Design, Synthesis, and Structure-Activity Relationship of New Pyrimidinamine Derivatives Containing an Aryloxy Pyridine Moiety

Article abstract of DOI:10.1021/acs.jafc.6b05580

The pyrimidinamine diflumetorim is an ideal template for the discovery of agrochemical lead compounds due to its unique mode of action, novel chemical structure, and lack of reported resistance. To develop a new pyrimidinamine fungicide effective against cucumber downy mildew (CDM), a series of new pyrimidinamine derivatives containing an aryloxy pyridine moiety were designed and synthesized by employing the recently reported intermediate derivatization method (IDM). The structures of all compounds were identified by ¹H NMR, elemental analyses, HRMS, and X-ray diffraction. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against CDM. Compound 9 gave the best activity (EC₅₀ = 0.19 mg/L), which is significantly better than the commercial fungicides diflumetorim, flumorph, and cyazofamid. The relationship between structure and fungicidal activity of the synthesized pyrimidinamines was explored. The study showed that compound 9 is a promising fungicide candidate for further development.

Full text of DOI:10.1021/acs.jafc.6b05580

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Article
Design, Synthesis and Structure-activity Relationship of New
Pyrimidinamine Derivatives Containing an Aryloxy Pyridine Moiety
Aiying Guan, Changling Liu, Wei Chen, FAN YANG, Yong Xie, Jinbo Zhang, Zhinian Li, and Ming-an Wang
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.6b05580 • Publication Date (Web): 25 Jan 2017
Downloaded from http://pubs.acs.org on January 30, 2017
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Page 1 of 41
Journal of Agricultural and Food Chemistry
1 Design, Synthesis and Structure-activity Relationship
2 of New Pyrimidinamine Derivatives Containing an
3 Aryloxy Pyridine Moiety
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Aiying Guan†,‡, Changling Liu*,‡, Wei Chen‡, Fan Yang‡, Yong Xie‡, Jinbo
Zhang‡, Zhinian Li‡, Mingan Wang*,†
† Department of Applied Chemistry, China Agricultural University, Beijing
100193, People’s Republic of China
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‡ 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)10-62734093; E-mail:
wangma@cau.edu.cn)
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ABSTRACT
The pyrimidinamine diflumetorim is an ideal template for the discovery of
agrochemical lead compounds due to its unique mode of action, novel
chemical structure and lack of reported resistance. In order to develop a new
pyrimidinamine fungicide effective against cucumber downy mildew (CDM), a
series of new pyrimidinamine derivatives containing an aryloxy pyridine moiety
were designed and synthesized by employing the recently reported
intermediate derivatization method (IDM). The structures of all compounds
were identified by 1H NMR, elemental analyses, HRMS and X-ray diffraction.
Bioassays demonstrated that some of the title compounds exhibited excellent
fungicidal activities against CDM. Compound 9 gave the best activity (EC50 =
0.19 mg/L), which is significantly better than the commercial fungicides
diflumetorim, flumorph and cyazofamid. The relationship between structure
and fungicidal activity of the synthesized pyrimidinamines was explored. The
study showed that compound 9 is a promising fungicide candidate for further
development.
KEYWORDS: intermediate derivatization method (IDM), fungicidal activities,
cucumber downy mildew, structure-activity relationship
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INTRODUCTION
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Agrochemicals play an important role in modern agriculture by increasing both
crop quality and yield while improving living standards. Fungicides are a major
section of crop protection products, which are applied widely to major crops
such as rice, corn, fruits and vegetables. In 2014 the global market for
fungicides was valued at $16,365 million, equivalent to 25.9% of the global
agrochemical market; this represents an increase of 4.4% in comparison with
2013.1 However, with the widespread application of fungicides, the
development of resistance is inevitable. Based on the report from the
Fungicide Resistance Action Committee (FRAC), fungicides with known
modes of action are classified according to target sites into more than 50
groups. Among these, it was reported that over 40 target sites have already
developed medium to high resistance risk to many familiar classes of
fungicides which involved the vast majority of fungicide structures.2 The
discovery of fungicide candidates with innovative structures is urgently needed
to address this problem. Pyrimidinamines, which act as mitochondrial complex
I electron transport inhibitors (MET I), are one of the few types of fungicides
without reported resistance.2 Diflumetorim is the representative pyrimidinamine
fungicide targeting MET I, its structure is significantly different from
commercially available fungicides, and also different from MET I inhibitors that
are insecticides. More importantly, it has no cross resistance with the existing
conventional fungicides, and is safe to non-target organisms.3a These
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properties suggest that pyrimidinamines may be promising templates for the
discovery of new fungicide candidates.
The diaryl ether moiety is commonly found in many molecules of agricultural
importance such as pyrethroid insecticides, (aryloxy)phenoxypropionate
herbicides and triazole fungicides such as difenoconazole.3 Additionally, the
pyridine moiety is found in several fungicides, insecticides/acaricides and
herbicides.4 The introduction of a pyridine ring in place of a phenyl ring usually
leads to pesticides that have lower toxicity and higher systemicity or
selectivity.5 2-Chloro-5-(chloromethyl)pyridine and substituted nicotinic acids
bearing reactive groups such as Cl, COOH and chloromethyl, are promising
intermediates of low cost and toxicity, which can be readily modified to give
structural diversity.
In this study, we sought to develop new pyrimidinamine derivatives with
improved fungicidal activity by employing intermediate derivatization method
(IDM), a recently reported highly efficient approach to discover agrochemical
candidates.6-20 2-Chloro-5-(chloromethyl)pyridine or 6-chloronicotinic acid
derivatives were used as starting materials to obtain key intermediates which
produced a series of pyrimidinamine derivatives containing an aryloxy pyridine
moiety (Figure 1). The detailed synthesis, bioassay results, and
structure−activity relationships of these compounds are discussed below.
MATERIALS AND METHODS
All chemicals such as starting materials and reagents were commercially
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available (Sinopharm Chemical reagent Co. Ltd., Shanghai, China) and used
without further purification except as indicated. Melting points were determined
on a Büchi M-569 melting point apparatus (Büchi Labortechnik AG, Flawil,
Switzerland) and are uncorrected. 1H NMR spectra were recorded with a
Mercury 300 MHz spectrometer (Varian, Palo Alto, CA) with deuterochloroform
as the solvent and tetramethylsilane (TMS) as the internal standard. Elemental
analyses were determined on a Yanaco MT-3CHN elemental analyzer
(Yanaco, Kyoto, Japan). Mass spectra were acquired with an Agilent
Accurate-Mass-Q-TOF MS 6520 system (Agilent Technologies, Milford, MA)
equipped with an electrospray ionisation (ESI) source. X-ray structure
determination was recorded with XtaLAB mini (Rigaku, The Woodlands, TX).
All plant and bacteria materials were obtained from the Agrochemical
Discovery Department in Shenyang Sinochem Agrochemicals R&D Co. Ltd
(Shenyang, China).
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The general synthetic methods for compounds 1-37 are shown in Figures 2, 3
and 5-9 and their structures are listed in Tables 1-4. The silica gel
chromatography was performed with a column of 254 mm x 26 mm i.d.
(Synthware glass Co. Ltd., Beijing, China) using 100-140 mesh silica gel
(Sinopharm Chemical reagent Co. Ltd., Shanghai, China).
Synthesis of
5-chloro-N-((6-(4-chlorophenoxy)pyridin-3-yl)methyl)-6-ethylpyrimidin-4-
amine, 26. (General procedure for compounds 1, 2, 25 and 26) (Figure 2)
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Synthesis of 6-(4-chlorophenoxy)nicotinonitrile (M-1, R = Cl)
Sodium hydride (1.03 g, 70%, 30 mmol) was added into a solution of
4-chlorophenol (2.57 g, 20 mmol) in 30 mL of DMF, the reaction mixture was
stirred at room temperature for
4
h, followed by addition of
6-chloronicotinonitrile (2.76 g, 20 mmol), and then the reaction mixture was
heated to 100 oC for another 10 h. After reaction completion, the mixture was
poured into water and extracted with ethyl acetate. The extract was dried over
anhydrous magnesium sulfate and concentrated under reduced pressure to
give intermediate M-1 as a pale brown solid: 4.27 g (93%).
Synthesis of (6-(4-chlorophenoxy)pyridin-3-yl)methanamine (M-2, R = Cl)
To a solution of M-1 (2.31 g, 10 mmol), Raney nickel (1.0 g) and 10 mL of 25%
aqueous ammonia in 50 mL ethanol, hydrogen was introduced, then the
reaction mixture was stirred at room temperature for 3-15 h and monitored by
TLC until the reaction was complete, Raney nickel was filtered, and the
solution was concentrated under reduced pressure to give M-2 as a jade-green
sticky liquid: 2.55 g (95%).
To a solution of M-2 (0.24 g, 1.0 mmol) and potassium carbonate (0.21 g, 1.5
mmol) in 10 mL DMF was added 4,5-dichloro-6-ethylpyrimidine (0.16 g, 1.0
mmol), prepared according to literature methods.21,22 Then the reaction
o
mixture was heated to 80 C for 2 h, and monitored by TLC until the reaction
was complete. The reaction mixture was poured into water and extracted with
ethyl acetate. The organic phase was washed successively with water and
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saturated brine, dried, filtered and evaporated under reduced pressure. The
residue was purified via silica gel chromatography with ethyl acetate/60-90 °C
petroleum ether (1:3, v/v) as eluent to obtain 0.28 g compound 26 as a white
solid: 0.28 g (75%), m.p. 86 oC. 1H NMR (300MHz, CDCl3) δ 1.31 (t, J=7.5Hz,
3H, CH2CH3), 2.80 (q, 2H, CH2CH3), 4.68 (d, J=6.0 Hz, 2H, CH2), 5.71 (bs, 1H,
NH), 6.91 (d, J=8.4Hz, 1H, pyridine 3-H), 7.07 (d, J=8.7Hz, 2H, Ph-2,6-2H),
7.34 (d, J=8.7Hz, 2H, Ph-3,5-2H), 7.72 (dd, J=8.4,2.7Hz, 1H, pyridine 4-H),
8.16 (s, 1H, pyridine 6-H), 8.44 (s, 1H, pyrimidine 2-H). Anal. Calcd (%) for
C18H16Cl2N4O: C, 57.61; H, 4.30; N, 14.93. Found: C, 57.53; H, 4.33; N, 14.89.
HRMS m/z 374.0698 [M + H]+ (calcd [M + H]+ 374.0701).
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Synthesis of
5-chloro-N-(2-(6-(4-chlorophenoxy)pyridin-3-yl)ethyl)-6-methylpyrimidin-
4-amine, 9. (General procedure for compounds 3-24) (Figure 3)
Synthesis of methyl 6-(4-chlorophenoxy)nicotinate (M-3, R = Cl)
To a solution of 4-chlorophenol (25.6 g, 0.2 mol) in 350 mL DMF was added
70% sodium hydride (103 g, 3.0 mol) in portions. The reaction mixture was
stirred for 4 h at room temperature, and then methyl 6-chloronicotinate (34.2 g,
0.2 mol) was added in portions. Next the reaction temperature was raised to
100 oC and maintained for 10 h, and monitored by TLC until the reaction was
complete. The resulting solution was poured into water and extracted with
ethyl acetate. The organic phase was successively washed with water and
saturated brine, dried, filtered and evaporated under reduced pressure, the
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cooled residue was filtered and washed with petroleum ether, to obtain
intermediate M-3 as a brown solid: 42.0 g, m.p. 65 oC.
Synthesis of (6-(4-chlorophenoxy)pyridin-3-yl)methanol (M-4, R = Cl)
To a solution of M-3 (52.6 g, 0.2 mol) in 500 mL anhydrous ether was added
dropwise 65% Red-Al (74.5 g, 0.24 mol) in toluene at 0 oC. The reaction
mixture was stirred for 4 h at room temperature, cooled to 0 oC, and 10%
sodium hydroxide solution prepared fresh was added dropwise until the
reaction solution was clarified. Then the reaction temperature was raised to 35
oC to react for 2 h, and monitored by TLC until the reaction was complete. The
solution was poured into water and extracted with ethyl acetate. The organic
phase was successively washed with water and saturated brine, dried, filtered
and evaporated under reduced pressure. The residue was purified via silica
gel chromatography with ethyl acetate/60-90 °C petroleum ether (1:3, v/v) as
eluent to obtain M-4 as a white solid: 42.2 g, m.p. 101 oC.
Synthesis of 5-(chloromethyl)-2-(4-chlorophenoxy)pyridine (M-5, R = Cl)
To a solution of M-4 (23.5 g, 0.1 mol) in 350 mL dichloromethane was
o
dropwise added thionyl chloride (17.9 g, 0.15 mol) at 0 C. The reaction
mixture was stirred for 4 h at room temperature, and monitored by TLC until
the reaction was complete, excess thionyl chloride was evaporated and the
residue was poured into water and extracted with ethyl acetate. The organic
phase was successively washed with water, saturated sodium bicarbonate
solution and saturated brine, dried, filtered and evaporated under reduced
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pressure, to obtain M-5 as a white solid: 22.8 g, m.p. 79 oC.
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Synthesis of 2-(6-(4-chlorophenoxy)pyridin-3-yl)acetonitrile (M-6, R = Cl)
To a solution of sodium cyanide (2.69 g, 55 mmol) dissolved in 300 mL
dimethyl sulfoxide was added M-5 (13.9 g, 50 mmol) and 18-Crown-6 (0.69 g,
2.63 mmol) at 40 °C. The reaction mixture was raised to 80 oC to react for 2 h,
and monitored by TLC until the reaction was complete. The residue was
poured into water, extracted with toluene, the organic phase was successively
washed with water and saturated brine, dried, filtered and evaporated under
reduced pressure. The residue was purified via silica gel chromatography with
ethyl acetate/60-90 °C petroleum ether (1:3, v/v) as eluent to obtain M-6 as a
white solid: 11.2 g, m.p. 101 oC.
Synthesis of 2-(6-(4-chlorophenoxy)pyridin-3-yl)ethanamine (M-7, R = Cl)
To a solution of M-6 (2.44 g, 10 mmol), Raney nickel (1.0 g) and 10 mL of 25%
aqueous ammonia in 50 mL ethanol was introduced hydrogen gas, then the
reaction mixture was stirred at room temperature for 3-15 h and monitored by
TLC until the reaction was complete. Raney nickel was filtered, and the
solution was concentrated under reduced pressure to give M-7 as a jade-green
sticky liquid: 2.30 g (95%).
To a solution of M-7 (0.25 g, 1.0 mmol) and potassium carbonate (0.21 g, 1.5
mmol) in 10 mL DMF was added 4,5-dichloro-6-methylpyrimidine (0.16 g, 1.0
mmol). Then the reaction temperature was raised to 80 oC and maintained for
2 h, and monitored by TLC until the reaction was complete. The mixture was
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poured into water and extracted with ethyl acetate. The organic phase was
successively washed with water and saturated brine, then dried, filtered and
evaporated under reduced pressure. The residue was purified via silica gel
chromatography with ethyl acetate/60-90 °C petroleum ether (1:4, v/v) as
1
eluent to obtain compound 9 as a colorless oil: 0.28 g (74%). H NMR
(300MHz, CDCl3) δ 2.46 (s, 3H, CH3), 2.91 (t, J=6.9Hz, 2H, CH2CH2NH), 3.75
(q, 2H, CH2CH2NH), 5.43 (bs, 1H, NH), 6.89(d, J=8.4Hz, 1H, pyridine 3-H),
7.07 (d, J=6.6Hz, 2H, Ph-2,6-2H), 7.35 (d, J=6.6Hz, 2H, Ph-3,5-2H), 7.58 (dd,
J=8.4,2.7Hz, 1H, pyridine 4-H), 8.03 (s, 1H, pyridine 6-H), 8.39 (s, 1H,
pyrimidine 2-H). Anal. Calcd (%) for C18H16Cl2N4O: C, 57.61; H, 4.30; N, 14.93.
Found: C, 57.59; H, 4.26; N, 14.99. HRMS m/z 374.0694 [M + H]+ (calcd [M +
H]+ 374.0701).
The crystal structure of target compound 9 was also determined by X-ray
diffraction analyses. Its crystal structure is shown in Figure 4.
Synthesis of
5-chloro-4-((6-(4-chlorophenoxy)pyridin-3-yl)methoxy)-6-methylpyrimidin
e, 27. (General procedure for compounds 27 and 28) (Figure 5)
To a solution of (6-(4-chlorophenoxy)pyridin-3-yl)methanol (M-4) (0.23 g, 1.0
mmol) and potassium carbonate (0.21 g, 1.5 mmol) in 10 mL DMF was added
4,5-dichloro-6-methylpyrimidine (0.16 g, 1.0 mmol). Then the reaction
temperature was raised to 80 °C and maintained for 2 h, and monitored by TLC
until the reaction was complete. The mixture was poured into water and
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extracted with ethyl acetate. The organic phase was successively washed with
water and saturated brine, dried, filtered and evaporated under reduced
pressure. The residue was purified via silica gel chromatography with ethyl
acetate/60-90 °C petroleum ether (1:4, v/v) as eluent to obtain compound 27
as a colorless oil: 0.28 g (77%). 1H NMR (300MHz, CDCl3) δ 2.43 (s, 3H, CH3)
5.07 (s, 2H, CH2), 6.92 (d, J=8.4Hz, 1H, pyridine 3-H), 7.06 (d, J=8.4Hz, 2H,
Ph-2,6-2H), 7.35 (d, J=8.4Hz, 2H, Ph-3,5-2H), 7.81 (dd, J=8.4,2.1Hz, 1H,
pyridine 4-H), 8.06 (s, 1H, pyridine 6-H), 8.17 (s, 1H, pyrimidine 2-H). Anal.
Calcd (%) for C17H13Cl2N3O2: C, 56.37; H, 3.62; N, 11.60. Found: C, 56.42; H,
3.59; N, 11.68. HRMS m/z 361.0391 [M + H]+ (calcd [M + H]+ 361.0385).
Synthesis of
N-(1-(6-(4-(tert-butyl)phenoxy)pyridin-3-yl)ethyl)-5-chloro-6-ethylpyrimidi
n-4-amine, 30. (General procedure for compounds 29 and 30) (Figure 6)
Compound 30 was obtained according to a literature method as a colorless oil
in 49% yield.23 1H NMR (300MHz, CDCl3) δ 1.26 (t, J=7.5Hz, 3H, CH2CH3),
1.33 (s, 9H, t-Bu), 1.61 (d, J=6.9Hz, 3H, CHCH3), 2.78 (q, 2H, CH2CH3), 5.36
(q, 1H, CHCH3), 5.52 (bs, 1H, NH), 6.87 (d, J=8.4Hz, 1H, pyridine 3-H), 7.05 (d,
J=6.9Hz, 2H, Ph-2,6-2H), 7.39 (d, J=6.9Hz, 2H, Ph-3,5-2H), 7.67 (dd,
J=8.4,2.7Hz, 1H, pyridine 4-H), 8.22 (s, 1H, pyridine 6-H), 8.39 (s, 1H,
pyrimidine 2-H). Anal. Calcd (%) for C19H19ClN4O: C, 64.31; H, 5.40; N, 15.79.
Found: C, 64.22; H, 5.44; N, 15.80. HRMS m/z 410.1878 [M + H]+ (calcd [M +
H]+ 410.1873).
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Synthesis
of
1-(5-chloro-6-methylpyrimidin-4-yl)-3-(2-(6-(4-chlorophenoxy)pyridin-3-yl)
ethyl)urea, 31. (Figure 7)
Synthesis of 2-(4-chlorophenoxy)-5-(2-isocyanatoethyl)pyridine (M-10)
To a 0 oC solution of triphosgene (3.5 mL) in dichloromethane (25 mL) and
saturated NaHCO3 (25 mL) was added
2-(6-(4-chlorophenoxy)-pyridin-3-yl)ethanamine (M-7) (0.74 g, 3.0 mmol). The
reaction mixture was stirred at room temperature for 2.5 h and then the layers
are separated. The organic layer was dried over anhydrous MgSO4 and
concentrated under reduced pressure to half volume. Dichloromethane (20 mL)
was added to obtain M-10 as a solution in dichloromethane.
To a 0 oC solution of 5-chloro-6-methylpyrimidin-4-amine (0.28 g, 2.0 mmol) in
dichloromethane (5 mL) was added isocyanate M-10 prepared above and then
N,N-diisopropylethylamine (DIPEA) (3 mL).24 The reaction mixture was stirred
at room temperature for 1 h and then diluted with ethyl acetate and washed
with saturated NH4Cl and brine. The organic layer was dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The residue was
purified via silica gel chromatography with ethyl acetate/60-90 °C petroleum
ether (1:2, v/v) as eluent to obtain compound 31 as a white solid: 0.33 g (40%).
1H NMR (300MHz, CDCl3) δ 2.48 (s, 3H, CH3), 2.73 (t, J=6.9Hz, 2H,
NHCH2CH2), 3.46-3.51 (m, 2H, NHCH2CH2), 4.92(bs, 1H, NHCH2CH2), 6.85 (d,
J=8.4Hz, 1H, pyridine 3-H), 7.03 (d, J=8.1Hz, 2H, Ph-2,6-2H), 7.33 (d, J=8.1Hz,
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2H, Ph-3,5-2H), 7.54 (d, J=7.2Hz, 1H, pyridine 4-H), 7.96 (s, 1H, pyridine 6-H),
8.32 (s, 1H, pyrimidine 2-H). Anal. Calcd (%) for C19H19ClN4O: C, 64.37; H,
5.30; N, 15.79. Found: C, 64.31; H, 5.40; N, 15.79. HRMS m/z 417.0755 [M +
H]+ (calcd [M + H]+ 417.0759).
Synthesis
of
5-Chloro-N-(2-(2-(4-chlorophenoxy)pyridin-3-yl)ethyl)-6-ethylpyrimidin-4-
amine, 35. (General procedure for compounds 32-35) (Figure 8)
The procedures for preparing intermediates (M-11 to M-15) and desired
compound 35 were analogous to those for the corresponding intermediates
(M-3 to M-7) and compound 9, only replacing the starting materials, methyl
6-chloronicotinate
and
4,5-dichloro-6-methylpyrimidine,
with
methyl
2-chloronicotinate (1.71 g, 10 mmol) and 4,5-dichloro-6-ethylpyrimidine (1.76 g,
10 mmol) respectively.
5-Chloro-N-(2-(2-(4-chlorophenoxy)pyridin-4-yl)ethyl)-6-ethylpyrimidin-4-
amine, 37. (General procedure for compounds 36 and 37) (Figure 9)
The procedures for preparing intermediates (M-16 to M-20) and desired
compound 37 were analogous to those for the corresponding intermediates
(M-3 to M-7) and compound 9, only replacing the starting materials, methyl
6-chloronicotinate
and
4,5-dichloro-6-methylpyrimidine,
with
ethyl
and
2-chloroisonicotinate
(1.86 g, 10 mmol)
4,5-dichloro-6-ethylpyrimidine(1.76 g, 10 mmol) respectively.
Fungicidal assay
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Each of the test compounds (4 mg) was first dissolved in 5 mL
acetone/methanol (1:1, v/v), 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, then the
test solution was sprayed on the host plant with a home-made sprayer. 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 5x105
spores/mL using PS289 Procon Boy WA double action 0.3 mm airbrush (GSI,
Tokyo, Japan). The cucumber plants were stored in a humidity chamber (24±1
oC, RH>95%, dark) and then transferred into a greenhouse (18-30 oC,
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 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] x 100.
The ED50 values were calculated by Duncan's new multiple range method
using DPS version 14.5.
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The fungicidal test results of compounds 1-37 against CDM are listed in Tables
1-4.
RESULTS AND DISCUSSION
Synthesis. According to the schemes shown in Figures 2-9, 37 title
compounds were synthesized with yields of 40-80%. Chemical structures of
compounds 1-37 are shown in Tables 1-4. The synthesized compounds were
characterized by 1H NMR and elemental analyses/HRMS. The chemical
structure of lead compound 9 was unequivocally determined by x-ray
crystallography (Figure 4). All spectral and analytical data were consistent with
the assigned structures.
Structure-Activity Relationships (SAR).
Discovery of lead compounds 3 and 4
Initially, in order to verify the feasibility of our design concept, mimicking the
skeleton of diflumetorim, the starting materials, phenol and
6-chloronicotinonitrile, were employed to obtain the key intermediate
(6-phenoxypyridin-3-yl)methanamine, from which we obtained compounds 1
and 2. These compounds can be considered as diflumetorim analogs in which
the phenyl moiety is replaced with a pyridinyl moiety. The bioassay results
indicated that the synthesized compounds had activity against four important
fungal diseases, CDM, cucumber grey mold (CGM), wheat powdery mildew
(WPM) and southern corn rust (SCR),25 particularly against CDM. The activity
of compound 1 (R1 = CH3) against CDM was very weak (EC50 > 400 mg/L)
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compared with diflumetorim (EC50 = 23.06 mg/L), however, compound 2 (R1 =
C2H5) displayed activity equal to diflumetorim (EC50 = 23.17 mg/L). On the
basis of these results, CDM was selected as the test target for optimization.
Next, taking inspiration from the structure of insecticide flufenerim, which is
similar to diflumetorim,26 we synthesized compounds 3 and 4 with Alk =
CH2CH2 (Table 1). These two compounds exhibited higher fungicidal activity
than the corresponding analogs with Alk = CH2 (7.33 mg/L and 7.02 mg/L
respectively versus 23.06 mg/L), which encouraged us to synthesize additional
analogs.
Optimization of lead compounds 3 and 4
Using compounds 3 and 4 as a starting point for additional analogs, we next
turned our attention to modifications in the phenyl ring including changes of
substituent position, numbers of substituents, the electronic properties and
spatial characteristics of the substituent groups (Table 2). First, six compounds,
5-10, were synthesized to evaluate the position effect of the substituent on
fungicidal activity using the chlorine atoms as probes. When a single chlorine
was present in the ortho-position of phenyl ring (compounds 5 and 6), there
was no improvement in fungicidal activity. When a single chlorine was present
in the meta-position of phenyl ring (compounds 7 and 8), the fungicidal activity
decreased significantly. When a single chlorine was present in the
para-position (compounds 9 and 10), we observed a significant increase in
fungicidal activity; compounds 9 and 10 gave much lower EC50 values of 0.19
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mg/L and 2.65 mg/L, respectively, versus initial leads 3 and 4 (7.33 mg/L and
7.02 mg/L), especially compound 9 displayed superior control to the
commercial fungicides flumorph and cyazofamid, indicating that single
substitution at the para-position probably has a positive effect on bioactivity.
Next, we further selected typical electron-donating groups CH3 and OCH3, and
electron-withdrawing group CF3 to carry out some fine modification on
para-position of phenyl ring to investigate the electronic properties of
substituents. We synthesized six compounds, 11 and 12 with the electron
donating group (CH3), 13 and 14 with the electron donating group (OCH3), 15
and 16 with the electron withdrawing group (CF3) respectively (Table 2). The
bioassay results showed that these six compounds 11 to 16 were less
efficacious than compounds 9 and 10 (3.13 - 11.65 mg/L versus 0.19 mg/L,
2.65 mg/L), indicating that higher electron donating or withdrawing group has
possibly a negative effect on bioactivity. Then in order to assess the effect of
substituent numbers specifically relating to double substituted phenyl on
fungicidal activity, we employed some low cost and commonly used phenol
intermediates bearing two substituents to prepare compounds 17 to 24 (Table
2). Compound 18 with Rn of 2-CH3-4-Cl showed low fungicidal activity with
30.25 mg/L EC50 and the other compounds of this type 17, 19 to 23 were also
less active, with EC50 values ranging from 3.75 mg/L to 10.44 mg/L. However,
compound 24 (Table 2) with Rn = 2-Cl-4-CF3 showed promising activity (EC50
of 1.10 mg/L) which is approaching of compound 9 and may be considered for
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exploring new compounds with improved activity. So far, the result of the
optimization of compounds 3 and 4 is identification of compound 9 with para-Cl
group on phenyl ring as the optimized structure, the third lead compound with
greatly improved fungicidal activity.
Effect of linker between pyrimidine and pyridine groups on fungicidal
activity
To determine if changing the linker between pyrimidine and pyridine groups
(X-Alk) would bring enhanced fungicidal activity, we synthesized and screened
a series of compounds 25 to 31 (Table 3). When CH2CH2 was replaced with
CH2 on Alk and keeping the X group fixed as NH, both compounds 25 which
gave EC50 of 7.91 mg/L and 26 which showed EC50 of 5.79 mg/L were much
less efficacious than compound 9 which gave EC50 of 0.19 mg/L. These results
were consistent with the conclusion obtained above. When introducing O-CH2
into X-Alk instead of NH-CH2CH2, both compounds 27 and 28 exhibited a
sharply reduced efficacy compared with the lead compound 9 (more than 400
mg/L for compound 27, 137.8 mg/L for compound 28 versus 0.19 mg/L for
compound 9). The branched Alk in diflumetorim was employed in compounds
29 and 30 with Alk = CH(CH3). The replacement of CH2 with CH(CH3) did not
enhance fungicidal activity. The introduction of t-Bu into the para-position on
phenyl suggests that the presence of a group with large spatial effect probably
leads to considerable reduction in activity. A possible explanation for the lower
activity associated with large substituents is that such substituents would block
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the interaction of target enzyme with these bulky compounds.10 Additionally,
we considered a urea bridge, an extensively utilized moiety in herbicides.3c We
designed NH(CO)NH substructure for X group based on compound 9 to
achieve compound 31. However, disappointedly, compound 31 had hardly any
fungicidal activity with a very high EC50 value of more than 400 mg/L.
Activity of different position of pyrimidinamine group attached to
pyridine ring
To investigate the effect of different position of pyrimidinamine group attached
to pyridine ring on the activity of intact molecules, six positional isomers were
designed and synthesized (Table 4). Generally speaking, when
pyrimidinamine group was attached to the 3-position of the pyridine ring
(compounds 32 to 35), the fungicidal activity indicated the lowest, followed by
4-position analogues 36 and 37, showing obviously higher activity especially
compound 36 with EC50 of 6.49 mg/L, but still much lower than compound 9. In
addition, we noted that compounds with CH3 on R1 were much more active in
contrast with their counterparts of C2H5 in this series. The poor results of
compounds 32-37 in Table 4 suggested that when the pyrimidinamine group
was attached to the pyridine ring at 3- or 4-position, the fungicidal activity
diminished dramatically in this class of compounds.
Based on data presented in Tables 1-4, a clear-cut, well-defined relationship
between chemical structure and biological activity has taken shape by
examining the effect of the substituted position, the numbers of substituents,
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the electronic properties and spatial characteristics of the substituent groups
on phenyl ring, linker between pyrimidine and pyridine groups, and the
different position of pyrimidinamine group attached to pyridine ring. The
para-position single chlorine substituted phenyl derivative, compound 9,
showed significantly improved fungicidal activity compared to the
commercialized controls. Compound 24 with Rn of 2-Cl-4-CF3 is a good
candidate for further exploration of new compounds with improved activity.
Variation in the linker between pyrimidine and pyridine groups did not enhance
fungicidal activity, while the 5-position where pyrimidinamine group is attached
to pyridine ring provided optimal activity.
From the above we can conclude that compound 9 is the optimal structure with
desired activity. It offers a control with EC50 value of 0.19 mg/L against CDM,
significantly higher than commercial fungicides diflumetorim, flumorph and
cyazofamid. Compound 9, which has also shown activities against CSR, WPM
and RB in addition to CDM,25 is a promising candidate for further development.
This study demonstrates the effectiveness of our design concept by using
intermediate derivatization method to discover bioactive compounds. The
discovery of new pyrimidinamine fungicides may delay the development of
resistance and contribute to resistance management. Further synthesis of
analogs, structure optimization studies and field trials of compound 9 are in
progress.
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ACKNOWLEDGEMENT
We thank Dr. Mark Dekeyser (Canada) for assistance with manuscript
preparation.
SUPPORTING INFORMATION
Characterization for intermediates M-1, 3-7, 11-20, and compounds 1-8, 10-25,
28, 29, 32-37. This material is available free of charge via the Internet at
http://pubs.acs.org. The atomic coordinates for compound 9 have been
deposited at the Cambridge Crystallographic Data Centre. CCDC ID: 1501756
contains the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
446 AUTHOR INFORMATION
447
448
449
450
451
Corresponding Author
*(M.W.) Tel: +86-(0)10-62734093. E-mail: wangma@cau.edu.cn.
*(C.L.) Tel: +86-(0)24-85869078. Fax: +86-(0)24-85869137. E-mail:
liuchangling@vip.163.com.
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FIGURE CAPTIONS
Figure 1. An overview of the design of new pyrimidinamine derivatives
containing an aryloxy pyridine moiety
Figure 2. Synthetic route to compounds 1, 2, 25 and 26
Figure 3. Synthetic route to compounds 3-24
Figure 4. X-ray single-crystal diffraction of compound 9.
Figure 5. Synthetic route to compounds 27 and 28
Figure 6. Synthetic route to compounds 29 and 30
Figure 7. Synthetic route to compound 31
Figure 8. Synthetic route to compounds 32-35
Figure 9. Synthetic route to compounds 36 and 37
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TABLES
Table 1. Chemical Structures and Fungicidal Activity of Pyrimidinamine
Derivatives Containing Aryloxy Pyridine Moiety (compounds 1 to 4)
compound
R1
Alk
EC50 (mg/L)
95% da
b
1
CH3
C2H5
CH3
CH2
CH2
>400
23.17
7.33
/
2
15.86-33.86
3.33-16.12
3.12-15.80
16.13-32.95
3
CH2CH2
CH2CH2
4
C2H5
7.02
diflumetorim
23.06
flumorph
7.77
1.01
6.48-9.32
0.62-1.63
cyazofamid
a confidence limit. b the value could not be measured accurately.
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Table 2. Chemical Structures and Fungicidal Activity of Pyrimidinamine
Derivatives Containing Aryloxy Pyridine Moiety (compounds 5 to 24)
compound
R1
Rn
EC50 (mg/L)
7.33
95% da
3 (Lead 1)
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
H
3.33-16.12
3.12-15.80
3.27-52.39
17.75-39.26
4 (Lead 2)
H
2-Cl
7.02
5
13.10
26.40
>400
6
2-Cl
b
7
3-Cl
/
b
8
3-Cl
>400
/
9 (Lead 3)
4-Cl
0.19
0.14-0.26
1.61-4.35
10
4-Cl
2.65
b
11
4-CH3
3.13-6.25
5.50
/
12
4-CH3
3.57-8.50
3.75-8.16
9.26-14.66
13
4-OCH3
4-OCH3
4-CF3
5.54
14
11.65
3.13-6.25
3.13-6.25
9.44
b
15
/
b
16
4-CF3
/
17
2-CH3-4-Cl
2-CH3-4-Cl
2,4-Cl2
2,4-Cl2
2,5-Cl2
2,5-Cl2
2-Cl-4-CF3
2-Cl-4-CF3
3.34-26.65
19.62-46.65
3.15-26.35
3.93-27.72
4.67-9.37
2.33-6.04
4.57-9.16
0.80-1.52
16.13-32.96
6.48-9.32
0.62-1.63
18
30.25
9.11
19
20
10.44
6.61
21
22
3.75
23
6.47
24
1.10
diflumetorim
flumorph
cyazofamid
23.06
7.77
1.01
a confidence limit. b the value could not be measured accurately.
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Table 3. Chemical Structures and Fungicidal Activity of Pyrimidinamine
Derivatives containing Aryloxy Pyridine Moiety (compounds 25 to 31)
EC50
(mg/L)
compound
R1
X
Alk
R
95% da
9 (Lead 3)
CH3
CH3
NH
NH
NH
O
CH2CH2
CH2
Cl
Cl
Cl
Cl
Cl
H
0.19
0.14-0.26
3.97-15.77
4.02-8.36
25
7.91
26
C2H5
CH3
CH2
5.79
b
27
CH2
>400
137.84
18.76
69.54
>400
23.06
7.77
/
28
29
C2H5
C2H5
C2H5
O
CH2
51.51-368.85
11.87-29.66
40.44-119.59
NH
NH
CH(CH3)
30
CH(CH3) t-Bu
Cl
b
31
CH3 NH(CO)NH CH2CH2
/
diflumetorim
flumorph
cyazofamid
16.13-32.96
6.48-9.32
0.62-1.63
1.01
a confidence limit. b the value could not be measured accurately.
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