Synthesis, anti-oomycete activity, and SAR studies of paeonol derivatives

Article abstract of DOI:10.1080/10286020.2020.1718116

Three series of sulfonate derivatives of paeonol were synthesized and screened in?vitro for their anti-oomycete activity against P. capsici, respectively. Among all the compounds, 4m displayed the best promising and pronounced anti-oomycete activity again

Full text of DOI:10.1080/10286020.2020.1718116

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: https://www.tandfonline.com/loi/ganp20
Synthesis, anti-oomycete activity, and SAR studies
of paeonol derivatives
Yue-E Tian, Di Sun, Xiao-Xiao Han, Jin-Ming Yang, Song Zhang, Nan-Nan Feng,
Li-Na Zhu, Zhong-Yuan Xu, Zhi-Ping Che, Sheng-Ming Liu, Xiao-Min Lin, Jia
Jiang & Gen-Qiang Chen
To cite this article: Yue-E Tian, Di Sun, Xiao-Xiao Han, Jin-Ming Yang, Song Zhang, Nan-Nan
Feng, Li-Na Zhu, Zhong-Yuan Xu, Zhi-Ping Che, Sheng-Ming Liu, Xiao-Min Lin, Jia Jiang & Gen-
Qiang Chen (2020): Synthesis, anti-oomycete activity, and SAR studies of paeonol derivatives,
Journal of Asian Natural Products Research, DOI: 10.1080/10286020.2020.1718116
To link to this article: https://doi.org/10.1080/10286020.2020.1718116
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JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
https://doi.org/10.1080/10286020.2020.1718116
Synthesis, anti-oomycete activity, and SAR studies of
paeonol derivatives
Yue-E Tian, Di Sun, Xiao-Xiao Han, Jin-Ming Yang, Song Zhang, Nan-Nan Feng,
Li-Na Zhu, Zhong-Yuan Xu, Zhi-Ping Che, Sheng-Ming Liu, Xiao-Min Lin, Jia
Jiang and Gen-Qiang Chen
Laboratory of Pharmaceutical Design and Synthesis, Department of Plant Protection, College of
Forestry, Henan University of Science and Technology, Luoyang 471023, China
ABSTRACT
ARTICLE HISTORY
Received 23 October 2019
Accepted 14 January 2020
Three series of sulfonate derivatives of paeonol were synthesized
and screened in vitro for their anti-oomycete activity against P.
capsici, respectively. Among all the compounds, 4m displayed the
best promising and pronounced anti-oomycete activity against P.
capsici than zoxamide, with the EC50 values of 24.51 and
26.87 mg/L, respectively. The results show that acetyl and 4-OCH3
are two necessary groups. The existence of these two sites is
closely related to the anti-oomycete activity. Relatively speaking,
hydroxyl group is well tolerated, and the results showed that after
modification of hydroxyl group with sulfonyl, the anti-oomycete
activity was significantly increased.
KEYWORDS
Natural product; paeonol;
sulfonylation; anti-oomycete
activity; structure–activity
relationship
1. Introduction
The impact of oomycetes on humankind is well documented as both a persistent
threat to subsistence and commercial farming and as destructive pathogens of native
plants [1]. The oomycete vegetable pathogen Phytophthora capsici, is a virulent,
CONTACT Z.-P. Che
zhipingche@163.com
Laboratory of Pharmaceutical Design and Synthesis, Department of
Plant Protection, College of Forestry, Henan University of Science and Technology, Luoyang 471023, China
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
Y.-E. TIAN ET AL.
Figure 1. Structures of paeonol (1), aminoguanidine derivatives of N-arylsulfonyl-3-acylindoles (I)
and sulfonate derivatives of maltol (II).
hemibiotrophic pathogen of vegetable crops, inflicting significant losses worldwide
[2]. The pathogen P. capsici has shown remarkable adaptation to new hosts and fun-
gicides [3]. Due to the lack of the resistant germplasm resources, fungicides control-
ling is still the main way to reduce the incidence of P. capsici on main hosts though
resistance is an inevitable result of evolution [4–7]. Therefore, design and synthesis of
novel compounds that effectively inhibit those agricultural diseases is still
highly desirable.
The effective ways for pesticide innovation are to develop new fungicides with
independent intellectual property rights from plant secondary metabolites as lead
compounds [8]. 2-Hydroxyl-4-methoxyacetophenone (1, Figure 1) is what people
commonly call “Paeonol,” which is one of the main phenolic components in moutan
cortex [9–11]. Paeonol is a traditional Chinese medicine, the derivatives of which
exhibit numerous biological activities, such as antitumor activity [12], anti-inflamma-
tory activity [13], anti-HBV activity [14], mushroom tyrosinase inhibitor [15], insecti-
cidal activity [16], acaricidal activity [17], and antifungal activity [18]. Recently, we
investigated the antifungal activity of paeonol containing hydroxyl against Botrytis
cinerea and Fusarium oxysporum [19]. We found that aminoguanidine derivatives of
N-arylsulfonyl-3-acylindoles (I, Figure 1) exhibited the promising and pronounced
antifungal activity [20]; and sulfonate derivatives of maltol (II, Figure 1) showed sig-
nificant anti-oomycete activity [21]. Inspired by the above-mentioned interesting
results, and according to the principle of superposition of bioactivity, we have
designed and prepared three series of sulfonate derivatives of paeonol in this study
[22–25], and first report the results of the anti-oomycete activity of forty-eight sulfon-
ate derivatives of paeonol against P. capsici in vitro. Additionally, their structure-
activity relationship (SAR) studies were also described.
2. Results and discussion
2.1. Chemistry
As shown in Scheme 1, paeonol/2-hydroxy acetophenone/3-methoxyphenol (1/2/3)
reacted with 1.2 equiv. of ethanesulfonyl chloride/arylsulfonyl chloride (7a–p) in the
presence of 1.5 equiv. of triethylamine to obtain three series of sulfonate derivatives
of paeonol (4a–p, 5a–p, and 6a–p) in relatively good yields. The structures of all tar-
1
get compounds were well characterized by H NMR, ESI-MS, and m.p.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Scheme 1. The synthetic route of sulfonate derivatives of paeonol (4a–p, 5a–p, and 6a–p).
2.2. Anti-oomycete activity
Forty-eight sulfonate derivatives of paeonol (4a–p, 5a–p, and 6a–p) were screened
in vitro for their anti-oomycete activity against P. capsici. Zoxamide, a commercially
available agricultural fungicide, was used as a positive control. And the inhibitory
effects showed an obviously dose-dependent manner that with the concentration of
compound increased, the colony diameter decreased.
As depicted in Table 1, among these tested sulfonate derivatives of paeonol, com-
pounds 4h, 4k, 4m, 4n–p, and 6m exhibited obvious anti-oomycete activity for P.
capsici with EC50 values of 45.23, 46.92, 24.51, 46.18, 47.66, 47.16, and 42.72 mg/L,
respectively. Among the compounds, 4m displayed the most promising and pro-
nounced anti-oomycete activity against P. capsici than zoxamide (EC50¼26.87 mg/L).
Meanwhile, a brief structure activity relationship (SAR) was determined. (1)
Generally, the introduction of different substitutions at the hydroxyl position of paeo-
nol/2-hydroxy acetophenone/3-methoxyphenol (1/2/3) has remarkable effect on anti-
oomycete activity. (2) The presence of two sites acetyl and 4-OCH3 groups is closely
related to its resistance activity; For example, the EC50 values of 1, 2 and 3 against P.
capsici were 75.47, 93.02 and 85.10 mg/L, respectively. Hydroxyl group is well toler-
ated, and sulfonylation of hydroxyl group enhances its anti-oomycete activity; For
example, the EC50 values of 4m, 5m and 6m for P. capsici were 24.51, 52.82 and
42.72 mg/L, respectively. (3) Moreover, through a comparative study on the relation-
ship between the chemical structures and anti-oomycete activity of 4a–p, 5a–p, and
6a–p, some interesting results were found as follows: (a) It is noteworthy that the
introduction of 4-chloro-3-nitrophenylsulfonyl as a two-electron-withdrawing sub-
stituent (such as NO2 and Cl) could result in more potent compounds 4m, 5m and
6m relative to those containing phenylsulfonyl as a one-electron-withdrawing sub-
stituent (e.g., 4h–l, 5h–l and 6h–l). For example, the EC50 values of 4h–l, 5h–l and
6h–l for P. capsici were 45.23/75.23/65.10/46.92/51.91, 77.56/97.76/90.56/69.54/75.23
and 69.54/92.56/77.56/114.34/101.63 mg/L, respectively. (b) The introduction of 4-flu-
orophenylsulfonyl at the hydroxyl position of paeonol could lead to more potent

4
Y.-E. TIAN ET AL.
Table 1. Anti-oomycete activities of compounds 4a–p, 5a–p, and 6a–p against P. capsici in vitro.
P. capsici
Compounds
EC50 (mg/L)
1/2/3
75.47/93.02/85.10
93.88/120.41/131.20
80.91/102.66/94.6
50.00/95.26/114.34
79.58/95.26/131.24
53.33/75.23/76.37
92.56/98.10/101.11
65.10/135.43/73.02
45.23/77.56/69.54
75.23/97.76/92.56
65.10/90.56/77.56
46.92/69.54/114.34
51.91/75.23/101.63
24.51/52.82/42.72
46.18/93.43/65.10
47.66/79.14/112.42
47.16/78.34/50.91
26.87
4a/5a/6a
4b/5b/6b
4c/5c/6c
4d/5d/6d
4e/5e/6e
4f/5f/6f
4g/5g/6g
4h/5h/6h
4i/5i/6i
4j/5j/6j
4k/5k/6k
4l/5l/6l
4m/5m/6m
4n/5n/6n
4o/5o/6o
4p/5p/6p
Zoxamide
compound than introducing 4-bromophenylsulfonyl group (e.g., 45.23 mg/L for 4h
versus 75.23 mg/L for 4i). In addition, we found that the introduction of nitrophenyl-
sulfonyl at the hydroxyl position of paeonol, and the nitro group at different position
of the benzene ring, could lead to derivatives with different anti-oomycete activity
[meta-position for 4k (EC50¼46.92 mg/L) versus para-position for 4 l
(EC50¼51.91 mg/L), ortho-position for 4j (EC50¼65.10 mg/L)]. (c) Some compounds
containing fused heterocycles (2-thiophenesulfonyl, 8-quinolinesulfonyl and 1-naph-
thalensulyonyl) exhibited more potent anti-oomycete activity (4n–p). For example,
the EC50 values of 4n–p for P. capsici were 46.18, 47.66 and 47.16 mg/L, respectively.
3. Experimental
3.1. General experimental procedures
Melting points were taken on an X-6 microscopic melting point apparatus (Beijing
Tech instrument Co., Ltd., Beijing, China) and are uncorrected. Nuclear magnetic res-
onance spectra (NMR) were recorded on a Bruker Avance DMX 400 MHz instrument
(Bruker Daltonik, Bremen, Germany) in CDCl3 (1H at 400 MHz) using TMS (tetra-
methylsilane) as the internal standard. Electrospray ion trap mass spectrometry (ESI-
TRAP-MS) was carried out with a Bruker ESI-TRAP Esquire 6000 plus mass
spectrometry instrument (Bruker, Germany). Paeonol, triethylamine, ethanesulfonyl
chloride and arylsulfonyl chloride were purchased from Aladdin Chemistry Co., Ltd.
(Shanghai, China). Ethyl acetate, dichloromethane and petroleum ether were pur-
chased from Beichen Fangzheng Reagent Factory (Tianjin, China). Analytical thin-
layer chromatography (TLC) was performed with silica gel plate using silica gel 60
GF254 (Qingdao Haiyang Chemical Co., Ltd., Shandong, China). Silica gel column
chromatography was performed with silica gel 200-300 mesh (Qingdao Haiyang
Chemical Co., Ltd., Shandong, China).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
3.2. General procedure for the synthesis of sulfonate derivatives of paeonol
(4a–p, 5a–p, and 6a–p)
To a solution of paeonol/2-hydroxy acetophenone/3-methoxyphenol (1/2/3, 1.0 mmol)
and ethanesulfonyl chloride/arylsulfonyl chloride (7, 1.2 mmol) in dry dichlorome-
thane (CH2Cl2, 10 ml) at room temperature, a solution of triethylamine (Et3N)
(1.5 mmol) in dry CH2Cl2 (5 ml) was added dropwise for 10 min. When the reaction
was completed by TLC analysis, the reaction mixture was diluted with water (15 ml),
and extracted with CH2Cl2 (30 ml ꢀ 3). Subsequently, the combined organic phase
was washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concen-
trated in vacuo, and purified by silica gel column chromatography to obtain title
compounds. The data for 4a–p, 5a–p, and 6a–p are shown as follows.
3.2.1. Data for 4a
1
Yield ¼ 38%, Reddish brown oily liquid. H NMR (400 MHz, CDCl3) d: 7.79 (d,
J¼ 8.8 Hz, 1H), 6.94 (d, J¼ 2.4 Hz, 1H), 6.89 (dd, J¼ 8.8, 2.4 Hz, 1H), 3.87 (s, 3H),
3.47 (q, J¼ 7.6 Hz, 2H), 2.59 (s, 3H), 1.58 (t, J¼ 7.6 Hz, 3H). ESI-MS: m/z (%) 259
[M þ H]þ (100).
3.2.2. Data for 4b
Yield ¼ 48%, Pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) d: 7.86 (d,
J¼ 8.8 Hz, 2H), 7.67–7.73 (m, 2H), 7.57 (t, J¼ 8.0 Hz, 2H), 6.85 (dd, J¼ 8.8, 2.4 Hz,
1H), 6.60 (d, J¼ 2.4 Hz, 1H), 3.77 (s, 3H), 2.46 (s, 3H). ESI-MS: m/z (%) 307
[M þ H]þ (100).
3.2.3. Data for 4c
1
Yield ¼ 33%, White solid, m.p. 67–68 ꢁC. H NMR (400 MHz, CDCl3) d: 7.71–7.74
(m, 2H), 7.70 (d, J¼ 8.8 Hz, 1H), 7.32–7.34 (m, 2H), 6.84 (dd, J¼ 8.8, 2.4 Hz, 1H),
6.65 (d, J¼ 2.4 Hz, 1H), 3.78 (s, 3H), 2.46 (s, 6H). ESI-MS: m/z (%) 321
[M þ H]þ (100).
3.2.4. Data for 4d
1
Yield ¼ 57%, White solid, m.p. 88–89 ꢁC. H NMR (400 MHz, CDCl3) d: 7.74–7.78
(m, 2H), 7.70 (d, J¼ 8.8 Hz, 1H), 6.96–7.00 (m, 2H), 6.84 (dd, J¼ 8.8, 2.4 Hz, 1H),
6.66 (d, J¼ 2.4 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 2.47 (s, 3H). ESI-MS: m/z (%) 337
[M þ H]þ (100).
3.2.5. Data for 4e
1
Yield ¼ 57%, White solid, m.p. 72–73 ꢁC. H NMR (400 MHz, CDCl3) d: 7.76–7.79
(m, 2H), 7.71 (d, J¼ 8.8 Hz, 1H), 7.53–7.56 (m, 2H), 6.82–6.85 (m, 1H), 6.58–6.59
(m, 1H), 3.75 (s, 3H), 2.45 (s, 3H), 1.35 (s, 9H). ESI-MS: m/z (%) 363
[M þ H]þ (100).
3.2.6. Data for 4f
1
Yield ¼ Yield ¼ 49%, White solid, m.p. 105–106 ꢁC. H NMR (400 MHz, CDCl3) d:
7.79 (d, J¼ 8.8 Hz, 1H), 7.02 (s, 2H), 6.83 (dd, J¼ 8.8, 2.4 Hz, 1H), 6.20 (d, J¼ 2.4 Hz,

6
Y.-E. TIAN ET AL.
1H), 3.64 (s, 3H), 2.57 (s, 3H), 2.56 (s, 6H), 2.34 (s, 3H). ESI-MS: m/z (%) 349
[M þ H]þ (100).
3.2.7. Data for 4g
1
Yield ¼ 51%, White solid, m.p. 109–110 ꢁC. H NMR (400 MHz, CDCl3) d: 7.85 (d,
J¼ 8.8 Hz, 1H), 7.24 (s, 2H), 6.81 (dd, J¼ 8.8, 2.4 Hz, 1H), 6.04 (d, J¼ 2.4 Hz, 1H),
4.00–4.07 (m, 2H), 3.53 (s, 3H), 2.92–2.99 (m, 1H), 2.66 (s, 3H), 1.28 (s, 3H), 1.26 (s,
3H), 1.21 (s, 6H), 1.19 (s, 6H). ESI-MS: m/z (%) 433 [M þ H]þ (100).
3.2.8. Data for 4h
1
Yield ¼ 42%, White solid, m.p. 78–79 ꢁC. H NMR (400 MHz, CDCl3) d: 7.86–7.91
(m, 2H), 7.70 (d, J¼ 8.8 Hz, 1H), 7.20–7.25 (m, 2H), 6.87 (dd, J¼ 8.8, 2.4 Hz, 1H),
6.66 (d, J¼ 2.8 Hz, 1H), 3.80 (s, 3H), 2.46 (s, 3H). ESI-MS: m/z (%) 325
[M þ H]þ (100).
3.2.9. Data for 4i
1
Yield ¼ 41%, White solid, m.p. 95–96 ꢁC. H NMR (400 MHz, CDCl3) d: 7.68–7.75
(m, 5H), 6.87 (dd, J¼ 8.8, 2.4 Hz, 1H), 6.65 (d, J¼ 2.4 Hz, 1H), 3.80 (s, 3H), 2.46 (s,
3H). ESI-MS: m/z (%) 384 [M þ H]þ (100).
3.2.10. Data for 4j
Yield ¼ 34%, Turquoise oily liquid. 1H NMR (400 MHz, CDCl3) d: 8.07 (d,
J¼ 7.2 Hz, 1H), 7.85–7.89 (m, 2H), 7.74–7.79 (m, 2H), 6.90 (dd, J¼ 8.8, 2.4 Hz, 1H),
6.70 (d, J¼ 2.4 Hz, 1H), 3.79 (s, 3H), 2.54 (s, 3H). ESI-MS: m/z (%) 352
[M þ H]þ (100).
3.2.11. Data for 4k
Yield ¼ 34%, Pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) d: 8.73 (t,
J¼ 2.0 Hz, 1H), 8.53–8.56 (m, 1H), 8.23–8.26 (m, 1H), 7.83 (t, J¼ 8.0 Hz, 1H), 7.70
(d, J¼ 8.8 Hz, 1H), 6.90 (dd, J¼ 8.8, 2.4 Hz, 1H), 6.74 (d, J¼ 2.4 Hz, 1H), 3.84 (s,
3H), 2.45 (s, 3H). ESI-MS: m/z (%) 352 [M þ H]þ (100).
3.2.12. Data for 4l
1
Yield ¼ 60%, White solid, m.p. 126–127 ꢁC. H NMR (400 MHz, CDCl3) d: 8.38–8.42
(m, 2H), 8.10–8.14 (m, 2H), 7.72 (d, J¼ 8.8 Hz, 1H), 6.90 (dd, J¼ 8.8, 2.4 Hz, 1H),
6.73 (d, J¼ 2.4 Hz, 1H), 3.84 (s, 3H), 2.46 (s, 3H). ESI-MS: m/z (%) 352
[M þ H]þ (100).
3.2.13. Data for 4m
Yield ¼ 40%, Pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) d: 8.38 (d,
J¼ 2.4 Hz, 1H), 8.09 (dd, J¼ 8.4, 2.0 Hz, 1H), 7.79 (d, J¼ 8.8 Hz, 1H), 7.73 (d,
J¼ 8.8 Hz, 1H), 6.92 (dd, J¼ 8.8, 2.4 Hz, 1H), 6.78 (d, J¼ 2.4 Hz, 1H), 3.86 (s, 3H),
2.46 (s, 3H). ESI-MS: m/z (%) 386 [M þ H]þ (100).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
3.2.14. Data for 4n
Yield ¼ 33%, Pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) d: 7.77 (d,
J¼ 5.2 Hz, 1H), 7.71 (d, J¼ 8.8 Hz, 1H), 7.63 (d, J¼ 4.0 Hz, 1H), 7.14 (t, J¼ 4.0 Hz,
1H), 6.87 (dd, J¼ 8.8, 2.4 Hz, 1H), 6.70 (d, J¼ 2.4 Hz, 1H), 3.80 (s, 3H), 2.51 (s, 3H).
ESI-MS: m/z (%) 335 [MþNa]þ (70).
3.2.15. Data for 4o
1
Yield ¼ 39%, White solid, m.p. 109–110 ꢁC. H NMR (400 MHz, CDCl3) d: 8.77–8.80
(m, 1H), 8.18–8.21 (m, 1H), 8.16 (dd, J¼ 7.6, 1.2 Hz, 1H), 7.99–8.02 (m, 1H),
7.76–7.80 (m, 1H), 7.67–7.73 (m, 2H), 7.55 (dd, J¼ 8.4, 7.6 Hz, 1H), 6.78 (dd, J¼ 8.8,
2.4 Hz, 1H), 6.08 (d, J¼ 2.4 Hz, 1H), 3.50 (s, 3H), 2.54 (s, 3H). ESI-MS: m/z (%) 357
[M þ H]þ (100).
3.2.16. Data for 4p
1
Yield ¼ 35%, White oily liquid. H NMR (400 MHz, CDCl3) d: 9.15 (dd, J¼ 4.4,
2.0 Hz, 1H), 8.46 (dd, J¼ 7.6, 1.6 Hz, 1H), 8.31 (dd, J¼ 8.4, 2.0 Hz, 1H), 8.18 (dd,
J¼ 8.4, 1.6 Hz, 1H), 7.67 (d, J¼ 8.8 Hz, 1H), 6.66 (dd, J¼ 8.4, 7.6 Hz, 1H), 7.62 (q,
J¼ 4.0 Hz, 1H), 6.76 (dd, J¼ 8.8, 2.4 Hz, 1H), 6.64 (d, J¼ 2.4 Hz, 1H), 3.66 (s, 3H),
2.58 (s, 3H). ESI-MS: m/z (%) 380 [MþNa]þ (96).
3.2.17. Data for 5a
1
Yield ¼ 54%, Pale yellow oily liquid. H NMR (400 MHz, CDCl3) d: 7.74 (dd, J¼ 7.6,
1.6 Hz, 1H), 7.52–7.56 (m, 1H), 7.37–7.43 (m, 2H), 3.42 (q, J¼ 7.6 Hz, 2H), 2.63 (s,
3H), 1.57 (t, J¼ 7.6 Hz, 3H). ESI-MS: m/z (%) 229 [M þ H]þ (100).
3.2.18. Data for 5b
Yield ¼ 72%, Pale yellow solid, m.p. 70–71 ꢁC. 1H NMR (400 MHz, CDCl3) d:
7.80–7.83 (m, 2H), 7.68–7.72 (m, 1H), 7.65 (dd, J¼ 7.6, 1.6 Hz, 1H), 7.52–7.56 (m,
2H), 7.42–7.46 (m, 1H), 7.32–7.36 (m, 1H), 7.10 (dd, J¼ 8.0, 1.2 Hz, 1H), 2.51 (s,
3H). ESI-MS: m/z (%) 277 [M þ H]þ (100).
3.2.19. Data for 5c
1
Yield ¼ 51%, White solid, m.p. 89–90 ꢁC. H NMR (400 MHz, CDCl3) d: 7.66–7.70
(m, 2H), 7.65 (dd, J¼ 7.6, 1.6 Hz, 1H), 7.41–7.46 (m, 1H), 7.30–7.35 (m, 3H), 7.10
(dd, J¼ 8.0, 1.2 Hz, 1H), 2.52 (s, 3H), 2.46 (s, 3H). ESI-MS: m/z (%) 291
[M þ H]þ (100).
3.2.20. Data for 5d
1
Yield ¼ 74%, Yellow oily liquid. H NMR (400 MHz, CDCl3) d: 7.70–7.74 (m, 2H),
7.65 (dd, J¼ 7.6, 1.6 Hz, 1H), 7.41–7.46 (m, 1H), 7.31–7.35 (m, 1H), 7.10 (dd, J¼ 8.0,
1.2 Hz, 1H), 6.94–6.99 (m, 2H), 3.89 (s, 3H), 2.53 (s, 3H). ESI-MS: m/z (%) 307
[M þ H]þ (100).

8
Y.-E. TIAN ET AL.
3.2.21. Data for 5e
1
Yield ¼ 81%, Pale yellow oily liquid. H NMR (400 MHz, CDCl3) d: 7.71–7.75 (m,
2H), 7.65 (dd, J¼ 7.6, 1.6 Hz, 1H), 7.52–7.55 (m, 2H), 7.42–7.47 (m, 1H), 7.31–7.36
(m, 1H), 7.13 (dd, J¼ 8.0, 1.2 Hz, 1H), 2.49 (s, 3H), 1.35 (s, 9 H). ESI-MS: m/z (%)
333 [M þ H]þ (100).
3.2.22. Data for 5f
Yield ¼ 67%, Pale yellow solid, m.p. 96–97 ꢁC 1H NMR (400 MHz, CDCl3) d:
7.70–7.72 (m, 1H), 7.26–7.36 (m, 2H), 7.00 (s, 2H), 6.71–6.74 (m, 1H), 2.60 (s, 3H),
2.52 (s, 6H), 2.34 (s, 3H). ESI-MS: m/z (%) 319 [M þ H]þ (100).
3.2.23. Data for 5g
Yield ¼ 56%, Pale yellow solid, m.p. 78–79 ꢁC 1H NMR (400 MHz, CDCl3) d:
7.76–7.79 (m, 1H), 7.30–7.33 (m, 2H), 7.22 (s, 2H), 6.65–6.67 (m, 1H), 3.96–4.03 (m,
2H), 2.91–2.98 (m, 1H), 2.68 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H), 1.19 (s, 6H), 1.17 (s,
6H). ESI-MS: m/z (%) 403 [M þ H]þ (100).
3.2.24. Data for 5h
1
Yield ¼ 66%, Pale yellow oily liquid. H NMR (400 MHz, CDCl3) d: 7.83–7.86 (m,
2H), 7.66 (dd, J¼ 7.6, 1.6 Hz, 1H), 7.44–7.48 (m, 1H), 7.34–7.38 (m, 1H), 7.20–7.24
(m, 2H), 7.12 (dd, J¼ 8.0, 1.2 Hz, 1H), 2.53 (s, 3H). ESI-MS: m/z (%) 295
[M þ H]þ (100).
3.2.25. Data for 5i
Yield ¼ 78%, Pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) d: 7.69 (d,
J¼ 0.8 Hz, 4H), 7.67 (dd, J¼ 7.6, 1.6 Hz, 1H), 7.44–7.48 (m, 1H), 7.38 (t, J¼ 7.6 Hz,
1H), 7.09 (dd, J¼ 8.0, 1.2 Hz, 1H), 2.53 (s, 3H). ESI-MS: m/z (%) 356
[M þ H]þ (100).
3.2.26. Data for 5j
1
Yield ¼ 71%, Yellow solid, m.p. 56–57 ꢁC H NMR (400 MHz, CDCl3) d: 7.96–8.02
(m, 1H), 7.87–7.91 (m, 2H), 7.69–7.75 (m, 2H), 7.38–7.51 (m, 2H), 7.25 (t, J¼ 8.4 Hz,
1H), 2.60 (s, 3H). ESI-MS: m/z (%) 322 ([M þ H]þ (100).
3.2.27. Data for 5k
Yield ¼ 56%, Pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) d: 8.69 (t,
J¼ 4.0 Hz, 1H), 8.54–8.57 (m, 1H), 8.18–8.21 (m, 1H), 7.82 (t, J¼ 8.0 Hz, 1H), 7.67
(dd, J¼ 7.6, 1.6 Hz, 1H), 7.49–7.53 (m, 1H), 7.38–7.42 (m, 1H), 7.20 (dd, J¼ 8.0,
1.2 Hz, 1H), 2.52 (s, 3H). ESI-MS: m/z (%) 322 [M þ H]þ (100).
3.2.28. Data for 5l
1
Yield ¼ 84%, Pale yellow solid, m.p. 115–116 ꢁC. H NMR (400 MHz, CDCl3) d:
8.38–8.41 (m, 2H), 8.05–8.09 (m, 2H), 7.69 (dd, J¼ 7.6, 1.6 Hz, 1H), 7.48–7.52 (m,
1H), 7.38–7.43 (m, 1H), 7.16 (dd, J¼ 8.0, 1.2 Hz, 1H), 2.53 (s, 3H). ESI-MS: m/z (%)
322 [M þ H]þ (100).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
9
3.2.29. Data for 5m
Yield ¼ 67%, Pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) d: 8.34 (d,
J¼ 2.0 Hz, 1H), 8.02 (dd, J¼ 8.4, 2.0 Hz, 1H), 7.79 (d, J¼ 8.4 Hz, 1H), 7.70 (dd,
J¼ 7.6, 1.6 Hz, 1H), 7.51–7.55 (m, 1H), 7.40–7.44 (m, 1H), 7.22 (dd, J¼ 8.0, 1.2 Hz,
1H), 2.54 (s, 3H). ESI-MS: m/z (%) 356 [M þ H]þ (100).
3.2.30. Data for 5n
1
Yield ¼ 89%, Pale red oily liquid. H NMR (400 MHz, CDCl3) d: 7.76 (dd, J¼ 5.2,
3.6 Hz, 1H), 7.65 (dd, J¼ 7.6, 1.6 Hz, 1H), 7.19 (dd, J¼ 4.4, 2.4 Hz, 1H), 7.45–7.49
(m, 1H), 7.34–7.38 (m, 1H), 7.19 (dd, J¼ 8.0, 1.2 Hz, 1H), 7.11–7.13 (m, 1H), 2.56 (s,
3H). ESI-MS: m/z (%) 305 [MþNa]þ (79).
3.2.31. Data for 5o
1
Yield ¼ 59%, White solid, m.p. 126–127 ꢁC H NMR (400 MHz, CDCl3) d: 8.80 (dd,
J¼ 8.4, 0.8 Hz, 1H), 8.19 (d, J¼ 8.4 Hz, 1H), 8.09 (dd, J¼ 7.2, 1.2 Hz, 1H), 8.02 (d,
J¼ 8.0 Hz, 1H), 7.76–7.80 (m, 1H), 7.63–7.71 (m, 2H), 7.52 (dd, J¼ 8.0, 7.2 Hz, 1H),
7.21–7.29 (m, 2H), 6.63 (dd, J¼ 7.6, 1.6 Hz, 1H), 2.55 (s, 3H). ESI-MS: m/z (%) 327
[M þ H]þ (100).
3.2.32. Data for 5p
1
Yield ¼ 68%, White solid, m.p. 95–96 ꢁC. H NMR (400 MHz, CDCl3) d: 9.15 (dd,
J¼ 4.4, 1.6 Hz, 1H), 8.41 (dd, J¼ 7.6, 1.6 Hz, 1H), 8.31 (dd, J¼ 8.4, 1.6 Hz, 1H), 8.17
(dd, J¼ 8.4, 1.6 Hz, 1H), 7.58–7.63 (m, 3H), 7.30–7.34 (m, 1H), 7.22–7.26 (m, 1H),
7.13 (dd, J¼ 8.0, 1.2 Hz, 1H), 2.61 (s, 3H). ESI-MS: m/z (%) 350 [MþNa]þ (98).
3.2.33. Data for 6a
Yield ¼ 60%, Pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) d: 7.32 (t,
J¼ 8.0 Hz, 1H), 6.82–6.88 (m, 3H), 3.81 (s, 3H), 3.31 (q, J¼ 7.2 Hz, 2H), 1.55 (t,
J¼ 7.2 Hz, 3H). ESI-MS: m/z (%) 217 [M þ H]þ (100).
3.2.34. Data for 6b
1
Yield ¼ 81%, Pale yellow oily liquid. H NMR (400 MHz, CDCl3) d: 7.84–7.86 (m,
2H), 7.65–7.68 (m, 1H), 7.51–7.55 (m, 2H), 7.14–7.19 (m, 1H), 6.77–6.80 (m, 1H),
6.52–6.56 (m, 2H), 3.71 (s, 3H). ESI-MS: m/z (%) 265 [M þ H]þ (100).
3.2.35. Data for 6c
1
Yield ¼ 96%, Pale yellow oily liquid. H NMR (400 MHz, CDCl3) d: 7.70–7.73 (m,
2H), 7.30–7.32 (m, 2H), 7.18 (t, J¼ 8.0 Hz, 1H), 6.76–6.79 (m, 1H), 6.52–6.56 (m,
2H), 3.72 (s, 3H), 2.44 (s, 3H). ESI-MS: m/z (%) 279 [M þ H]þ (100).
3.2.36. Data for 6d
1
Yield ¼ 86%, Pale yellow oily liquid. H NMR (400 MHz, CDCl3) d: 7.74–7.78 (m,
2H), 7.18 (t, J¼ 8.0 Hz, 1H), 6.94–6.98 (m, 2H), 6.76–6.79 (m, 1H), 6.52–6.57 (m,
2H), 3.88 (s, 3H), 3.72 (s, 3H). ESI-MS: m/z (%) 295 [M þ H]þ (100).

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Y.-E. TIAN ET AL.
3.2.37. Data for 6e
1
Yield ¼ 89%, Pale yellow oily liquid. H NMR (400 MHz, CDCl3) d: 7.75–7.78 (m,
2H), 7.51–7.54 (m, 2H), 7.19 (t, J¼ 8.0 Hz, 1H), 6.77–6.80 (m, 1H), 6.57–6.60 (m,
1H), 6.52 (t, J¼ 2.4 Hz, 1H), 3.69 (s, 3H), 1.34 (s, 9 H). ESI-MS: m/z (%) 321
[M þ H]þ (100).
3.2.38. Data for 6f
1
Yield ¼ 97%, White solid, m.p. 71–72 ꢁC. H NMR (400 MHz, CDCl3) d: 7.17 (t,
J¼ 8.0 Hz, 1H), 6.97 (s, 2H), 6.75–6.78 (m, 1H), 6.51–6.53 (m, 2H), 3.70 (s, 3H), 2.56
(s, 6H), 2.32 (s, 3H). ESI-MS: m/z (%) 307 [M þ H]þ (100).
3.2.39. Data for 6g
1
Yield ¼ 60%, White solid, m.p. 55–56 ꢁC. H NMR (400 MHz, CDCl3) d: 7.20 (s,
2H), 7.19 (t, J¼ 8.0 Hz, 1H), 6.76–6.79 (m, 1H), 6.57–6.60 (m, 1H), 6.50 (t,
J¼ 2.4 Hz, 1H), 4.03–4.10 (m, 2H), 3.66 (s, 3H). 2.89–2.96 (m, 1H), 1.27 (s, 3H), 1.26
(s, 3H), 1.19 (s, 6H), 1.18 (s, 6H). ESI-MS: m/z (%) 391 [M þ H]þ (100).
3.2.40. Data for 6h
1
Yield ¼ 85%, White solid, m.p. 52–53 ꢁC. H NMR (400 MHz, CDCl3) d: 7.84–7.89
(m, 2H), 7.16–7.23 (m, 3H), 6.78–6.81 (m, 1H), 6.52–6.56 (m, 2H), 3.73 (s, 3H). ESI-
MS: m/z (%) 283 [M þ H]þ (100).
3.2.41. Data for 6i
1
Yield ¼ 91%, Pale yellow oily liquid. H NMR (400 MHz, CDCl3) d: 7.65–7.72 (m,
4H), 7.20 (d, J¼ 8.0 Hz, 1H), 6.79–6.82 (m, 1H), 6.57 (t, J¼ 2.4 Hz, 1H), 6.51–6.54
(m, 1H), 3.74 (s, 3H). ESI-MS: m/z (%) 344 [M þ H]þ (100).
3.2.42. Data for 6j
1
Yield ¼ 64%, Yellow solid. m.p. 88–89 ꢁC. H NMR (400 MHz, CDCl3) d: 7.94–7.97
(m, 1H), 7.82–7.84 (m, 2H), 7.66–7.70 (m, 1H), 7.24 (t, J¼ 8.0 Hz, 1H), 6.81–6.84 (m,
1H), 6.75–6.78 (m, 2H), 3.75 (s, 3H). ESI-MS: m/z (%) 310 [M þ H]þ (100).
3.2.43. Data for 6k
1
Yield ¼ 61%, Pale yellow solid, m.p. 70–73 ꢁC. H NMR (400 MHz, CDCl3) d: 8.71
(q, J¼ 2.0 Hz, 1H), 8.51–8.54 (m, 1H), 8.16–8.19 (m, 1H), 7.80 (t, J¼ 8.0 Hz, 1H),
7.22 (t, J¼ 8.0 Hz, 1H), 6.81–6.84 (m, 1H), 6.59–6.61 (m, 1H), 6.53–6.56 (m, 1H),
3.75 (s, 3H). ESI-MS: m/z (%) 310 [M þ H]þ (100).
3.2.44. Data for 6l
1
Yield ¼ 93%, White solid, m.p. 108–109 ꢁC. H NMR (400 MHz, CDCl3) d: 8.36–8.39
(m, 2H), 8.03–8.07 (m, 2H), 7.22 (t, J¼ 8.0 Hz, 1H), 6.81–6.84 (m, 1H), 6.60 (t,
J¼ 2.4 Hz, 1H), 6.50–6.53 (m, 1H), 3.75 (s, 3H). ESI-MS: m/z (%) 310
[M þ H]þ (100).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
11
3.2.45. Data for 6m
1
Yield ¼ 82%, Pale yellow solid, m.p. 66–67 ꢁC. H NMR (400 MHz, CDCl3) d: 8.33
(d, J¼ 2.4 Hz, 1H), 7.97 (dd, J¼ 8.4, 2.0 Hz, 1H), 7.76 (d, J¼ 8.4 Hz, 1H), 7.25 (t,
J¼ 8.0 Hz, 1H), 6.83–6.86 (m, 1H), 6.63 (t, J¼ 2.4 Hz, 1H), 6.54–6.57 (m, 1H), 3.77
(s, 3H). ESI-MS: m/z (%) 344 [M þ H]þ (100).
3.2.46. Data for 6n
1
Yield ¼ 97%, Pale yellow oily liquid. H NMR (400 MHz, CDCl3) d: 7.73 (dd, J¼ 5.2,
1.2 Hz, 1H), 7.61 (dd, J¼ 4.0, 1.6 Hz, 1H), 7.21 (t, J¼ 8.0 Hz, 1H), 7.12 (dd, J¼ 5.2,
4.0 Hz, 1H), 6.80–6.83 (m, 1H), 6.58–6.63 (m, 2H), 3.73 (s, 3H). ESI-MS: m/z (%) 293
[MþNa]þ (86).
3.2.47. Data for 6o
1
Yield ¼ 82%, Pale yellow solid, m.p. 49–50 ꢁC. H NMR (400 MHz, CDCl3) d: 8.82
(d, J¼ 8.8 Hz, 1H), 8.13 (t, J¼ 7.6 Hz, 2H), 7.99 (d, J¼ 8.4 Hz, 1H), 7.76–7.80 (m,
1H), 7.65–7.69 (m, 1H), 7.49 (t, J¼ 8.0 Hz, 1H), 7.07 (t, J¼ 8.0 Hz, 1H), 6.68–6.71
(m, 1H), 6.40–6.43 (m, 2H), 3.58 (s, 3H). ESI-MS: m/z (%) 315 [M þ H]þ (100).
3.2.48. Data for 6p
1
Yield ¼ 96%, Pale yellow oily liquid. H NMR (400 MHz, CDCl3) d: 9.27 (dd, J¼ 4.4,
2.0 Hz, 1H), 8.41 (dd, J¼ 7.6, 1.2 Hz, 1H), 8.31 (dd, J¼ 8.4, 2.0 Hz, 1H). 8.14 (dd,
J¼ 8.4, 1.6 Hz, 1H), 7.58–7.63 (m, 2H), 7.10 (t, J¼ 8.0 Hz, 1H), 6.69–6.72 (m, 1H),
6.58–6.63 (m, 2H), 3.64 (s, 3H). ESI-MS: m/z (%) 338 [MþNa]þ (89).
3.3. Anti-oomycete activity of compounds 4a–p, 5a–p, and 6a–p against
P. capsici
Forty-eight sulfonate derivatives of paeonol (4a–p, 5a–p, and 6a–p) were screened
in vitro for their anti-oomycete activity against P. capsici. Potato dextrose agar (PDA)
medium was prepared in the flasks and sterilized. Paeonol (1), 2-hydroxy acetophenone
(2), 3-methoxyphenol (3), 4a–p, 5a–p, and 6a–p and zoxamide (used as a positive con-
trol) were dissolved in acetone before mixing with PDA. The ranges of 1, 2, 3, 4a–p,
5a–p, 6a–p and zoxamide concentrations for the assays were defined in preliminary
experiments, and the final concentrations in medium were 5, 25, 50, 75, 100 mg/L.
Pure acetone mixed with PDA was served as the control, while zoxamide, a commer-
cially available agricultural fungicide, was used as a positive control. The medium was
then poured into sterilized Petri dishes. Mycelial plugs (5-mm diameter) were cut from
the growing edge of a 7-day-old colony and then placed on the PDA plates, and incu-
bated at 28ꢁC in the dark, respectively. Colony growth rate (mm/7 days) was deter-
mined on PDA medium. Three plates were evaluated for each compounds and an
average colony diameter was calculated. The radial growths of the colonies were meas-
ured and the data were statistically analyzed. Mean colony diameter (minus the diam-
eter of the plug) was measured for each treatment and expressed as a percentage of
growth inhibition. The median effective concentration (EC50) of 1, 2, 3, 4a–p, 5a–p,
6a–p and zoxamide for P. capsici isolate was calculated by linear regression of relative
percentage of growth inhibition against log transformed samples concentration.

12
Y.-E. TIAN ET AL.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was financially supported by the National Natural Science Foundation of China
(Grant No. U1604105, 31901863), the Natural Science Foundation of Henan Province (Grant
No. 182300410043, 182300410016, 152300410082), the SRTP Project of Henan University of
Science and Technology (2019406).
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