Journal of Molecular Structure 1291 (2023) 136055

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Journal of Molecular Structure

journal homepage: www.elsevier.com/locate/molstr

Synthesis, anti-oomycete and anti-fungal activities of novel cinchona

alkaloid derivatives bearing carbamate moiety
Zhiping Che a, *, Song Zhang a, Yihao Guo a, Yibo Liu a, Ruxue Wei a, Lin Zhou b, Xiaobo Huang a,
Shengming Liu a, Genqiang Chen a, Yuee Tian a, *
a
Laboratory of Pesticidal Design & Synthesis, Department of Plant Protection, College of Horticultrue and Plant Protection, Henan University of Science and Technology,
Luoyang, Henan Province 471023, China
b
College of Plant Protection, Henan Agricultural University, Zhengzhou 450002, China

A R T I C L E I N F O A B S T R A C T

Keywords: In order to explore novel natural product-based anti-oomycete and anti-fungal agents, twenty cinchona alkaloid
Natural product carbamate derivatives (1a-d, 2a-d, 3a-d, 4a-d, and 5a-d) were designed and prepared, and structurally
Cinchona alkaloid confirmed by 1H NMR, 13C NMR, HRMS, and melting point. The stereochemical configuration of compound 1a
Carbamylation
was unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, we evaluated the anti-oomycete
Anti-oomycete activity
and anti-fungal activities of these target compounds against Phytophthora capsici and Fusarium graminearum in
Anti-fungal activity
vitro. The results showed that five compounds 1d, 2d, 3d, 4d, and 5d exhibited prominent anti-oomycete and
anti-fungal activities, and the median effective concentration (EC50) values of 1d, 2d, 3d, 4d, and 5d against
P. capsici and F. graminearum were 21.1, 16.6, 22.4, 14.4, 13.9 mg/L and 38.2, 19.8, 36.6, 30.3, 27.7 mg/L,
respectively. This study suggested that when a specific substituent is introduced into the cinchona alkaloid
skeleton, i.e. R1/R2 = Ph/Ph, the corresponding derivatives exhibit significant anti-oomycete and anti-fungal
activities. And the configuration of the C8/9 position of the target compound is crucial for its anti-oomycete
and anti-fungal activities, and 9S-configuration is optimal.

1. Introduction capsici Leonian, is one of the most devastating diseases in pepper culti­
vation worldwide [8]. P. capsici has a wide range of hosts and strong
Phytopathogenic fungi are one of the most harmful plant parasitic vitality, which can survive for several years in soil without a host plant
organisms in the world, and fungal diseases can cause severe damage to [9]. Phenylamide fungicides, such as metalaxyl, are effective against
crops, resulting in decreased yield and quality of agricultural products P. capsici. However, with increasing frequency of use,
[1]. More seriously, phytopathogenic fungi, such as Fusarium grami­ metalaxyl-resistant phytophthora isolates have emerged rapidly
nearum Schwabe, can produce deoxynivalenol (DON) toxin, which [10–12]. Fungicides play an important role in the control and preven­
brings various food safety problems to people [2]. So far, the use of tion of oomycetes, but due to the many physiological and biochemical
chemical fungicides to control plant diseases is still one of the most differences between oomycetes and fungi, the effect of using fungicides
effective means [3]. However, the extensive use of fungicides has led to to control oomycetes is limited [13]. To solve the above problems, it is
the continuous evolution of fungi to produce more virulent urgent for researchers to discover and screen novel fungicides with
fungicide-resistant strains, give rise to a decline in the efficacy of some unique modes of action, higher selectivity and lower application doses to
fungicides [4]. In addition, many traditional fungicides also pose po­ control oomycete diseases [14].
tential threats to human health, animals and the environment [5]. Quinine (1, Fig. 1), is the main alkaloids in the bark of Cinchona and
Therefore, it is necessary to develop new and safe fungicides to solve the its homologous plants of Rubiaceae, and analogues include quinidine (2,
increasingly serious fungal diseases [6]. Fig. 1), cinchonidine (3, Fig. 1), and cinchonine (4, Fig. 1) [15–18]. In
Moreover, Phytophthora is one of the most important genera of the addition to being antimalarial drugs [19–21] and synthetic catalysts and
oomycetes [7]. Phytophthora blight of pepper, caused by Phytophthora ligands [22–24], quinine and its analogues also have a variety of

* Corresponding authors.
E-mail addresses: [email protected] (Z. Che), [email protected] (Y. Tian).

https://doi.org/10.1016/j.molstruc.2023.136055
Received 21 April 2023; Received in revised form 31 May 2023; Accepted 16 June 2023
Available online 17 June 2023
0022-2860/© 2023 Elsevier B.V. All rights reserved.
Z. Che et al. Journal of Molecular Structure 1291 (2023) 136055

biological activities, such as insecticidal activity [16–18], antifungal determined the optimal equivalence ratio of 1, dimethylcarbamoyl
activity [25], antibacterial activity [26], anticancer activity [27], anti­ chloride, Et3N, and DMAP reactions to be 1.0:1.2:1.5:1.0.
viral activity [28,29], trypanocidal activity [30], etc. Quinine and its Based upon the above findings, subsequently, a wide range of
analogues are highly sought after by people because of their various cinchona alkaloid, for example, quinine (1), quinidine (2), cinchonidine
biological activities. However, there are few studies on quinine and its (3), cinchonine (4), and dihydroquinidine (5), with the corresponding
analogues to control plant pathogens. carbamoyl chlorides (dimethylcarbamoyl chloride, diethylcarbamyl
One of the effective ways to create new pesticides is to modify the chloride, ethylmethyl-carbamic chloride and diphenylcarbamyl chlo­
structure of natural products to obtain more effective structural frame­ ride) was investigated to explore the scope of the reaction. As depicted in
work [31–33]. Our research group has been committed to the creation Scheme 3, cinchona alkaloid derivatives (1a-d, 2a-d, 3a-d, 4a-d, and
and development of novel biorational pesticides based on natural 5a-d) were obtained in 12–94% yields for 24-96 h. The structures of
products for a long time [33–42]. In addition, carbamate fungicides, cinchona alkaloid derivatives (1a-d, 2a-d, 3a-d, 4a-d, and 5a-d) were
such as propamocarb and diethofencarb, can effectively control oomy­ well characterized by proton nuclear magnetic resonance (1H NMR),
cete/fungal diseases [43–45]. F. graminearum and P. capsici are two carbon-13 nuclear magnetic resonance (13C NMR), high-resolution mass
typical plant pathogens in the world that cause serious diseases on spectrometry (HRMS), and melting point (mp), and the data of com­
various plants and seriously threaten the safe production of agriculture pounds 1a-d, 2a-d, 3a-d, 4a-d, and 5a-d can be found in the Supporting
every year [3,7,33]. Quinine and its analogues are renewable and Information. To determine the precise three-dimensional configuration
bioactive products with a wide range of biological activities. The of the cinchona alkaloid derivatives, compound 1a was subjected to
structural modification of quinine and its analogues into carbamate single-crystal X-ray diffraction, as shown in Fig. 2. Crystallographic data
derivatives is a potential way to develop new pesticides, and its toxicity (excluding structure factors) for the structure of 1a has been deposited
is higher than precursor. However, there are no reports on the with the Cambridge Crystallographic Data centre as supplementary
anti-oomycete and fungal activities of carbamate derivatives of quinine publication CCDC 2,246,922. Copies of the data can be obtained, free of
and its analogues to control plant pathogens. Encouraged by the above charge, on application to the CCDC, 12 Union Rd., Cambridge CB2 1EZ,
results, a series of carbamate derivatives of quinine and its analogues U.K. [fax +44 (0)1223 336,033 or e-mail [email protected]].
were prepared, and their anti-oomycete and fungal activities were
further evaluated against two major plant pathogens, F. graminearum 2.2. Anti-oomycete activity
and P. capsici, in this study.
As outlined in Table 2, the inhibitory activities of the cinchona
2. Results and discussion alkaloid compounds 1a-d, 2a-d, 3a-d, 4a-d, and 5a-d against P. capsici
were determined at concentrations of 50 and 100 mg/L with metalaxyl
2.1. Chemistry as positive control. The results showed that some title compounds
exhibited significant anti-oomycete activity. For example, at concen­
In order to clarify the impact of quinuclidine double bond on bio­ trations of 50 and 100 mg/L, title compounds 1d, 2d, 3d, 4d, and 5d
logical activity, dihydroquinidine (5) was obtained by reducing the exhibited good anti-oomycete activity. Especially, at the concentration
quinidine (2) double bond with a high yield of 92% under Pd-C catalysis of 50 mg/L, the anti-oomycete activity of compounds 1d, 2d, 3d, 4d,
[17,18], as shown in Scheme 1. In addition, carbamate compounds and 5d against P. capsici exceeded that of the positive control metalaxyl
exhibit potential biological activity. Firstly, using a conventional (71.3%), with inhibition rates of 79.3%, 77.5%, 73.9%, 73.3%, and
method [46], quinine (1) reacts with p-nitrophenyl chloroformate under 74.7%, respectively.
the catalysis of pyridine to obtain intermediate 6, which is further reacts At the concentration of 100 mg/L, some interesting information was
with dimethylamine (MeNHMe) under the catalysis of 4-dimethylami­ found through the comparative analysis of structure-activity relation­
nopyridine (DMAP) and triethylamine (Et3N) to generate quinine de­ ship (SAR). (1) When R1/R2 = Ph/Ph, after the introduction of carba­
rivative bearing carbamate moiety (1a) in a total yield of 45%, as mate into the C9 hydroxy position of quinine (1), quinidine (2),
depicted in Scheme 2. Secondly, in order to synthesize the target com­ cinchonidine (3), cinchonine (4) or dihydroquinidine (5), the anti-
pound 1a in one step, it was attempted to synthesize compound 1a by oomycete activity was significantly improved, which was significantly
reacting quinine with dimethylcarbamoyl chloride under the catalysis of higher than R1/R2 = Me/Me, R1/R2 = Et/Et and R1/R2 = Me/Et. For
Et3N. Even if the reaction time was extended to 48 h, compound 1a was example, the inhibition rates of 1d, 2d, 3d, 4d, and 5d were 91.3%,
not obtained, as depicted in Scheme 2. Finally, as described in Table 1, 94.9%, 82.5%, 84.1%, and 89.0%, respectively. (2) Interestingly, the
we optimized the reaction conditions. Under the catalysis of Et3N, configuration of C8/9 position is important for anti-oomycete activity,
compound 1a was not obtained after 48 h of reaction without or with and 9S-configuration is optimal (e.g. 91.3% for 1d versus 94.9% for 2d;
DMAP in a molar ratio of one-tenth of 1 (Entry 1 and 2). However, when 82.5% for 3d versus 84.1% for 4d). (3) The proper length of amino­
DMAP with a molar ratio equal to 1 was added, the target compound 1a oyloxy group (R1/R2) at the 9-position of 1–5 were usually significant
was obtained in 47% yield after 48 h of reaction (Entry 3). The opti­ for their anti-oomycete activity. For example, when R1/R2 = Et/Et, the
mization method not only has a simple synthesis step, but also has a anti-oomycete activity was significantly higher than R1/R2 = Me/Me
higher yield than conventional method. Therefore, we preliminarily and R1/R2 = Me/Et (e.g., 62.8%/42.6%/43.7%/32.2%/49.7% for 1b/

Fig. 1. Chemical structures of quinine (1), quinidine (2), cinchonidine (3), and cinchonine (4).

2
Z. Che et al. Journal of Molecular Structure 1291 (2023) 136055

Scheme 1. Route for the synthesis of dihydroquinidine (5).

Scheme 2. Synthesis route of target compound 1a.

Table 1
Optimization of the reaction conditions α.

Entry Et3N (mmol) DMAP (mmol) Time (h) Yield of 1a (%) β

1 1.5 0 48 0
2 1.5 0.1 48 0
3 1.5 1.0 48 47
α
1.0 mmol 1 reacted with 1.2 mmol dimethylcarbamoyl chloride.
β
Isolated yield.

3
Z. Che et al. Journal of Molecular Structure 1291 (2023) 136055

Scheme 3. Synthetic route for the preparation of cinchona alkaloid derivatives 1a-d, 2a-d, 3a-d, 4a-d, and 5a-d.

2b/3b/4b/5b versus 21.3%/34.9%/20.2%/28.4%/29.5% for 1a/2a/ 2.3. Anti-fungal activity

3a/4a/5a and 42.0%/37.1%/37.7%/31.1%/29.5% for 1c/2c/3c/4c/
5c). As shown in Table 4, with triadimefon as the positive control, the
In order to further investigate the SAR of these target compounds, we inhibitory activity of the cinchona alkaloid compounds 1a-d, 2a-d, 3a-
selected representative target compounds and conducted EC50 deter­ d, 4a-d, and 5a-d against F. graminearum at concentrations of 50 and
mination, as shown in Table 3. When R1/R2 = Ph/Ph, the corresponding 100 mg/L was determined respectively. Among the twenty cinchona
target compounds have significant anti-oomycete activity. For example, alkaloid carbamate derivatives determined, five (1d, 2d, 3d, 4d, and
the EC50 values of 1d, 2d, 3d, 4d, and 5d against P. capsici were 21.1, 5d) of them showed good anti-fungal activity. The anti-fungal activity of
16.6, 22.4, 14.4, and 13.9 mg/L, respectively. When the C9 position is in these five compounds at five concentration gradients was further
the S configuration, its corresponding target compounds have more determined using the mycelial growth rate method, which is outlined in
excellent anti-oomycete activity (e.g., 2d versus 1d; 4d versus 3d). Table 5.

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Z. Che et al. Journal of Molecular Structure 1291 (2023) 136055

Fig. 2. X-ray crystal structure of compound 1a.

Table 2 Table 3
Anti-oomycete activity of 1a-d, 2a-d, 3a-d, 4a-d, and 5a-d at 50 and 100 mg/L Anti-oomycete activity of 1d, 2d, 3d, 4d, and 5d at different concentration
concentrations against P. capsici in vitro†. gradients against P. capsici in vitro†.
Compounds Inhibition rate (%)‡ Compounds Toxicity Correlation Confidence EC50
50 (mg/L) 100 (mg/L) regression coefficient interval 95% (mg/
equation (mg/L) L)‡
1a 16.8 ± 1.4a‖ 21.3 ± 0.8a
1b 37.5 ± 3.3f 62.8 ± 0.4h 1d y = 2.3315 + 0.9968 19.2–23.2 21.1
1c 15.7 ± 1.8a 42.0 ± 2.0ef 2.0126x
1d 79.3 ± 0.8i 91.3 ± 0.0kl 2d y = 2.7122 + 0.9741 12.1–22.7 16.6
2a 22.2 ± 0.4bc 34.9 ± 2.3cd 1.8722x
2b 30.4 ± 0.4e 42.6 ± 0.8f 3d y = 2.7730 + 0.9961 20.3–24.8 22.4
2c 27.1 ± 1.2de 37.1 ± 0.4d 1.6479x
2d 77.5 ± 0.0hi 94.9 ± 0.0l 4d y = 3.4966 + 0.9943 12.3–16.8 14.4
3a 19.5 ± 0.4ab 20.2 ± 0.4a 1.2968x
3b 21.7 ± 0.0bc 43.7 ± 2.6f 5d y = 3.4072 + 0.9930 11.6–16.7 13.9
3c 21.7 ± 0.0bc 37.7 ± 0.0de 1.3908x
3d 73.9 ± 0.8 g 82.5 ± 0.9i Metalaxyl§ y = 4.2949 + 0.9863 5.7–10.0 7.6
4a 21.7 ± 1.4bc 28.4 ± 0.9b 0.7988x
4b 23.9 ± 1.2cd 32.2 ± 2.3bc
4c 23.3 ± 0.8bcd 31.1 ± 2.9bc
†
Regression analysis by IBM SPSS Statistics 22.0, p < 0.05.
4d 73.3 ± 0.4 g 84.1 ± 0.4i
‡
Median effective concentration.
5a 26.6 ± 0.8de 29.51 ± 0.0b
§
Metalaxyl was used as a positive control.
5b 26.6 ± 0.8de 49.7 ± 2.0 g
5c 28.2 ± 0.8e 29.5 ± 0.0b
As shown in Table 4, whether determined at concentrations of 50
5d 74.7 ± 0.4 gh 89.0 ± 0.4jk
Metalaxyl§ 71.3 ± 0.4 ghi 84.2 ± 0.8ij mg/L or 100 mg/L, only 1d, 2d, 3d, 4d, and 5d showed good anti-fungal
activity among all target compounds. This result indicates that the anti-
†
Multiple range test using Duncan′s test, p < 0.05.
fungal activity of these derivatives against F. graminearum is signifi­
‡
Values are means ± standard deviation of three replicates.
cantly increased only when specific substituents are introduced into the
‖
The same letters denote treatments that are not significantly different from
each other. skeleton, i.e. R1/R2 = Ph/Ph. For example, the inhibition rates for 1d,
§
Metalaxyl was used as a positive control. 2d, 3d, 4d, and 5d at a concentration of 100 mg/L were 54.7%, 68.6%,
69.1%, 67.6%, and 73.5%, respectively.
Interestingly, the results in Table 5 indicate that the configuration at

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Z. Che et al. Journal of Molecular Structure 1291 (2023) 136055

Table 4 derivatives exhibits significant inhibitory activity against both oomycete

Anti-fungal activity of 1a-d, 2a-d, 3a-d, 4a-d, and 5a-d at 50 and 100 mg/L and fungi. Moreover, the results showed that the configuration at the
concentrations against F. graminearum in vitro†. C8/9 position is closely related to activity, and the S configuration at the
Compounds Inhibition rate (%)‡ C9 position of cinchona alkaloid carbamate derivatives has better anti-
50 (mg/L) 100 (mg/L) oomycete and anti-fungal activities than the R configuration. The
1a 27.4 ± 0.0bc‖ 28.3 ± 0.0b impact of double bond reduction in the target compound on anti-
1b 33.7 ± 0.4ef 49.6 ± 0.4h oomycete and fungal activities cannot be determined at present, and
1c 20.5 ± 0.0a 23.9 ± 0.4a the research team is currently conducting further research to confirm.
1d 53.4 ± 0.0 gh 54.7 ± 0.8i
The study provides an idea for further exploring the biological activities
2a 27.8 ± 0.4c 29.5 ± 0.4b
2b 32.4 ± 0.9de 34.5 ± 0.9d of cinchona alkaloid carbamate derivatives, and develops the applica­
2c 34.2 ± 0.0ef 37.2 ± 0.4ef tion of cinchona alkaloid carbamate derivatives in agriculture.
2d 64.2 ± 2.0 g 68.6 ± 2.3j
3a 33.7 ± 1.2ef 36.7 ± 0.0ef 4. Experimental section
3b 30.1 ± 0.0cd 32.3 ± 0.8c
3c 30.1 ± 2.1cd 41.6 ± 0.4 g
3d 61.1 ± 2.0i 69.1 ± 0.0l 4.1. Chemistry
4a 28.7 ± 1.4c 36.2 ± 0.4e
4b 36.9 ± 2.1f 38.2 ± 0.0f See supporting information for general procedures.
4c 33.7 ± 1.2ef 41.1 ± 0.0 g
4d 60.2 ± 0.8h 67.6 ± 1.4k
5a 24.2 ± 2.0b 36.7 ± 0.0ef 4.2. Synthesis of dihydroquinidine (5)
5b 35.1 ± 0.4ef 50.4 ± 0.9h
5c 34.2 ± 0.0ef 36.76 ± 0.0ef The synthesis of dihydroquinidine (5) is based on previous reports by
5d 58.8 ± 1.6h 73.5 ± 1.6l our research group [17,18]. The data of 5 can be found in the Supporting
Triadimefon§ 77.9 ± 0.4j 82.5 ± 0.4m
Information.
†
Multiple range test using Duncan′s test, p < 0.05.
‡
Values are means ± standard deviation of three replicates. 4.3. Synthesis of target compound (1a)
‖
The same letters denote treatments that are not significantly different from
each other. To a solution of p-nitrophenyl chloroformate (3.35 mmol) in anhy­
§
Triadimefon was used as a positive control.
drous dichloromethane (DCM, 10 mL) at room temperature was added
dropwise for 5 min a solution of dry pyridine (4.00 mmol) in anhydrous
Table 5
DCM (2 mL). And a solution of quinine (1, 1.00 mmol) in anhydrous
Anti-fungal activity of 1d, 2d, 3d, 4d, and 5d at different concentration gradi­ DCM (5 mL) was added dropwise for 5 min. The reaction process was
ents against F. graminearum in vitro†. detected by TLC. After 1 h, H2O (15 mL) was added to the reaction and
extracted with DCM (30 mL × 3). Then, combined the organic phases,
Compounds Toxicity Correlation Confidence EC50
regression coefficient interval 95% (mg/ washed them with saturated aq. brine (30 mL), dried them with anhy­
equation (mg/L) L)‡ drous Na2SO4, concentrated them under reduced pressure, and purified
1d y = 3.3767 + 0.9574 28.7–50.6 38.2
them through CC to obtain an important intermediate (6) in 89% yield
1.0260x [46].
2d y = 4.0256 + 0.9884 16.4–23.8 19.8 To a solution of 6 (0.50 mmol) in anhydrous DCM (10 mL) was added
0.7513x the dimethylamine (0.60 mmol), Et3N (0.60 mmol) and DMAP (0.08
3d y = 3.3024 0.9259 25.0–53.8 36.6
+
mmol) at room temperature. After 12 h, the reaction mixture was
1.0850x
4d y = 3.5441 + 0.9789 24.7–37.2 30.3 washed with cold saturated NaHCO3 and then water until pH = 7. The
0.9823x extract was dried over anhydrous Na2SO4, concentrated them under
5d y = 3.3821 + 0.9639 20.9–36.7 27.7 reduced pressure, and purified them through CC to afford compound
1.1206x (1a) in 51% yield [46].
Triadimefon§ y = 4.5285 + 0.9891 3.1–6.7 4.6
0.7107x
4.4. General procedure for preparation of cinchona alkaloid derivatives
†
Regression analysis by IBM SPSS Statistics 22.0, p < 0.05. 1a-d, 2a-d, 3a-d, 4a-d, and 5a-d
‡
Median effective concentration.
§
Triadimefon was used as a positive control.
Cinchona alkaloid 2, 3, 4, 5, or 1 (1.00 mmol) was added to a 50 mL
flask, and DCM (10 mL) was added to dissolve it completely, then Et3N
the C8/9 position is closely related to anti-fungal activity, and the S (1.50 mmol) was slowly added dropwise for 5 min, and the reaction was
configuration at the C9 position of cinchona alkaloid derivatives has stirred at room temperature after the drop was completed. After 15 min,
better anti-fungal activity against F. graminearum than the R configura­ DMAP (1.00 mmol) and the corresponding carbamoyl chloride
tion (e.g., EC50 = 19.8 mg/L for 2d versus EC50 = 38.2 mg/L for 1a; R1R2NCOCl (1.20 mmol) were added to the flask to continue the reac­
EC50 = 30.3 mg/L for 4d versus EC50 = 36.6 mg/L for 3d). tion. The reaction process was detected by TLC. After 24-96 h, H2O (15
mL) was added to the reaction and extracted with DCM (30 mL × 3).
3. Conclusion Then, combined the organic phases, washed them with saturated aq.
brine (30 mL), dried them with anhydrous Na2SO4, concentrated them
In summary, twenty cinchona alkaloid carbamate derivatives (1a-d, under reduced pressure, and purified them through CC to obtain
2a-d, 3a-d, 4a-d, and 5a-d) were synthesized, and their anti-oomycete, cinchona alkaloid derivatives 1a-d, 2a-d, 3a-d, 4a-d and 5a-d in
and anti-fungal activities against P. capsici and F. graminearum were 12–94% yield. The data of 1a-d, 2a-d, 3a-d, 4a-d and 5a-d can be found
determined in this study. Among the all tested derivatives, five com­ in the Supporting Information.
pounds 1d, 2d, 3d, 4d, and 5d showed more potent anti-oomycete and
anti-fungal activities, which can be used as a key research object for
further study. This result indicates that only when a specific substituent
is introduced into the skeleton, i.e. R1/R2 = Ph/Ph, the corresponding

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Z. Che et al. Journal of Molecular Structure 1291 (2023) 136055

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Author contribution statement novel fungicide pyrimorph in Phytophthora capsici: risk assessment and detection of
point mutations in CesA3 that confer resistance, PLoS ONE 8 (2013) e56513,
https://doi.org/10.1371/journal.pone.0056513.
Designed the experiments: Zhiping Che, Yuee Tian, Lin Zhou, [12] G. Parra, J.B. Ristaino, Resistance to mefenoxam and metalaxyl Among field
Shengming Liu and Genqiang Chen; Synthesized the compounds, and isolates of Phytophthora capsici causing phytophthora blight of bell pepper, Plant
analyzed the data: Song Zhang, Yihao Guo, Yibo Liu, Ruxue Wei and Dis. 85 (2001) 1069–1075, https://doi.org/10.1094/PDIS.2001.85.10.1069.
[13] D. Lin, Z.L. Xue, J.Q. Miao, Z.Q. Huang, X.L. Liu, Activity and resistance assessment
Xiaobo Huang; Wrote the paper: Yuee Tian and Zhiping Che; All authors of a new OSBP inhibitor, R034-1, in Phytophthora capsici and the detection of point
approved the final manuscript. mutations in PcORP1 that confer resistance, J. Agric. Food Chem. 68 (2020)
Zhiping Che reports financial support was provided by Henan Uni­ 13651–13660, https://doi.org/10.1021/acs.jafc.0c05531.
[14] P. Tao, C.Y. Wu, J. Hao, Y.Q. Gao, X.H. He, J. Li, S.B. Shang, Z.Q. Song, J. Song,
versity of Science and Technology. No Antifungal application of rosin derivatives from renewable pine resin in crop
protection, J. Agric. Food Chem. 68 (2020) 4144–4154, https://doi.org/10.1021/
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Declaration of Competing Interest [15] Z.P. Che, J.M. Yang, Y.E. Tian, S.M. Liu, J. Jiang, G.Q. Chen, Research progress in
quinine compounds, Chem. Bull. 81 (2018) 792–796, https://doi.org/10.14159/j.
The authors declare no conflict of interest. cnki.0441-3776.2018.09.002.
[16] Z.P. Che, J.M. Yang, S. Zhang, D. Sun, Y.E. Tian, S.M. Liu, X.M. Lin, J. Jiang, G.
Q. Chen, Synthesis of novel 9R/S-acyloxy derivatives of cinchonidine and
Data availability cinchonine as insecticidal agents, J. Asian Nat. Prod. Res. 23 (2021) 163–175,
https://doi.org/10.1080/10286020.2020.1729136.
[17] Z.P. Che, J.M. Yang, D. Sun, Y.E. Tian, S.M. Liu, X.M. Lin, J. Jiang, G.Q. Chen,
Data will be made available on request. Synthesis of novel (9S)-acyloxy derivatives of quinidine and dihydroquinidine as
insecticidal agents, Chem. Biodivers. 17 (2020), e1900696, https://doi.org/
10.1002/cbdv.201900696.
[18] Z.P. Che, J.M. Yang, D. Sun, Y.E. Tian, S.M. Liu, X.M. Lin, J. Jiang, G.Q. Chen,
Acknowledgments Combinatorial synthesis of novel 9R-acyloxyquinine derivatives as insecticidal
agents, Comb. Chem. High T. Scr. 23 (2020) 111–118, https://doi.org/10.2174/
This work was financially supported by the Henan Provincial Science 1386207323666200120112714.
[19] J. Achan, A.O. Talisuna, A. Erhart, A. Yeka, J.K. Tibenderana, F.N. Baliraine, P.
and Technology Major Project (Grant No. 221100110100), National J. Rosenthal, U. D’Alessandro, Quinine, an old anti-malarial drug in a modern
Natural Science Foundation of China (Grant No. 31901863), Young world: role in the treatment of malaria, Malaria J 10 (2011) 144, https://doi.org/
Teacher Funding Program of the Henan Higher School (Grant No. 10.1186/1475-2875-10-144.
[20] V. Kumar, A. Mahajan, K. Chibale, Synthetic medicinal chemistry of selected
2020GGJS080), Key Science and Technology Program of Henan Prov­
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addition: synthesis of modified chiral 2-(ethylthio)-thiazolone derivatives with
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