Antiviral properties and interaction of novel chalcone derivatives containing a purine and benzenesulfonamide moiety

Article abstract of DOI:10.1016/j.bmcl.2018.04.042

A new concise and facile method was explored to synthesize a series of novel chalcone derivatives containing a purine and benzenesulfonamide moiety and their antiviral properties were evaluated against TMV and CMV. Biological assays indicated that several

Full text of DOI:10.1016/j.bmcl.2018.04.042

Accepted Manuscript
Antiviral properties and interaction of novel chalcone derivatives containing a
purine and benzenesulfonamide moiety
Dagui Zhou, Dandan Xie, Fangcheng He, Baoan Song, Deyu Hu
PII:
S0960-894X(18)30354-8
https://doi.org/10.1016/j.bmcl.2018.04.042
BMCL 25789
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Accepted Date:
15 February 2018
12 April 2018
15 April 2018
Please cite this article as: Zhou, D., Xie, D., He, F., Song, B., Hu, D., Antiviral properties and interaction of novel
chalcone derivatives containing a purine and benzenesulfonamide moiety, Bioorganic & Medicinal Chemistry
Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.04.042
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Antiviral properties and interaction of novel chalcone
derivatives containing a purine and benzenesulfonamide moiety
Dagui Zhou, Dandan Xie, Fangcheng He, Baoan Song, Deyu Hu*
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key
Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou
University, Huaxi District, Guiyang 550025, China
*Corresponding author
Tel.: +86(851)88292170
E-mail: dyhu@gzu.edu.cn

ABSTRACT: A new concise and facile method was explored to synthesize a series of novel
chalcone derivatives containing a purine and benzenesulfonamide moiety and their antiviral
properties were evaluated against TMV and CMV. Biological assays indicated that several of the
derivatives exhibited significant anti-TMV and anti-CMV activities in vivo. In particular,
compound d2 displayed excellent inactivating activity against TMV, with the EC50 value of 51.65
μg/mL, which was better than that of ribavirin (150.45 μg/mL). Molecular docking showed that
there are four hydrogen bonds between compound d2 and TMV coat protein (TMV-CP).
Compound d2 demonstrated strong binding capacity to TMV-CP with Ka = 1.58×105 L/mol and Kd
= 12.16 μM. These findings indicated that chalcone derivatives are worthy of further research and
development as templates for new antiviral agents.
Keywords: Chalcone derivatives, purine moiety, benzenesulfonamide moiety, antiviral property,
tobacco mosaic virus, cucumber mosaic virus
___________
Abbreviations used
TMV, tobacco mosaic virus; CMV, cucumber mosaic virus; TMV-CP, tobacco mosaic virus coat
1
protein; 1H NMR, H nuclear magnetic resonance; 13C NMR, 13C nuclear magnetic resonance;
EC50, 50% effective concentration; HRMS, high-resolution mass spectrometry; SAR,
structure–activity relationship; FT, fluorescence titration; MST, microscale thermophoresis.

Tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) are two significant plant
viruses and can cause serious economic losses in crop production.1,2 The controlling of TMV and
CMV are very difficult, because of their absolute parasitism in plants and the lack of a complete
immune metabolism system. Although ribavirin is widely used as antiviral agent, its inhibitory
effect on plant viruses is less than 50% when applied at the concentration of 500 μg/mL.3
Effective treatments for TMV- and CMV-infected plants remain unavailable. Therefore, pesticide
researchers continue to search for novel and highly effective drugs against plant viruses. Natural
products have attracted the close attention of medical and pesticide researchers because of many
properties, such as nontoxicity toward no target organisms, unique mode of action, easy
degradation, and environmental friendliness.4 Some natural products and their derivatives possess
significant activity against TMV, for example phenanthroindolizidine and its analogues,5 antofine
and its derivative NK-007,6,7 and so on. Hence, the derivation of small molecules from natural
products has become an effective method for development of antiviral agent.
As important natural flavonoid, chalcone and its derivatives have extensive biological activities,
including antibacterial,8,9 anti-inflammatory,10,11 anti-cancer,11,12 insecticide,13,14 anti-virus.15,16 In
recent years, some chalcone compounds with excellent anti-TMV effects were isolated from
rose.17 In our previous work, a series of chalcone quinazoline derivatives were designed and
synthesized, some compounds exhibited good anti-TMV activities.18 Purine is an important
biological compound with a crucial role in human health. Some purine drugs, such as
ganciclovir,19 abacavir20 have been applied as antivirals. At the same time, a series of
purine-containing plant-growth-regulating pesticides have been discovered, such as
6-benzylaminopurine,21 isopentenyladenine.22 Our research group discovered that purine
derivatives containing 1,4-pentadien-3-one moiety have good anti-CMV activities.23
Benzenesulfonamide derivatives are mainly applied for the fungicide and herbicide. Recently,
more recent renewed attention has focused on potent HIV protease inhibitors and anti-influenza
hemagglutinin inhibitors.24,25 While its anti-plant virus activity has not been reported.
In this study, structural optimization was performed to improve the biological activity and the
selectivity of the lead compound (Fig. 1). These new compounds were synthesized and their
anti-TMV and anti-CMV properties were evaluated. Furthermore, the interaction models of the
derivatives with TMV coat protein (TMV-CP) were observed through molecular docking. The
binding constant between the derivatives and TMV-CP were obtained by using fluorescence

titration (FT) and microscale thermophoresis (MST) techniques. These results may lay the
foundation for the exploitation of this hybrid scaffold to seek potential antiviral agents.
Fig. 1. Design of target compounds.
The synthetic route for the target compounds d1-d25 was performed in accordance with
previously reported methods and is shown in Scheme 1.26,27 Synthesis route mainly consists of
four steps: sulfonamide, aldehyde and ketone condensation, substitution and etherification. The
1
structures of the target compounds were confirmed through H nuclear magnetic resonance (1H
NMR), 13C nuclear magnetic resonance (13C NMR), and high-resolution mass (HRMS). The
1HNMR spectra of the target compounds revealed two doublets in the regions δ 7.78–7.90 and
6.80–7.62 ppm with characteristic coupling constants (J) of 15.5–16.0 Hz. The 13C NMR spectra
of the target compounds exhibited a characteristic (C=O) signal at δ 185.76–189.41 ppm. The
1
appearance of this signal confirmed chalcones formation. The H NMR spectra of the target
compounds exhibited one or two single peaks in the region δ 8.69–8.40 ppm region and the
characteristic signals of purine-2-H and purine-8-H (see Supporting Information for details).
Scheme 1. Synthesis route of target compounds d1-d25.

The in vivo anti-TMV activities of target compounds d1-d25 at the concentration of 500 μg/mL
were evaluated through the half-leaf method, Ribavirin was used as reference drug.28 The results
of the anti-TMV activities of the compounds are shown in Table 1. The target compounds
displayed excellent antiviral activity against TMV. Compounds d2, d3, d7, d11, and d16 exhibited
good curative activities of 55.7%, 50.5%, 54.8%, 52.9%, and 48.0%, respectively, against TMV.
These values are superior to those exhibited by ribavirin (40.6%). The curative activities of
compounds d1, d8, and d9 are similar to ribavirin, with the values of 43.3%, 45.7%, and 41.8%,
respectively. Compounds d2, d7, d8, d11, and d12 displayed superior protective activities of
57.0%, 64.1%, 55.4%, 56.7%, and 55.8%, respectively, against TMV. The protective activities of
these compounds are superior to those of ribavirin (51.0%). Compounds d2, d7, d8, and d11
exhibited high inactivation effects of 88.6%, 88.5%, 78.6%, and 84.6%, respectively, against TMV.
The inactivation effects of these compounds are higher than those of ribavirin (70.4%). By
contrast, the inactivation effects of these compounds d1, d3, and d9 are similar to those of
ribavirin, with the values of 70.9%, 72.8%, and 74.5%, respectively. In addition, the 50% effective
concentration (EC50) values of the target compounds for TMV inactivation were assessed. As
shown in Table 1. The EC50 values of compounds d2, d7, d8, and d11 are 51.65, 53.47, 92.69, and
70.68 μg/mL, respectively, and are superior to those of ribavirin (150.45 μg/mL). The curative,
protective, and inactivation activity of compounds d2, d7, d8, and d11 against TMV are superior
to the other derivatives. In particular, Compound d2 exhibited prominent inactivation activity
against TMV. Therefore, we further studied the interaction between compound d2 and TMV-CP.
Table 1
Antiviral activity of target compounds against TMV in vivo and in vitro
In vivo effect
In vitro effect
Kd a (μM)
Compound
Curative
Protective
Inactivating EC50 of inactivating
activitya (%) activitya (%) activitya (%)
activitya (μg/mL)
150.84±3.6
51.65±3.0
43.3±1.4
55.7±2.1
50.5±2.4
32.7±1.4
32.7±1.8
31.4±1.8
54.8±1.1
36.1±0.2
57.0±2.5
47.9±1.2
31.6±1.5
40.5±1.7
32.6±2.2
64.1±1.9
70.9±2.1
88.6±2.4
72.8±1.6
51.7±1.0
62.9±1.6
52.0±3.0
88.5±0.6
104.43±60.2
12.16±7.1
d1
d2
d3
d4
d5
d6
d7
137.70±2.1
424.30±5.8
173.85±3.3
417.62±4.5
53.47±2.4
90.58±37.7
251.04±88.4
136.77±60.6
185.72±55.2
20.63±9.5

45.7±0.9
41.8±1.2
37.4±1.6
52.9±1.5
34.9±2.4
36.2±1.6
36.2±1.0
34.5±1.1
48.0±2.1
32.4±1.6
39.3±0.9
31.3±1.6
30.8±1.2
38.8±1.5
33.8±1.6
25.4±1.5
37.0±1.1
36.5±2.0
40.6±2.4
55.4±2.1
44.2±1.2
40.1±1.2
56.7±1.8
55.8±2.4
34.1±1.5
35.9±1.7
34.8±0.9
39.5±0.9
35.0±1.5
40.1±1.2
30.2±1.1
28.2±0.9
31.2±1.3
31.5±2.4
16.1±0.8
36.3±1.4
42.2±1.3
51.0±2.3
78.6±0.8
74.5±1.3
52.9±1.6
84.6±1.2
54.9±1.4
52.8±2.4
62.4±1.5
55.0±2.8
55.6±2.2
54.3±1.6
68.8±2.4
54.7±1.2
51.9±2.3
54.2±1.7
52.3±1.7
42.6±1.3
54.5±2.6
65.4±1.9
70.4±2.2
92.69±1.8
122.31±3.6
392.60±2.5
70.68±2.7
61.23±24.9
85.06±33.2
204.29±93.7
48.11±13.4
d8
d9
d10
d11
344.50±4.4
388.63±4.7
179.39±4.0
332.64±5.3
322.75±6.4
353.69±4.8
175.07±5.3
345.89±4.2
417.07±4.6
349.14±2.9
407.57±5.1
711.52±8.6
357.22±5.2
166.43±4.2
150.45±1.8
161.62±93.5
218.32±105.6
134.07±46.7
221.46±94.2
200.53±73.8
197.18±52.3
121.46±60.2
190.88±63.0
247.66±80.1
216.15±56.4
184.68±73.9
272.44±84.7
176.04±98.3
128.55±75.5
97.97±22.3
d12
d13
d14
d15
d16
d17
d18
d19
d20
d21
d22
d23
d24
d25
Ribavirin
a Average of three replicates.
The in vivo anti-CMV activity of target compounds d1-d25 at the concentration of 500 μg/mL
were evaluated through the half-leaf method with ribavirin as positive control.28 The results for
anti-CMV activity of the target compounds are shown in Table 2. The target compounds
demonstrated excellent anti-CMV activity. Compounds d2, d7, and d11 revealed good curative
activities of 56.4%, 53.4%, and 45.9%, respectively, against CMV. The curative activities of these
compounds are superior to those of ribavirin (39.8%). The curative activities exhibited by
compounds d1, d14, and d17 are the same as those exhibited by ribavirin was of 41.7%, 41.8%,
and 40.6%, respectively. The protective activities of d2, d7, and d8 against CMV were 57.3%,
55.6%, and 55.0%, respectively, and are higher than those of ribavirin (49.2%). The protective
activities of compounds d5, d11, and d12 were equal to those of ribavirin was 48.8%, 50.1%, and
48.2%, respectively. Compound d2 indicated moderate anti-CMV inactivation activity with value
of 66.4%, which was similar to that of ribavirin (68.7%). The EC50 values of the title compounds
for curative and protective effects against CMV were assessed. As shown in Table 2. Compounds
d2, d7, and d11 exhibited remarkable curative activities with EC50 values of 347.34, 381.30, and

499.10 μg/mL, respectively. Compounds d2, d7, d8, and d11 showed protective effects at EC50
values of 353.49, 381.30, 388.44, 499.10 μg/mL, respectively, The EC50 values of these
compounds are superior to those of ribavirin (1240.16, 501.99 μg/mL). Compounds d2, d7, and
d11 exhibited superior curative and protective activities against CMV. Notably, compound d2
exhibited the best anti-CMV activity.
Table 2
Antiviral activity of target compounds against CMV in vivo.
Curative
Protective
Inactivating EC50 of curative EC50 of protective
Compound
activitya (%) activitya (%) activitya (%) activitya (μg/mL) activitya (μg/mL)
41.7±0.9
56.4±1.8
28.5±2.9
16.7±1.9
37.9±1.6
25.1±1.4
53.4±1.1
38.9±2.5
29.8±2.9
28.1±1.1
45.9±2.7
31.2±2.4
36.8±1.5
41.8±2.3
25.8±1.7
29.0±1.5
40.6±1.6
43.9±2.5
26.9±2.5
33.8±1.4
25.2±1.6
19.9±1.0
11.8±1.3
27.8±3.2
35.4±1.8
39.8±2.1
44.2±3.4
57.3±1.5
47.2±1.7
32.5±1.7
48.8±2.0
39.0±2.2
55.6±1.2
55.0±1.1
44.1±1.0
32.9±1.3
50.1±1.8
48.2±2.5
44.2±1.2
46.9±1.2
33.5±3.1
46.8±1.8
45.6±2.1
47.7±1.4
40.6±2.6
24.2±2.3
38.8±2.9
30.5±2.3
21.3±1.4
45.1±2.6
47.3±2.2
49.2±2.3
53.8±1.5
66.4±1.9
50.8±1.7
34.5±1.5
50.1±2.1
44.0±1.7
63.2±2.3
58.0±2.3
47.3±1.7
34.8±1.6
54.4±1.1
44.3±2.0
37.6±1.4
41.3±1.7
30.1±2.3
30.7±2.0
42.9±1.5
49.7±1.1
43.5±2.2
35.0±2.1
34.2±2.4
36.8±2.2
27.4±1.8
48.4±2.3
37.4±2.0
68.7±1.6
967.27±8.2
856.08±8.0
353.34±2.8
557.62±6.0
2023.24±14.0
508.89±3.8
1416.31±14.3
381.30±3.3
388.44±3.9
878.67±7.4
2353.59±14.6
499.10±2.6
523.65±5.3
840.19±8.4
583.56±3.8
1876.75±13.4
570.76±6.2
651.78±4.0
556.06±6.1
1237.36±11.7
/
d1
d2
347.34±2.6
/
d3
/
d4
1390.46±13.6
d5
/
d6
386.22±3.5
d7
1334.79±13.7
d8
/
d9
/
d10
d11
d12
d13
d14
d15
d16
d17
d18
d19
d20
d21
d22
d23
d24
d25
Ribavirin
662.11±2.1
1824.38±15.3
1458.65±12.4
995.56±9.2
/
/
1176.93±11.3
694.58±6.4
/
1752.98±14.0
/
1434.18±13.6
2707.82±16.4
/
/
/
/
660.78±5.2
563.87±5.6
501.99±4.0
1569.46±12.7
1240.16±12.3
a Average of three replicates.

The above results showed that benzenesulfonamide chalcone derivatives containing a purine
moiety exhibited considerable anti-TMV and anti-CMV activities. In particular, Compound d2 has
prominent inactivating activity against TMV and excellent curative and protective activities
against CMV.
Based on the EC50 values of anti-TMV activities, the preliminary analysis of structure-activity
relationships (SAR) showed that the presence of an electron-donating group at the 2- or 4-position
of the R1 benzenesulfonamide aromatic rings intensifies the anti-TMV activity of the compounds,
as follow: d17 (2-CH3-Ph) > d6 (2-Br-Ph) > d20 (2-Cl-Ph) > d23 (2-F-Ph), and d11 (4-CH3-Ph) >
d3 (4-Br-Ph) > d14 (4-Cl-Ph) > d15 (4-F-Ph). This effect, however, was not observed in
compounds d12. By contrast, the presence of an electron-withdrawing group at the 2- or
4-position of R1 does not promote anti-TMV activity. Meanwhile, we found that the antiviral
activity of the derivatives improved when an electron-donating is presence at the 2-position
instead of at the 4-position, of R1, as follow: d2 (R1 = 2-CH3-Ph, R2 = CH3) > d11 (4-CH3-Ph, R2 =
CH3) and d17 (R1 = 2-CH3-Ph, R2 = Ph) > d16 (R1 = 4-CH3-Ph, R2 = Ph). The antiviral activity of
the derivatives are weakened when an electron-withdrawing group at the 2-position, instead of at
the 4-position, of R1, This effect is observed in d10 (2-F-Ph) < d9 (4-F-Ph) and d13 (2-Cl-Ph) <
d14 (4-Cl-Ph). Observably, the R2 with low steric hindrance promote anti-TMV activity of the
derivatives in the following order: d7 (R1 = 4-CH3-Ph, R2 = H) > d11 (R1 = 4-CH3-Ph, R2 = CH3) >
d4 (R1 = 4-CH3-Ph, R2 = Ph) and d10 (R1 = 2-F-Ph, R2 = H) > d4 (R1 = 2-F-Ph, R2 = CH3) > d23
(R1 = 2-F-Ph, R2 = Ph).
TMV coat protein (TMV-CP), as a key functional protein of the TMV, played a crucial role in
translation of mRNAs, transcription of tRNA, elongation, and self-assembly of TMV, which might
be a potential action target protein for screening of anti-TMV agents.4,29 We used Discovery
Studio 4.5 to perform molecular docking study.4,30 Compound d23, d14, and d2 with poor to
prominent anti-TMV inactivation activities, which were selected for docking with TMV-CP (PDB
code: 1EI7)31, the results of docking are shown in Fig. 2. The anti-TMV inactivation activities of
these compounds could be explained through hydrogen bond as well as non-hydrogen bond
interaction with amino-acid residues. As shown in Fig. 2. A, the binding mode between ribavirin
and TMV-CP were observed, which formed three conventional hydrogen bonds with amino-acid
residues of ASP266, ASP219, and GLU222 into the active site of TMV-CP, with the distances of

2.77 Å, 2.19 Å, and 1.98Å, respectively, one pi-cation bond with LYS268 (2.32 Å), five carbon
hydrogen bonds with ALA218 (2.84 Å), PRO254 (3.07 Å & 2.44 Å), SER255 (2.95 Å & 2.40 Å),
The amino-acid PRO254 showed two carbon hydrogen bond interactions with distance of 3.07 Å
and 2.44 Å respectively, with hydrogen atom of furan and triazole ring. The amino-acid SER255
showed two carbon hydrogen bond interactions with distance of 2.95 Å and 2.40 Å respectively,
with hydrogen and oxygen atoms of furan ring. Compound d2, which exhibited prominent
anti-TMV inactivation activity, formed four conventional hydrogen bonds with amino-acid
residues of SER138, GLY137, ASN72, and ARG134, with the distances of 3.00 Å, 2.47 Å, 2.73 Å,
and 2.68 Å, respectively, one pi-donor hydrogen bond with ASN72 (2.67 Å), seven carbon
hydrogen bonds with PRO263 (2.37 Å), GLU131 (2.87 Å), LYS269 (196 Å) , SER255 (2.51 Å &
2.11 Å), TRP217 (2.53 Å & 2.84 Å), the amino-acid SER255 showed two carbon hydrogen bond
interactions with distance of 2.51 Å and 2.11 Å respectively with oxygen and nitrogen atoms of
ether and imidazole ring, the amino-acid TRP217 showed two carbon hydrogen bond interactions
with distance of 2.53 Å and 2.84 Å respectively with hydrogen atom of 8-position of purine and
methylene shown in Fig. 2. B, three pi-alky bonds with amino-acid residues of VAL260, VAL75,
and LYS253, with the distances of 4.46 Å, 4.22 Å, and 5.13 Å. Compound d23 and d14 exhibited
poor to moderate inactivation effect, which only existed non-hydrogen bond interaction.
Compound d14, formed two alkyl bonds with LYS253 (3.85 Å), PHE267 (4.42 Å), two pi-alkyl
bonds with VAL75 (4.49 Å), PRO220 (5.40 Å), one carbon hydrogen bond with ASP219 (2.62 Å),
one pi-anion bond with ASP219 (3.82 Å). However, when the methyl on R2 was replaced with
benzene ring, the small molecule could not effectively combine with TMV-CP, due to the
molecular structure is too large. Compound d23 was observed to form two carbon hydrogen bonds
with THR136 (3.00 Å), SER255 (2.39 Å), four pi-alky bonds with PRO220 (4.45 Å), PRO254
(5.15 Å), ALA74 (4.45 Å), VAL75 (4.27 Å), one pi-anion bond with ASP266 (3.28 Å), and the
main action is on the benzene ring at both ends of the molecular structure. The docking results
revealed that compound d2 contains four conventional hydrogen bonds to TMV-CP, ribavirin
contains three conventional hydrogen bonds, while compounds d14 and d23 only existed
non-hydrogen bond. Therefore, the hydrogen bond plays an important role in the interaction of
compound with TMV-CP, which remarkably stabilized molecule–protein interactions. These
findings suggested that a strong interaction may exist between compound d2 and TMV-CP.

Fig. 2. Docking models of compounds ribavirin (A), d2 (B), D14 (C), and D23 (D) in active sites
of TMV-CP. Conventional hydrogen bond, carbon hydrogen bond and pi-donor hydrogen bond,
pi–alkyl and alkyl bond, pi-cation and pi-anion bond are showed by dotted lines in green, red,
purple, and orange-yellow, respectively.
As a fast, sensitive, nondestructive, and selective method for studying the conformation of
protein molecules,32 FT can not only do the general quantitative analysis, but also can infer the
conformational changes of protein molecules in various environments, so as to elucidate the
relationship between protein structure and function. It is widely used in the study of the interaction
between drugs and proteins. To further investigate the result of molecular docking, we elucidated
the binding interactions between compound d2 and TMV-CP through FT and MST. The binding
affinities of d2, d14, d23, and ribavirin with TMV-CP were obtained through FT. As shown in Fig.
3 and Table 3, the association constant (Ka) between d2 and TMV-CP was 1.58×105 L/mol. The
binding affinity compound d2 and TMV-CP is stronger than that between ribavirin and TMV-CP
(7.07×103 L/mol), d14 and TMV-CP (3.01×103 L/mol), and d23 and TMV-CP (1.34×102 L/mol).
Then, the dissociation constant (Kd) of the interaction between all compounds and TMV-CP was
determined by MST and the results was shown in Table 1. The binding of compounds d2, d14,
d23, and ribavirin with TMV-CP yielded Kd values of 12.16 ± 7.1, 134.07 ± 46.7, 272.44 ± 84.7,

and 97.97 ± 22.3 μM, respectively (Fig. 4 and Table 3). Compound d2 exhibited strong affinity for
TMV-CP; ribavirin and d14 exhibited moderate affinity for TMV-CP; and d23 exhibited weak
affinity for TMV-CP. Combining capacity increased in the order of d2 > ribavirin > d14 > d23.
This trend is consistent with the trends of inactivation activity and the results of FT. The
experimental results indicated that compound d2 has strong combining capacity with TMV-CP.
Fig. 3. Fluorescence emission spectra of TMV-CP in the presence of d2 (A), d14 (B), d23 (C), and
Ribavirin (D) with different concentrations. λex = 278 nm. Inset: the linear relationship for
quenching TMV-CP by d2, d14, d23, and Ribavirin, respectively.

Fig. 4. Microscale thermophoresis (MST) of d2 (A); d14 (B); d23(C); and Ribavirin (D).
Table 3
The value of Ka, Kd and activity of compounds d2, d14, d23, and Ribavirin
Compound
Ka (L/moL)
Kd (μM)
Ribavirin
7.07×103
d2
d14
d23
1.58×105
12.16±7.1
51.65±3.0
3.01×103
134.07±46.7
179.39±4.0
1.34×102
272.44±84.7
711.52±8.6
97.97±22.3
150.45±1.8
EC50 (μg/mL)
In summary, a series of novel chalcone derivatives containing a purine and benzenesulfonamide
moiety were synthesized. The anti-TMV and anti-CMV activities of the derivatives were
evaluated. Bioactivity tests revealed that several of target compounds exhibited considerable
antiviral activity in vivo. In particular, compound d2 showed prominent inactivation activity
against TMV and excellent curative and protective activities against CMV. SAR analysis showed
that introduced an electron-donating group at the 2-position of benzenesulfonamide aromatic rings
R1 and R2 with low steric hindrance group promotes antiviral activity. Furthermore, FT and MST
revealed that the compound d2 has strong combining capacity for TMV-CP. The experimental

results were consistent with the inactivation activity results and docking simulation. These
findings showed that chalcone derivatives are worthy of further research and development as
templates for new antiviral agents.
Acknowledgments
This study was supported by the National Natural Science Foundation of China (Nos. 21562013
and 21362004), Subsidy Project for Outstanding Key Laboratory of Guizhou Province in China
(No. 20154004), the Provincial University Cooperation Plan of Guizhou Province in China (No.
20147001) and Collaborative Innovation Center for Natural Products and Biological Drugs of
Yunnan.
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Graphical Abstract
Novel chalcone derivatives containing a purine and benzenesulfonamide moiety were
synthesized. Compound d2 exhibited excellent antiviral activity against TMV and CMV. The
interaction mode of the compound d2 with TMV-CP was performed through molecular docking,
fluorescence titration (FT) and microscale thermophoresis (MST) techniques.
Highlights
1. Twenty-five novel chalcone derivatives were designed and synthesized.
2. Compound d2 exhibited excellent antiviral activity against TMV and CMV.
3. Compound d2 showed a strong combining capacity with TMV-CP.