Synthesis and Anti-Oomycete Activity of 1-Sulfonyloxy/Acyloxydihydroeugenol Derivatives

Article abstract of DOI:10.1002/cbdv.202100329

Endeavor to discover biorational natural products-based fungicides, two series (26) of novel 1-sulfonyloxy/acyloxydihydroeugenol derivatives (3a–p and 5a–j) were prepared and assessed for their fungicidal activity against P. capsici Leonian, in vitro. Res

Full text of DOI:10.1002/cbdv.202100329

doi.org/10.1002/cbdv.202100329
FULL PAPER
Synthesis and Anti-Oomycete Activity of 1-
Sulfonyloxy/Acyloxydihydroeugenol Derivatives
Genqiang Chen+,a Lina Zhu+,a Jiaxuan He+,a Song Zhang,a Yuanhao Li,a Xiaolong Guo,a Di Sun,a
Yuee Tian,*a Shengming Liu,a Xiaobo Huang,a and Zhiping Che*a
a
Laboratory of Pesticidal Design and Synthesis, Department of Plant Protection, College of Horticulture and
Plant Protection, Henan University of Science and Technology, Luoyang 471023, P. R. China,
e-mail: zhipingche@163.com; tianyuee1985@163.com
Endeavor to discover biorational natural products-based fungicides, two series (26) of novel 1-sulfonyloxy/
acyloxydihydroeugenol derivatives (3a–p and 5a–j) were prepared and assessed for their fungicidal activity
against P. capsici Leonian, in vitro. Results of fungicidal activity revealed that, among all compounds, especially
compounds 3a, 5c, and 5e displayed the most potent anti-oomycete activity against P. capsici with EC50 values
of 69.33, 68.81, and 67.77 mg/L, respectively. Overall, the anti-oomycete activities of 1-acyloxydihydroeugenol
derivatives (5a–j) were higher than that of 1-sulfonyloxydihydroeugenol derivatives (3a–p). It is proved that the
introduction of the acyl group at hydroxy position of dihydroeugenol is more beneficial to improve its anti-
oomycete activity than that of the sulfonyl group. These preliminary results will pave the way for further
modification of dihydroeugenol in the development of potential new fungicides.
Keywords: natural bioresource, dihydroeugenol, 1-sulfonyloxy/acyloxy, fungicidal activity, botanical fungicides.
effectively to research and develop high-efficiency and
low-risk small-molecule green-fungicide.
Introduction
The filamentous oomycete pathogen Phytophthora
Essential oils (Eos) do not have any obvious
capsici, is a virulent and hemibiotrophic pathogen, physiological significance for the growth of the plant
causes root, crown, foliage and fruit rot on a number itself but function mainly as defense mechanisms
of important vegetables, such as pepper and against a variety of pathogenic infections, including
cucurbits.[1] P. capsici is one of the most destructive oomycetes, fungi, bacteria, and virus.[10] Eos play a very
pathogens of vegetables, which causes serious signifi- important role in the discovery of new
cant losses worldwide every year.[2–4] The reason is fungicides.[11–13] Thus, it is in line with the develop-
that the P. capsici has strong adaptability to fungicides ment trend of pesticide science to develop botanical
and new hosts plants.[1–6] Fungicide is still an effective fungicides with plant secondary metabolites with
way to control P. capsici because the research on antifungal activity as leading compounds.[14]
resistant germplasm resources lags behind the evolu-
Dihydroeugenol (1; Figure 1), 2-methoxy-4-propyl-
tion of pathogens.[5–9] Like other members of this phenol is the reducing product of eugenol (4-allyl-2-
destructive genus, P. capsici has strong infectivity, a methoxyphenol). Eugenol was mainly isolated from
wide host and high resistance frequency.[1–6] There- the unopened and dried flower buds of Syzygium
fore, it is still a feasible way to control P. capsici aromaticum of the Myrtaceae family. Studies have
shown that eugenol, dihydroeugenol and its deriva-
tives have many biological activities, such as antibacte-
rial activity,[15–18] antidiabetic and anticholinergic
+
activity,[18]
antioxidant
activity,[19]
insecticidal
These authors contributed equally to this work.
activity,[20,21] antifungal activity,[22] etc. More recently,
sulfonate esterification of hydroxy of maltol, paeonol,
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/cbdv.202100329
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Chem. Biodiversity 2021, 18, e2100329
Figure 1. Chemical structures of dihydroeugenol and sulfonate derivatives of maltol (I), paeonol (II), carvacrol (III), and thymol (IV).
carvacrol and thymol had been investigated in our Results and Discussion
research group, and some sulfonate derivatives of
maltol (I), paeonol (II), carvacrol (III) and thymol (IV,
Chemistry
Figure 1) exhibited more pronounced anti-oomycete As depicted in Scheme 1, 1 reacted with R1SO2Cl (2a–
activity against P. capsici.[23–25] Overall, to the best of p) to afford a series of 1-sulfonyloxydihydroeugenol
our knowledge, study on the synthesis of novel 1- derivatives (3a–p) in suitable yields.[23–25] Meanwhile,
sulfonyloxy/acyloxydihydroeugenol derivatives (3a–p as described in Scheme 2, R2COOH (4a–j) first reacted
and 5a–j, Schemes 1 and 2) as fungicidal agents with Br3CSO2Ph to obtain the corresponding acyl
against P. capsici has not yet been reported. In the bromine. Then introduction of the different acyloxy
meantime, our long-term goal is to find more active groups at the C-1 position of 1 gave 1-acyloxydihy-
natural product-based antifungal hits.[23–25] Given that, droeugenol derivatives (5a–j) in suitable yields.[26] The
we designed and synthesized of novel dihydroeugenol structures of all title compounds were well character-
1
derivatives (Schemes 1 and 2) by introducing of the ized by H-NMR, HRMS, and m.p., and the data of 3a–
sulfonyloxy or acyloxy fragments on the dihydroeuge- p and 5a–j can be found in the Supporting Informa-
nol skeleton. The antifungal activities of two series of tion.
dihydroeugenol derivatives against P. capsici in vitro
were reported for the first time.
Anti-Oomycete Activity
The anti-oomycete activity of dihydroeugenol (1),
eugenol, novel 1-sulfonyloxydihydroeugenol deriva-
tives (3a–p) and 1-acyloxydihydroeugenol derivatives
(5a–j) against P. capsici is outlined in Table 1.
Scheme 1. Synthetic route for the preparation of 3a–p.
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Chem. Biodiversity 2021, 18, e2100329
Scheme 2. Synthetic route for the preparation of 5a–j.
Results of fungicidal activity showed that, out of different positions of the benzene ring could lead to
twenty-six evaluated compounds, three (3a, 5c, and derivatives with different anti-oomycete activities
5e) exhibited significant anti-oomycete activity (EC50 (para>ortho>meta position, e.g., 3l>3j>3k, 5j>
values of 69.33, 68.81, and 67.77 mg/L, respectively), 5h>5i and 5c>5a>5b). For example, the EC50 values
ten (3c, 3m, 3n, 5a, 5b, 5d, 5f–h, and 5j) showed of 3l, 3j, 3k, 5j, 5h, 5i, 5c, 5a and 5b against P. capsici
moderate anti-oomycete activity (EC50 values of 93.94, were 108.69, 145.64, 177.17, 80.50, 83.96, 101.35,
86.71, 90.18, 74.50, 81.96, 83.50, 84.27, 77.72, 83.96, 68.81, 74.50 and 81.96 mg/L, respectively. Similarly, the
and 80.50 mg/L, respectively), while the remaining introduction of the p-chlorobenzoyl/p-bromobenzoyl
compounds displayed weak anti-oomycete activity at the hydroxy position of 1 could lead to produce
(EC50 values of 101.35 to 177.17).
more potent compound than introducing of the o-
In order to elucidate the anti-oomycete activity of chlorobenzoyl/o-bromobenzoyl groups (e.g., 67.77
compounds 3a–p and 5a–j at a molecular basis and and 77.72 mg/L for 5e and 5g versus 83.50 and
to reveal structural features critical for their anti- 84.27 mg/L for 5d and 5f). (3) In 1-sulfonyloxydihy-
oomycete activity, a brief investigation of structure- droeugenol derivatives, as compared with fused ring
activity relationship (SAR) was determined, which (1-naphthalensulyonyl and 8-quinolinesulfonyl) deriva-
revealed how the substituents on 3a–p and 5a–j tives, 2-thiophenesulfonyl derivative displayed the
were related to the anti-oomycete. This mainly best anti-oomycete activity (3n>3p>3o, e.g., EC50 =
includes six aspects. (1) On the whole, the anti- 90.18 mg/L for 3n versus EC50 =115.68 mg/L for 3p
oomycete activity of dihydroeugenol with the acyloxy and EC50 =125.37 mg/L for 3o). (4) The introduction of
group was higher than that with the sulfonyloxy the tosyl at the hydroxy position of 1 could lead to
group, and the EC50 values of 3a–p and 5a–j were more potent compound than possessing of the
69.33–177.17 mg/L and 67.77–101.35 mg/L, respec- phenylsulfonyl
group,
p-tert-butylphenylsulfonyl
tively. In addition, it is noteworthy that introduction of group, and p-methoxyphenylsulfonyl group (3c>3b>
the acyl group at the hydroxy position of 1 could lead 3e>3d). For example, the EC50 values of 3c, 3b, 3e
to produce more potent compound compared to their and 3d against P. capsici were 93.94, 127.12, 132.76
precursor dihydroeugenol (e.g., 5a–j vs. 1). (2) Inter- and 143.34 mg/L, respectively. Similarly, comparing
restingly, we found that the introduction of the the EC50 value of R1 =2,4,6-trimethylphenyl derivative
nitrophenylsulfonyl/nitrobenzoyl/methylbenzoyl at the (EC50 =104.90 mg/L for 3f), it exhibited more potent
hydroxy position of 1, the nitro/methyl groups at anti-oomycete activity than R1 =2,4,6-triisopropyl-
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Chem. Biodiversity 2021, 18, e2100329
can consider the synthesis of derivatives with the
proper chain length of R1.
Table 1. Anti-oomycete activities of compounds 3a–p and 5a–
j against P. capsici in vitro.
Compound
P. capsici
EC50 (mg/L)
Conclusion
1
108.17
243.19
69.33
127.12
93.94
Eugenol
3a
3b
3c
In summary, 26 novel 1-sulfonyloxy/acyloxydihydroeu-
genol derivatives (3a–p and 5a–j) were prepared and
their structures were well characterized by H-NMR,
1
HRMS, and m.p. Their fungicidal activity was evaluated
against P. capsici in vitro. Among all of the tested
compounds, half of the compounds 3a, 3c, 3m, 3n,
5a-h, and 5j showed more potent anti-oomycete
activity than their precursor dihydroeugenol, and the
EC50 values of 69.33, 93.94, 86.71, 90.18, 74.50, 81.96,
68.81, 83.50, 67.77, 84.27, 77.72, 83.96, and 80.50 mg/L,
respectively. Especially compounds 3a, 5c, and 5e,
displayed the most potent anti-oomycete activity
against P. capsici with EC50 values of less than 70 mg/L.
Overall, the anti-oomycete activities of 1-acyloxydihy-
droeugenol derivatives (5a–j) was higher than that of
1-sulfonyloxydihydroeugenol derivatives (3a–p). It is
proved that the introduction of the acyl group at
hydroxy position of dihydroeugenol is more beneficial
to improve its anti-oomycete activity than that of the
sulfonyl group. This will pave the way for further
design, structural modification, and to develop dihy-
droeugenol derivatives as fungicidal agents.
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
5a
5b
5c
5d
5e
5f
143.34
132.76
104.90
138.88
134.73
170.47
145.64
177.17
108.69
86.71
90.18
125.37
115.68
74.50
81.96
68.81
83.50
67.77
84.27
77.72
5g
5h
5i
83.96
101.35
80.50
5j
Zoxamide
26.87
Experimental Section
Chemistry
phenyl derivative (EC50 =138.88 mg/L for 3g). (5) It is
noteworthy that the introduction of the p-chloro-m- Dihydroeugenol (2-methoxy-4-propylphenol, 1), Euge-
nitrophenylsulfonyl as a two-electron-withdrawing nol (4-allyl-2-methoxyphenol), ethanesulfonyl chloride
substituent (such as NO2 and Cl) could result in more (C2H5SO2Cl), arylsulfonyl chloride (R1SO2Cl), aryl acid
potent compound 3m relative to those containing (R2COOH), and triethylamine (Et3N) were ordered from
phenylsulfonyl as a one-electron-withdrawing sub- Aladdin Chemistry Co., Ltd. (Shanghai, China). Triphe-
stituent (e.g., 3h–l). For example, the EC50 values of nylphosphine (PPh3), and phenyl tribromomethyl
3h–m against P. capsici were 134.73, 170.47, 145.64, sulfone (Br3CSO2Ph) were ordered from Shanghai
177.17, 108.69 and 86.71 mg/L, respectively. Moreover, Macklin Biochemical Co., Ltd. (Shanghai, China).
the introduction of 4-fluorophenylsulfonyl to the
hydroxy position of dihydroeugenol could lead to
General Procedure for Preparation of 1-Sulfonyloxydihy-
more potent compound than possessing 4-bromophe-
droeugenol Derivatives (3a–p)
nylsulfonyl group (e.g., 134.73 mg/L for 3h versus
170.47 mg/L for 3i). (6) The anti-oomycete activity of To
a
mixture of 2-methoxy-4-propylphenol (1,
eugenol was significantly improved after allyl reduc- 1.0 mmol) and R1SO2Cl (2a–p, 1.2 mmol) in dry CH2Cl2
tion (e.g., EC50 =243.19 mg/L for eugenol versus (10 mL) at room temperature, a solution of Et3N
EC50 =108.17 mg/L for 1). In addition, the substituent (1.5 mmol) in dry CH2Cl2 (2 mL) was added dropwise
1R is aliphatic, which is essential for anti-oomycete for 5 min. The reaction was detected by TLC, H2O
activity (EC50 =69.33 mg/L for 3a). In the future, we (15 mL) was added to the reaction, and extracted with
CH2Cl2 (30 mL×3). Subsequently, the organic phase
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Chem. Biodiversity 2021, 18, e2100329
was combined, washed by saturated aq. brine (30 mL), and Zhiping Che; All authors approved the final
dried over anhydrous Na2SO4, concentrated under manuscript.
reduced pressure, and purified by CC to obtain 1-
sulfonyloxydihydroeugenol derivatives in 17–79%
yields.[23–25]. The data of 3a–p can be found in the
Supporting Information.
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(1 M), the mixture was stirred at room temperature for
1–2 h, and the reaction process was checked by TLC
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Author Contribution Statement
Designed the experiments, synthesized the com-
pounds, and analyzed the data: Lina Zhu, Jiaxuan He,
Song Zhang, Yuanhao Li, Xiaolong Guo, Di Sun, Yuee
Tian, Shengming Liu, Xiaobo Huang Genqiang Chen
and Zhiping Che; Wrote the article: Genqiang Chen
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Received April 26, 2021
Accepted July 16, 2021
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