Zhao
Vol 000
solution was smeared on the left side of the leaves, and the
solvent was smeared on the right side for control. General
procedure for protective effects of compound C was shown
as follows: the compound solution was smeared on the left
side of the leaves, and the solvent was smeared on the right
side for control. After 12 h, two sides of the leaves were
inoculated with purified virus. General procedure for
inactive effects of compound C was shown as follows:
the virus was inhibited after it was mixed with a
compound solution of the same volume for 30 min. The
compound solution with the virus for 30 min was
smeared on the left side of the N. tabacum L. leaves; the
right side of the N. tabacum L. leaves was then
inoculated with the virus without the compound C. The
number of local lesions was recorded 3 to 4 days after
the inoculation. Three replications were reproduced for
each compound. The inhibitory rate of the compound was
calculated according to the references [34].
[12] Song, B. A.; Chen, Z. W.; Hu, D. Y.; Xue, W.; Jin, L. H.;
Dong, L. R.; Zhang, W. Y.; Pan, J. K.; Luo, L. Z. China Patent,
1
04,628,631A, 2015; Chem Abstr 2015, 163, 21647.
13] Song, B. A.; Xie, Y.; Hu, D. Y.; Xue, W.; Wu, F.; Wan, Z. H.;
Li, X. Y.; Du, X. L. China Patent 103,755,646A, 2014; Chem Abstr 2014,
60, 665592.
14] Hu, D. Y.; Wan, Z. H.; Song, B. A.; Xue, W.; Jin, L. H.; Li, X. Y.;
[
1
[
Xie, D. D.; Zhang, W. Y. China Patent 104,592,132A, 2015; Chem Abstr
2015, 162, 657019.
[15] Allenberger, F.; Klare, Y. Antimicrob Chemother 1999, 43,
211.
[16] Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassall, C. H.;
Holmes, S. W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S. Nature
1978, 272, 56.
[17] Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett
1990, 31, 5587.
[18] Bader, A. Aldrichimica Acta 1988, 21, 15.
[19] Dellaria, J. F. J.; Maki, R. G.; Stei, H. H.; Cohen, J.; Whittern,
D.; Marsh, K.; Hoffman, D. J. J.; Plattner, J.; Perun, T. J. J Med Chem
990, 33, 534.
20] Stowasser, B.; Budt, K. H.; Jian-Qi, L.; Peyman, A.; Ruppert,
D. Tetrahedron Lett 1992, 33, 6625.
21] Song, B. A.; Zhang, G. P.; Hu, D. Y.; Pang, L. L.; Yang, S.;
Liu, G.; Wang, H. China Patent 1,687,088 A, 2005.
22] Wu, L. T.; Song, B. A.; Bhadury, P. S.; Yang, S.; Hu, D. Y.;
1
[
[
[
Jin, L. H. J Heterocycl Chem 2011, 48, 389.
[23] Chen, M. H.; Chen, Z.; Song, B. A.; Bhadury, P. S.; Yang, S.;
Cai, X. J.; Hu, D. Y.; Xue, W.; Zeng, S. J Agric Food Chem 2009,
Acknowledgments. We gratefully acknowledge the financial
support of this work by the National Natural Science
Foundation of China (Nos. 21132003 and 21362004).
5
7, 1383.
24] Long, N.; Cai, X. J.; Song, B. A.; Yang, S.; Chen, Z.;
Bhadury, P. S.; Hu, D. Y.; Jin, L. H.; Xue, W. J Agric Food Chem
[
2
008, 56, 5242.
REFERENCES AND NOTES
[25] Hu, D. Y.; Wan, Q. Q.; Yang, S.; Song, B. A.; Bhadury, P. S.;
Jin, L. H.; Yan, K.; Liu, F.; Chen, Z.; Xue, W. J Agric Food Chem 2008,
56, 998.
[26] Bartroli, J.; Turmo, E.; Algueró, M.; Boncompte, E.;
Vericat, M. L.; Conte, L.; Ramis, J.; Merlos, M.; Gracía-Rafanell,
J.; Forn, J. J Med Chem 1998, 41, 1869.
[
[
1] Bos, L. Crop Prot 1982, 1, 263.
2] Palukaitis, P.; Roossinck, M. J.; Dietzgen, R. G.; Francki, R. I.
Adv Virus Res 1992, 41, 281.
3] Zhang, G. P.; Hao, G. F.; Pan, J. K.; Zhang, J.; Hu, D. Y.;
Song, B. A. J Agric Food Chem 2016, 64, 4207.
[
[27] Zhu, S.; Wang, J.; Chandrashekar, G.; Smith, E.; Liu, X.;
Zhang, Y. Eur J Med Chem 2010, 45, 3864.
[
4] Mann, R. S.; Kaufman, P. E. Mini-Rev Org Chem 2012, 9, 185.
[
5] Zhao, P. L.; Liu, C. L.; Huang, W.; Wang, Y. Z.; Yang, G. F. J
[28] Al-Rashood, S. T.; Hassan, G. S.; El-Messery, S. M.; Nagi, M. N.;
Habib, E. S. E.; Al-Omary, F. A. M.; El-Subbagh, H. I. Bioorg Med Chem
Lett 2014, 24, 4557.
[29] Liu, G.; Song, B. A.; Yang, S.; Jin, L. H. China Patent
1,597,671A, 2005; Chem Abstr 2005, 144, 192278.
[30] Ma, J.; Li, P.; Li, X. Y.; Shi, Q. C.; Wan, Z. H.; Hu, D. Y.; Jin,
L. H.; Song, B. A. J Agric Food Chem 2014, 62, 8928.
[31] Bhagat, M. P.; Shantakumar, S. M.; Salahuddin, M. Int J
Pharm Sci Lett 2014, 4, 454.
Agric Food Chem 2007, 46, 1163.
6] Mahapatra, D. K.; Bharti, S. K.; Asati, V. Eur J Med Chem
015, 98, 69.
[
2
2
[7] Mahapatra, D. K.; Asati, V.; Bharti, S. K. Eur J Med Chem
015, 92, 839.
[8] Chen, M.; Christensen, B. S.; Zhai, L.; Rasmussen, M. H.;
Theander, T. G.; Frøkjaer, S.; Steffansen, B.; Davidsen, J.; Kharazmi,
A. J Infect Dis 1997, 176, 1327.
[
9] Mishra, L.; Sinha, R.; Itokawa, H.; Bastow, K. F.; Tachibana,
Y.; Nakanishi, Y.; Kilgore, N.; Lee, K. Bioorg Med Chem 2001, 9, 1667.
10] Israf, D. A.; Khaizurin, T. A.; Syahida, A.; Lajis, N. H.;
Khorizah, S. Mol Immunol 2007, 44, 673.
11] Chen, M. H.; Li, P.; Hu, D. Y.; Zeng, S.; Li, T. X.; Jin, L. H.;
Xue, W.; Song, B. A. Bioorg Med Chem Lett 2016, 26, 168.
[32] Margaret, M. E.; Emily, W.; Marie, L. M.; Mary, L. S. J Am
Chem Soc 1946, 94, 1299.
[
[33] Scott, H. Virology 1963, 20, 103.
[34] Song, B. A.; Zhang, H. P.; Wang, H.; Yang, S.; Jin, L. H.;
Hu, D. Y.; Pang, L. L.; Xue, W. J Agric Food Chem 2005, 53,
7886.
[
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet