Design, Synthesis, and Structure-Activity Relationship of New Arylpyrazole Pyrimidine Ether Derivatives as Fungicides

Article abstract of DOI:10.1021/acs.jafc.9b05185

To explore a novel fungicide effectively against cucumber downy mildew (CDM), a series of new arylpyrazole containing pyrimidine ether derivatives were designed and synthesized by employing the intermediate derivatization method (IDM). The structures of synthesized compounds were identified by ¹H NMR, ¹³C NMR, elemental analyses, MS, and X-ray diffraction. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against CDM. Especially, compound 7 (EC₅₀ = 1.22 mg/L) displayed significantly higher bioactivity than that of commercial fungicides diflumetorim and flumorph and nearly equal effect to that of cyazofamid. The relationship between the structure and fungicidal activity of the synthesized compounds was discussed as well. The study showed that compound 7 was a promising fungicide candidate for further development.

Full text of DOI:10.1021/acs.jafc.9b05185

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Agricultural and Environmental Chemistry
Design, Synthesis, and Structure-Activity Relationship of
New Arylpyrazole Pyrimidine Ether Derivatives As Fungicides
Pengfei Zhang, Aiying Guan, Xiaoli Xia, Xufeng Sun, Siyuan Wei,
Jinlong Yang, Junfeng Wang, Zhinian Li, Jie lan, and Changling Liu
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b05185 • Publication Date (Web): 23 Sep 2019
Downloaded from pubs.acs.org on September 23, 2019
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Page 1 of 36
Journal of Agricultural and Food Chemistry
Design,
Synthesis,
and
Structure−Activity
Relationship of New Arylpyrazole Pyrimidine Ether
Derivatives As Fungicides
Pengfei Zhang, Aiying Guan*, Xiaoli Xia, Xufeng Sun, Siyuan Wei, Jinlong
Yang, Junfeng Wang, Zhinian Li, Jie Lan and Changling Liu*
State Key Laboratory of the Discovery and Development of Novel Pesticide,
Shenyang Sinochem Agrochemicals R&D Co. Ltd., Shenyang 110021,
People’s Republic of China
*Corresponding author (Tel: +86-(0)24-85869278; E-mail:
guanaiying@sinochem.com. Tel: +86-(0)24-85869078; E-mail:
liuchangling@vip.163.com)
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ABSTRACT
To explore a novel fungicide for effectively against cucumber downy mildew
(CDM), a series of new arylpyrazole containing pyrimidine ether derivatives
were designed and synthesized by employing the intermediate derivatization
1
method (IDM). The structures of synthesized compounds were identified by H
13
NMR, C NMR, elemental analyses, MS, and X-ray diffraction. Bioassays
demonstrated that some of the title compounds exhibited excellent fungicidal
activities against CDM. Especially, compound 7 (EC = 1.22 mg/L) displayed
50
significantly higher bioactivity than commercial fungicides diflumetorim,
flumorph, and nearly equal effect to cyazofamid. The relationship between
structure and fungicidal activity of the synthesized compounds was discussed
as well. The study showed that compound 7 was a promising fungicide
candidate for further development.
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KEYWORDS: pyrimidine ether derivatives, intermediate derivatization method
(IDM), fungicidal activities, structure−activity relationship
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INTRODUCTION
Fungicides are one of important parts in agrochemical crops protection
products, which are applied widely to major crops, such as rice, fruits, corn and
1
vegetables against diseases. However, the frequent use and misuse of
fungicides inevitably lead to developing serious resistance. So it is a huge
challenge and an urgent need for discovering and developing new fungicides
with innovated structures and improved activities.2
Arylpyrazolol is a common chemical intermediate often found not only in
medicines field for treatment of diseases such as pain, cancer, inflammation,
neurodegenerative, heart failure and renal diseases,3,4 but also in
agrochemical field to protect crops from pests or diseases. Pyraclostrobin,
pyrametostrobin and pyraoxystrobin are commercial/in development
fungicides containing an arylpyrazole moiety.5-8 Pyraclostrobin is the most
outstanding representative for its advantages of broad spectrum, high efficacy
and safety on non-targets, and its big market value with global sales of $920
million in 2017. More importantly, some excellent features in arylpyrazolol itself
including ease of synthesis, ease of diverse derivation, low toxicity and low
cost, fully meet the requirement of intermediate selection of the intermediate
derivatization method (IDM), a highly efficient approach to discover
agrochemical candidates.9-23
In prior arts, more and more literatures regarding pyrimidine ether compounds
with fungicidal activity have been published. For example, Ciba-Geigy
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(Syngenta) reported pyrimidine ethers containing pyrazolyl acrylic acid
derivatives as effective microbicides for controlling fungal diseases, especially
against cercospora arachidicola on groundnut plants and phytophthora
infestans on tomatoes.24 Imperial Chemical Industriesplc (Syngenta) found a
series of pyrimidine diethers for combating fungi, especially fungal infections of
plants, such as pyricularia oryzae on rice, puccinia recondita, puccinia
striiformis
and
other
rusts
on
wheat.25
Bayer
reported
a
pyrimidinyloxyphenyl-2-methoxyiminoacetates with a promising bioactivity
against leptosphaeria nodorum on wheat, phytophthora on tomato, and
26
venturia on apple. High & New Tech Research Center of Henan Academy of
Sciences found a series of ((6-substituted-pyrimidine-4-oxy)phenyl)-3-methyl
methoxyacrylates, which had a excellent control for fusarium oxysporum,
cercospora arachidicola hori, rhizoctonia cerealis and more.27
In this study, considering the excellent performance of the arylpyrazolol in crop
protection field, in order to explore new skeleton fungicidal compounds with
improved activity, (4-chlorophenyl)hydrazine hydrochloride was used as
starting material by employing the intermediate derivatization method to obtain
the key intermediate 1-(4-chlorophenyl)-1H-pyrazol-3-ol, followed by
replacement with methoxy acrylate group of azoxystrobin to achieve a series
of novel pyrimidine ether derivatives containing an arylpyrazole moiety (Figure
1). The detailed synthesis and structure−activity relationships of these
compounds were discussed below.
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MATERIALS AND METHODS
All chemicals such as starting materials and reagents were commercially
available (Sinopharm Chemical reagent Co. Ltd., Shanghai, China) and used
without further purification except as indicated. Elemental analyses were
determined on a Yanaco MT-3CHN elemental analyzer (Yanaco, Kyoto,
1
Japan). H NMR spectra was recorded with a Mercury 300 or 600 MHz
spectrometer (Varian, Palo Alto, CA) with deuterochloroform or deuterium
dimethyl sulfoxide as the solvent and tetramethylsilane (TMS) as the internal
standard. 13C NMR spectra was recorded with a Mercury 151 MHz
spectrometer (Varian, Palo Alto, CA) with deuterochloroform or deuterium
dimethyl sulfoxide as the solvent and tetramethylsilane (TMS) as the internal
standard. Mass spectra were acquired with Agilent 1100 series
LC-MSD-Trap-VL (Agilent Technologies, Milford, MA). Melting points were
determined on a Büchi M-569 melting point apparatus (Büchi Labortechnik AG,
Flawil, Switzerland) and were uncorrected. X-ray structure determination was
recorded with XtaLAB mini (Rigaku, The Woodlands, TX). All plant and fungus
materials were obtained from the Agrochemical Discovery Department in
Shenyang Sinochem Agrochemicals R&D Co. Ltd. (Shenyang, China).
The general synthetic methods for compounds 1−31 were shown in Figures 2,
4 and 5, and their structures were listed in Tables 1−5. The silica gel
chromatography was performed with a column of 254 mm × 26 mm i.d.
(Synthware glass Co. Ltd., Beijing, China) using 100−140 mesh silica gel
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(Sinopharm Chemical reagent Co. Ltd., Shanghai, China).
Synthesis of 4-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)-6-(4-(trifluoro-
methyl)phenoxy)-pyrimidine, 7. (General procedure for compounds 1-26)
(Figure 2)
Synthesis of 1-(4-chlorophenyl)pyrazolidin-3-one (A-1)
Sodium (10.35 g, 450 mmol) was cut into small pieces and added to 250 mL of
ethanol. Then (4-chlorophenyl)hydrazine hydrochloride (26.85 g, 150 mmol)
o
was added at 30-35 C after sodium was completely dissolved, followed by
addition of acrylamide (14.2 g, 200 mmol) after stirring for 15 min. The reaction
o
mixture was stirred for 6 h when the temperature rised to 80 C, until the color
of reaction mixture gradually turned from red to light red. After reaction
completion, the mixture was concentrated under reduced pressure, the residue
was poured into water, and extracted with ethyl acetate. The extract was dried
over anhydrous magnesium sulfate, filtered, and evaporated to obtain
intermediate A-1 as a brown solid: 27.2 g (92%).
Synthesis of 1-(4-chlorophenyl)-1H-pyrazol-3-ol (B-1)
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A-1 (27.2 g, 138 mmol) was dissolved in N-methylpyrrolidone, following ferric
chloride (0.26 g, 1.6 mmol) was added to the flask equipped with a bubbler,
o
and then the reaction mixture was heated to 100 C for 6-7 h. After the reaction
completion, the mixture was extracted, dried, filtered and concentrated. The
o
residue was purified via silica gel chromatography with ethyl acetate/60−90 C
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petroleum ether (1:7, v/v) as eluent to obtain intermediate B-1 as a pale white
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solid: 25.6 g (94%), m.p. 190.8 C.
Synthesis of 4-chloro-6-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)pyrimidine
(C-1)
To a solution of 4,6-dichloropyrimidine (3.83 g, 26 mmol) and potassium
carbonate (7.09 g, 51 mmol) in 120 mL of DMF was added B-1 (5 g, 26 mmol).
o
The reaction mixture was then heated to 90 C for 4 h, and monitored by TLC
until the reaction was completed. The mixture was extracted, dried, filtered,
concentrated to obtain intermediate C-1 as a yellow solid: 7.3 g (92%), m.p.
o
150.4 C.
Synthesis
of
4-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)-6-(4-(trifluoro-
methyl)phenoxy)pyrimidine (compound 7)
To a solution of C-1 (0.4 g, 1.3 mmol) and potassium carbonate (0.36 g, 2.6
mmol) in 20 mL of DMF was added 4-(trifluoromethyl)phenol (0.21 g, 1.3
o
mmol). The reaction mixture was then heated to 100 C for 2 h, and monitored
by TLC until the reaction was completed. The reaction mixture was poured into
water and extracted with ethyl acetate. The organic phase was washed
successively with water and saturated brine, dried, filtered, and evaporated
under reduced pressure. The residue was purified via silica gel
o
chromatography with ethyl acetate/60−90 C petroleum ether (1:5, v/v) as
eluent to obtain 0.47 g compound 7 as a light yellow solid: 0.47 g (84%), m.p.
o
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157 C. H NMR (600 MHz, CDCl ) δ 8.50 (s, 1H, pyrimidyl-2-H), 7.89 (s, 1H,
3
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pyrazol-5-H), 7.71 (d, J = 8.1 Hz, 2H, 4-CF -Ph-3,5-2H), 7.60 (d, J = 8.4 Hz,
3
2H, 4-Cl-Ph-2,6-2H), 7.42 (d, J = 8.4 Hz, 2H, 4-Cl-Ph-3,5-2H), 7.29 (d, J = 8.1
Hz, 2H, 4-CF -Ph-2,6-2H), 6.64 (s, 1H, pyrimidyl-5-H), 6.37 (s, 1H,
3
pyrazol-4-H). 13C NMR (151 MHz, CDCl ) δ 170.77, 170.31, 158.12, 157.87,
3
154.89, 138.14, 132.02, 129.51, 128.14, 127.12 (d, J = 3.4 Hz), 121.87,
119.72, 99.25, 93.24. Anal. Calcd (%) for C H ClF N O : C, 55.51; H, 2.79; N,
20
12
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4
2
+
12.95. Found: C, 55.55; H, 2.74; N, 12.98. MS m/z 433.0 [M + H] (calcd [M +
+
H] 433.06).
The crystal structure of target compound 7 was also determined by X-ray
diffraction analyses. Its crystal structure is shown in Figure 3.
Synthesis of 4-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)oxy)-6-(4-(trifluoro-
methyl)phenoxy)-pyrimidine, 27. (Figure 4)
Synthesis of (E)-1-chloro-3-(2-(4-chloro-phenyl)hydrazono)propan-2-one (D)
86 mL of water and 43 mL of 37% concentrated hydrochloric acid were
dropped into 4-chloroaniline (11.16 g, 120 mmol), which was stirred in ice bath
o
for 30 min ahead of time. When the reaction solution reached 0 C, sodium
nitrite (8.69 g, 126 mmol) in aqueous solution was dropwise added within 30
min. Then 4-chloroacetoacetic acid (16.38 g, 120 mmol) and sodium acetate
(24.60 g, 300 mmol) in aqueous solution were added to the reaction mixture in
turn after it turned the starch potassium iodide paper to blue, and they were
stirred at room temperature until a large amount of solid was generated. After
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reaction completion, the mixture was filtered, washed and dried to obtain
intermediate D as a pale orange solid: 18 g (76%).
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Synthesis of 1-(4-chlorophenyl)-1H-pyrazol-4-ol (E)
To a solution of D (9.80 g, 50 mmol) and sodium hydroxide (5.00 g, 125 mmol)
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in 100mL of methanol, stirring at 40 C for 3-6 h, and the reaction was
monitored by TLC until the reaction was completed. Then the mixture was
concentrated under reduced pressure, added water, adjusted the pH to
neutral, and poured into water and extracted with ethyl acetate. The extract
was dried over anhydrous magnesium sulfate and evaporated. The residue
o
was purified via silica gel chromatography with ethyl acetate/60−90 C
petroleum ether (1:8 v/v) as eluent to obtain E as a yellow solid: 6 g (75%),
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m.p. 122.5 C.
Synthesis of 4-chloro-6-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)oxy)pyrimidine
( F )
To a solution of 4,6-dichloropyrimidine (3.83 g, 26 mmol) and potassium
carbonate (7.09 g, 51 mmol) in 120 mL of DMF was added E (5 g, 26 mmol).
o
The reaction mixture was then heated to 90 C for 4 h, and monitored by TLC
until the reaction was completed. The mixture was extracted, dried, filtered,
concentrated to obtain intermediate F as a white solid: 7.1 g (90%).
Synthesis
of
4-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)oxy)-6-(4-(trifluoro-
methyl)phenoxy)pyrimidine (compound 27)
To a solution of F (0.4 g, 1.3 mmol) and potassium carbonate (0.36 g, 2.6
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mmol) in 20 mL of DMF was added 4-(trifluoromethyl)phenol (0.21 g, 1.3
o
mmol). The reaction mixture was then heated to 100 C for 2 h, and monitored
by TLC until the reaction was completed. The reaction mixture was poured into
water and extracted with ethyl acetate. The organic phase was washed
successively with water and saturated brine, dried, filtered, and evaporated
under reduced pressure. The residue was purified via silica gel
o
chromatography with ethyl acetate/60−90 C petroleum ether (1:7 v/v) as
eluent to obtain 0.43 g compound 27 as a yellow solid: 0.43 g (77%), m.p. 142
o
1
C. H NMR (600 MHz, DMSO) δ 8.78 (s, 1H, pyrazol-5-H), 8.54 (s, 1H,
pyrimidyl-2-H), 7.92 (s, 1H, pyrazol-3-H), 7.87 (dd, J = 15.6, 8.7 Hz, 4H,
4-Cl-Ph-2,6-2H; 4-CF -Ph-3,5-2H), 7.59 (d, J = 8.7 Hz, 2H, 4-Cl-Ph-3,5-2H),
3
7.48 (d, J = 8.4 Hz, 2H, 4-CF -Ph-2,6-2H), 6.90 (s, 1H, pyrimidyl-5-H). Anal.
3
Calcd (%) for C H ClF N O : C, 55.51; H, 2.79; N, 12.95. Found: C, 55.56; H,
20
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4
2
2.76; N, 12.92.
Synthesis of 3-((6-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)pyrimidin-
4-yl)oxy)-5-methylisoxazole, 30. (General procedure for compounds 28-31)
(Figure 5)
To a solution of C-1 (0.4 g, 1.3 mmol) and potassium carbonate (0.36 g, 2.6
mmol) in 20 mL of DMF was added 5-methylisoxazol-3-ol (0.13 g, 1.3 mmol).
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The reaction mixture was then heated to 100 C for 2 h, and monitored by TLC
until the reaction was completed. The reaction mixture was poured into water
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and extracted with ethyl acetate. The organic phase was washed successively
with water and saturated brine, dried, filtered, and evaporated under reduced
pressure. The residue was purified via silica gel chromatography with ethyl
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acetate/60−90 C petroleum ether (1:8 v/v) as eluent to obtain 0.38 g
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compound 30 as a white solid: 0.38 g (79%), m.p. 207.1 C. H NMR (600
MHz, DMSO) δ 8.75 (s, 1H, pyrimidyl-2-H), 8.62 (d, J = 2.7 Hz, 1H,
pyrazol-5-H), 7.85 (d, J = 9.0 Hz, 2H, 4-Cl-Ph-2,6-2H), 7.69 (s, 1H,
oxazolyl-H), 7.58 (d, J = 9.0 Hz, 2H, 4-Cl-Ph-3,5-2H), 6.53 (d, J = 2.7 Hz, 1H,
pyrazol-4-H), 6.00 (s, 1H, pyrimidyl-5-H)), 2.41 (s, 3H, CH ). Anal. Calcd (%)
3
for C H ClN O : C, 55.22; H, 3.27; N, 18.94. Found: C, 55.26; H, 3.23; N,
17
12
5
3
18.99.
Fungicidal Assay.
Each of the test compounds (4 mg) was first dissolved in 5 mL of
acetone/methanol (1:1, v/v), and then 5 mL of water containing 0.1% Tween
80 was added to generate a 10 mL stock solution of concentration 400 mg/L.
Serial test solutions were prepared by diluting the above solution (testing
range 3.13−400 mg/L).
Evaluations of fungicidal activity of the synthesized compounds against
cucumber downy mildew (CDM) was performed as follows: cucumber seeds
(Cucumis sativus L.) were grown to the one-leaf and one-heart stage, and then
the test solution was sprayed on the host plant with a homemade sprayer.
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After 24 h, the leaf of host plant was inoculated with Sporangium suspension of
the fungus Pseudoperonospora cubensis cultured by Shenyang Sinochem
Agrochemicals R&D Co. Ltd. (Shenyang, China) at a concentration of 5 × 105
spores/mL using a PS289 Procon Boy WA double action 0.3 mm airbrush (GSI,
Tokyo, Japan). The cucumber plants were stored in a humidity chamber (24 ±
o
o
1 C, RH > 95%, dark) and then transferred into a greenhouse (18−30 C, RH >
50−60%) 24 h after infection. Three replicates were carried out. The activity of
each compound was estimated by visual inspection after 7 d, and screening
results were reported in the range from 0% (no control) to 100% (complete
control). The inhibitory activity (%) was estimated as [(viability of the blank
control − viability of the treatment)/viability of the blank control] × 100. The
EC50 values were calculated by Duncan’s new multiple range method using
DPS version 14.5. The fungicidal test results of compounds 1−31 against CDM
are listed in Tables 1−5.
RESULTS AND DISCUSSION
1
Synthesis. The synthesized compounds were characterized by H NMR and
13
elemental analyses, and some compounds were further characterized by C
NMR and MS. The chemical structure of lead compound 7 was unequivocally
determined by X-ray crystallography (Figure 3). All spectral and analytical data
were consistent with the assigned structures.
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Structure−Activity Relationships (SAR).
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Discovery of Lead Compound 4
Initially, to verify the feasibility of our design concept, the starting material,
(4-chlorophenyl)hydrazine hydrochloride, was employed to obtain the key
intermediate 1-(4-chlorophenyl)-1H-pyrazol-3-ol, the crucial moiety of
pyraclostrobin. Then the obtained intermediate was used to replace the
methoxy acrylate moiety of azoxystrobin, to achieve primary compound 1
(Table 1). The bioassay results indicated that the synthesized compound only
had weak activity (EC > 400 mg/L) against CDM, and hardly any bioactivity
50
against other tested market targets wheat powdery mildew (WPM), southern
rust (SR), and cucumber anthracnose (CA). Next, considering the structure
feature, we tried to changing the substituent position of cyanogen by using
3-hydroxybenzonitrile and 4-hydroxybenzonitrile to synthesize compounds 2
and 3. However, these two compounds both didn’t show improved activity
(EC > 400 mg/L) against CDM, so did against the other diseases. Then we
50
selected 4-chlorophenol as the probe to design compound 4 by means of
usual optimization strategy around phenyl ring. Then, we replaced the cyanide
group with the chlorine atom to get the compound 4, fortunately, it had better
activity (EC = 167.21 mg/L) against CDM than the first three compounds. So
50
compound 4 (Table 1) was regarded as the lead compound to carry out further
optimization on phenyl ring targeting CDM.
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2
2
2
2
2
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Optimization of Lead Compound 4
Compound 4 was conducted optimization from 4 aspects, including the
electronic properties, spatial characteristics of the substituent groups, changes
of substituent position and numbers of substituents. Firstly, we changed the
substituent group of para-position according to the the electronic properties.
We synthesized six compounds, compounds 5-8 with the electron-withdrawing
groups, 9-10 with the electron-donating groups (Table 2). We could find that
the compounds 5-8, which had the electron-withdrawing groups, all showed
higher bioactivity than lead compound 4. Although the improvement in activity
of the compounds 5 and 6 (replaced with fluorine and bromine atoms
respectively) was not relatively obvious, compounds 7 and 8 (substituted with
strong electron-withdrawing groups CF and NO respectively) exhibited a
3
2
sharply increased efficacy compared to the lead compound 4, especially
compound 7 (EC = 1.22 mg/L) displayed significantly higher bioactivity than
50
commercial fungicides diflumetorim (EC50 = 23.06 mg/L), flumorph (EC50
=
7.77 mg/L), and nearly equal effect to cyazofamid (EC50 = 1.01 mg/L). The
reasons why compound 7 had excellent bioactivity were listed as below: CF3
group usually provides a very strong positive contribution to biological
activities;28 there existed the unique properties of the fluorine atom, such as
high thermal stability and lipophilicity.29 These indicated that
electron-withdrawing groups possibly have positive effect on activity,
especially the strong electron-withdrawing substituent. While compound 9 with
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2
2
3
3
3
81
Rn of CH , a weak electron-donating substituent, had hardly any fungicidal
3
82
83
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85
86
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95
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99
00
01
02
activity (EC50 > 400 mg/L), however, compound 10 with Rn of OCH , a high
3
electron-donating substituent, showed much better activity (EC50 = 57.24
mg/L) versus the lead compound 4 (EC50 = 167.21 mg/L). Secondly,
compound 11 with Rn of t-Bu was synthesized to explore the influence of
spatial effect. Surprisingly, the results displayed that the presence of a larger
group probably could not produce negative influence as usual rather than
positive influence on activity. Thirdly, two compounds were synthesized to
evaluate the effect of the substituent position on fungicidal activity using the
chlorine atoms as probes. We changed the position of single chlorine atom to
meta-position and ortho-position of the phenyl ring to obtain compounds 12
and 13, these two compounds both exhibited higher fungicidal activity than the
lead compound 4 (29.57 and 26.08 mg/L, respectively, versus 167.21 mg/L),
indicating meta-position and ortho-position are both helpful to enhance activity
and could be selected as potential lead compounds for further optimization in
future studies. Finally, we introduced one more or two chlorine atoms into
other positions of phenyl ring, while keeping the 4 position fixed as chlorine.
Compounds 14-16 were prepared. The assay result exhibited that compound
14 with Rn of 2,4-Cl showed almost equal activity (EC = 174.35 mg/L) to the
2
50
compound 4; while the fungicidal activity of compounds 15 and 16 decreased
sharply, which suggested that the increase of substituent numbers probably
brings negative influence on bioactivity. Consequently, based on the significant
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contribution of CF group in compound 7 and similar contribution of 2,4-Cl
3
2
groups in compound 14, compound 17 with Rn of 2-Cl-4-CF was further
3
designed and synthesized, to our disappointment, compound 17 did not
express satisfactory control as we anticipated; meanwhile, compound 18
bearing two CF groups didn’t work well either, not embodying the synergistic
3
effect of two dominant groups. So far, the result of the optimization of
compound 4 was identification of compound 7 with a para-Cl group on the left
phenyl ring and a para-CF group on the right phenyl ring as the optimized
3
structure, the second lead compound with greatly improved fungicidal activity.
Effect of Substituents of Pyrimidine Ring and Linker between Pyrimidine
and Phenyl Groups on Fungicidal Activity
To determine if changing the substituents of pyrimidine and the linker between
pyrimidine and phenyl groups would bring enhanced fungicidal activity, we
synthesized and screened a series of compounds 19-26 (Table 3). First of all,
we used lead compound 7 as template for further optimization, and kept Rn
group fixed as 4-CF , while changing R , R , X in turn to synthesize
3
1
2
compounds 19-21. When CH group was introduced into R and R position to
3
1
2
get the compounds 19 and 20 respectively, the bioactivity both reduced greatly.
So did replacing O with NH for changing linker (compound 21). When Rn was
4-OCH , neither replacement of R with CH nor replacement of X with NH
3
2
3
resulted in dramatical reduction of activity. However, when Rn was 4-CH , the
3
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3
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25
above mentioned substitution of R and X both result in outstanding activity
2
26
27
28
29
30
31
32
33
34
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36
37
38
39
40
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42
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46
enhancement. On the basis of the positive information, we further synthesized
compound 26 bearing both R of CH and X of NH with hope to find higher
2
3
activity compound than compound 25, even than compound 7, but the results
went contrary to our wishes. Generally speaking, the effect of substituent of
pyrimidine ring and linker between pyrimidine and phenyl groups on fungicidal
activity mostly depends on Rn group of phenyl ring.
Activity of Different Position of Pyrimidine Ether Group Attached to
Pyrazole Ring
To investigate the effect of different position of pyrimidine ether group attached
to pyrazole ring on the activity of molecules, compound 27 was designed and
synthesized (Table 4). The activity decreased obviously (EC50 > 400 mg/L)
versus compound 7 (EC = 1.22 mg/L). The poor result showed that when we
50
changed attached position of pyrimidine ether group to pyrazole ring from
3-position to 4-position, the bioactivity diminished dramatically.
Activity of Different Heterocycles Attached to Pyrimidine Ring
To primarily evaluate if replacing the right side phenyl ring with a
nitrogen-containing heterocycle would change bioactivity of intact molecules,
we synthesized a series of compounds 28-31 (Table 5). The compounds 29
and 31 relating to pyridinyl substituted with CF and pyridazinonyl had hardly
3
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3
3
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3
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58
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any bioactivity. On the contrary, the compounds 28 and 30, whose heterocyclic
groups were pyridin-2-yl and 5-CH -isoxazol-3-yl respectively, both exhibited
3
superior bioactivity, although still less than compound 7. The result suggested
that various kinds of nitrogen-containing heterocycles might have different
influence on the biological activity of compounds, further detailed studies are in
progress.
On the basis of data presented in Tables 1−5, a clear-cut, well-defined
relationship between chemical structure and biological activity had taken
shape by examining the effect of the electronic properties, the spatial
characteristics, the substituted position and numbers, substituents of
pyrimidine ring, linker between pyrimidine and phenyl groups, different position
of pyrimidine ether group attached to pyrazole ring, different heterocycles
attached to pyrimidine ring. The para-position single CF -substituted phenyl
3
derivative, compound 7, exhibited significantly improved bioactivity compared
to some commercial varieties. Compound 25 (Rn = 4-CH , X = NH, R = R =
3
1
2
H) was a good lead compound for further modification. Single
electron-withdrawing substituent on the para-position of phenyl ring and the
3-position where the pyrimidine ether group was attached to pyrazole ring
might improve fungicidal activity effectively.
Above all, we can conclude that compound 7 is the optimal structure with
desired activity. It offers a control with an EC50 value of 1.22 mg/L against
CDM, displaying significantly higher bioactivity than commercial fungicides
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69
diflumetorim, flumorph, and nearly equal effect to cyazofamid, which is a
promising candidate for future development. Further synthesis of analogues,
structure optimization studies, and field trials of compound 7 are in progress.
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SUPPORTING INFORMATION
Characterization for intermediates B-1, C-1, C-2, C-3, E, F, and compounds
1-6, 8-26, 28, 29, 31. This material is available free of charge via the Internet at
http://pubs.acs.org. The atomic coordinates for compound 7 have been
deposited at the Cambridge Crystallographic Data Centre. CCDC ID: 1946262
contains the supplementary crystallographic data for this Article. These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
AUTHOR INFORMATION
Corresponding Author
*(A.G.) Tel: +86-(0)24-85869278; E-mail: guanaiying@sinochem.com.
*(C.L.) Tel: +86-(0)24-85869078; E-mail: liuchangling@vip.163.com.
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Chemical Society (ACS): Washington, D.C., 1995; pp 979, 1145.
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FIGURE CAPTIONS
Figure 1. An overview of the design of new arylpyrazole pyrimidine ether
derivatives
Figure 2. Synthetic route to compounds 1-26
Figure 3. X-ray single-crystal diffraction of compound 7
Figure 4. Synthetic route to compound 27
Figure 5. Synthetic route to compounds 28-31
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TABLES
Table 1. Chemical Structures and Fungicidal Activity of Arylpyrazole
Pyrimidine Ether Derivatives (compounds 1 to 4)
N
N
Cl
N
Rn
N
O
O
compound
Rn
EC (mg/L)
95% da
/ b
50
1
2
3
2-CN
3-CN
4-CN
4-Cl
>400
>400
>400
167.21
23.06
7.77
/ b
/ b
4
(lead 1)
17.52-1595.67
16.13−32.96
6.48−9.32
0.62−1.63
diflumetorim
flumorph
cyazofamid
1.01
a
b
Confidence limit. The value could not be measured accurately.
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Table 2. Chemical Structures and Fungicidal Activity of Arylpyrazole
Pyrimidine Ether Derivatives (compounds 5 to 18)
N
N
R
N
Rn
N
O
O
compound
R
Rn
4-Cl
4-F
EC (mg/L)
95% da
17.52-1595.67
49.27-72.76
59.25-95.76
1.04-1.42
20.92-28.59
/ b
50
4
(lead 1)
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
167.21
59.87
75.32
1.22
24.45
>400
57.24
54.25
29.57
26.08
174.35
>400
5
6
4-Br
7
(lead 2)
4-CF3
4-NO2
4-CH3
4-OCH3
4-t-Bu
8
9
10
11
12
13
14
15
16
17
18
47.00-69.72
45.11-65.24
25.90-33.77
22.91-29.69
12.99-2339.93
/ b
3-Cl
2-Cl
2,4-Cl2
3,4-Cl2
2,4,6-Cl3
2-Cl-4-CF3
4-CF3
>400
/ b
182.78
100-400
23.06
7.77
11.25-2970.68
/ b
16.13−32.96
6.48−9.32
0.62−1.63
CF3
diflumetorim
flumorph
cyazofamid
1.01
a
b
Confidence limit. The value could not be measured accurately.
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Table 3. Chemical Structures and Fungicidal Activity of Arylpyrazole
Pyrimidine Ether Derivatives (compounds 19 to 26)
R1
N
N
Cl
N
N
Rn
O
X
R2
EC50
mg/L)
1.22
>400
>400
25.64
57.24
>400
>400
>400
43.97
3.87
85.76
23.06
7.77
compound
(lead 2)
R1
R2
X
Rn
95% da
(
7
H
CH3
H
H
H
H
H
H
H
H
H
CH3
H
H
CH3
H
H
CH3
H
O
O
O
NH
O
O
NH
O
4-CF3
4-CF3
4-CF3
4-CF3
4-OCH3
4-OCH3
4-OCH3
4-CH3
1.04-1.42
/ b
19
20
21
10
22
23
/ b
22.23-29.57
47.00-69.72
/ b
/ b
/ b
9
24
25
26
O
NH
NH
4-CH3
4-CH3
4-CH3
37.54-51.50
0.46-32.49
64.05-114.83
16.13−32.96
6.48−9.32
0.62−1.63
H
H
CH3
diflumetorim
flumorph
cyazofamid
1.01
a
b
Confidence limit. The value could not be measured accurately.
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Table 4. Chemical Structures and Fungicidal Activity of Arylpyrazole
Pyrimidine Ether Derivatives (compound 27)
CF3
4
3
N
N
Cl
N
O
O
N
Position of Pyrimidine ether
Group Attached to Pyrazole
Ring
EC50
mg/L)
compound
(lead 2)
95% da
(
7
3-position
4-position
1.22
>400
1.04-1.42
/ b
27
a
b
Confidence limit. The value could not be measured accurately.
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