Design, synthesis and antifungal activity of novel furancarboxamide derivatives

Article abstract of DOI:10.1016/j.ejmech.2016.04.060

Twenty-seven novel furancarboxamide derivatives with a diphenyl ether moiety were synthesized and evaluated for their antifungal activity against Rhizoctonia solani, Botrytis cirerea, Valsa Mali and Sphaceloma ampelimum. Antifungal bioassay results indicated that most compounds had good or excellent fungicidal activities for R. solani and S. ampelimum at 20 mg L^-1. Among synthesized compounds, compound 18e showed a greater inhibitory effect against S. ampelimum, with half maximal effective concentration (EC₅₀) values of 0.020 mg L^-1. This strong activity rivals currently used commercial fungicides, such as Boscalid and Carbendazim, and has great potential as a lead compound for future development of novel fungicides.

Full text of DOI:10.1016/j.ejmech.2016.04.060

Accepted Manuscript
Design, synthesis and antifungal activity of novel furancarboxamide derivatives
Fang Wen, Hong Jin, Ke Tao, Taiping Hou
PII:
S0223-5234(16)30353-1
10.1016/j.ejmech.2016.04.060
EJMECH 8575
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 22 September 2014
Revised Date: 19 April 2016
Accepted Date: 22 April 2016
Please cite this article as: F. Wen, H. Jin, K. Tao, T. Hou, Design, synthesis and antifungal activity of
novel furancarboxamide derivatives, European Journal of Medicinal Chemistry (2016), doi: 10.1016/
j.ejmech.2016.04.060.
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ACCEPTED MANUSCRIPT
Graphical abstract
O
O
R1
R2
R
R
N
H
R3
O
Diphenyl ether
N-phenyl-3-furancarboxamide
O
R1
N
H
O
R3
R2
O
R
Target compounds

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Design, synthesis and antifungal activity of novel
furancarboxamide derivatives
Fang Wen a, Hong Jin b, *, Ke Tao b, *, Taiping Hou b
a
Key Laboratory of Green Chemistry and Technology of Ministry of Education,
College of Chemistry, Sichuan University, Chengdu, 610064, China
b Key Laboratory of Bio-Resource and Eco-environment of Ministry of Education,
College of Life Sciences, Sichuan University, Chengdu, 610064, China
*Corresponding author:
E-mail: jinhong@scu.edu.cn; taoke@scu.edu.cn
Phone No: 86-28-854105611
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ABSTRACT
Twenty-seven novel furancarboxamide derivatives with a diphenyl ether moiety were
synthesized and evaluated for their antifungal activity against Rhizoctonia solani,
Botrytis cirerea, Valsa mali and Sphaceloma ampelimum. Antifungal bioassay results
indicated that most compounds had good or excellent fungicidal activities for
Rhizoctonia solani and Sphaceloma ampelimum at 20 mg L-1. Among synthesized
compounds, compound 18e showed a greater inhibitory effect against Sphaceloma
ampelimum, with half maximal effective concentration (EC50) values of 0.020 mg L-1.
This strong activity rivals currently used commercial fungicides, such as Boscalid and
Carbendazim, and has great potential as a lead compound for future development of
novel fungicides.
Keywords: Furancarboxamides; Synthesis; Antifungal activity; Diphenyl ether
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1. Introduction
Fungal infections cause a persistent burden on human, animal and plants health
worldwide [1-7]. Since the 1970s, chemical control of agricultural fungal diseases
was mainly achieved by several classes of chemicals, including carboxamides,
methoxyacrylates, pyrimidinamines and triazoles. [8-10]. Among them, carboxamide
fungicides have played an important role in the fungicide market [11,12], with the
ability to inhibit the growth of pathogens and can cause their eventual death by
interfering with the pathogen respiration systems [13,14]. One class of the
carboxamide fungicides are furancarboxamide fungicides, such as Fenfuram,
Furancarbanil and Methfuroxam (Fig. 1) [15]. The furancarboxamide fungicides
harbor effective antifungal activities [16-18], however fungicide resistance is
beginning to emerge in fungal populations [19,20].
Past research has demonstrated that the diphenyl ether derivatives with biological
activities are found in a number of natural products, and they have pharmacologically
powerful properties [21-22], such as antifungal, antibiotic, antimitotic and
immunosuppressive activities [23-26].
In our previous work, many diphenyl ether derivatives were synthesized and
found to have good antibacterial activities [27-28]. Recently, on the basis of the
principle of “splicing-up” bioactive substructures we synthesized a class of
nicotinamide derivatives containing a diphenyl ether moiety [29]. Bioassays indicated
that the nicotinamide derivatives had better antifungal activities than Boscalid. To
extend our research work on developing furancarboxamides [30], based on the
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principle of splicing-up bioactive substructures, we exchanged a phenyl group with a
more potent diphenyl ether moiety in the present work (Fig. 2).
A series of novel furancarboxamide derivatives with a diphenyl ether moiety were
synthesized and subsequently tested for their antifungal activity against Rhizoctonia
solani, Botrytis cirerea, Valsa mali and Sphaceloma ampelimum. To the best of our
knowledge, this is the first report of furancarboxamide derivatives with a diphenyl
ether moiety with potent controlling effects against R. solani and S. ampelimum.
2. Results and discussion
2.1. Chemistry
The synthesis of intermediates and target compounds was performed as illustrated
in Schemes 1, 2, 3, 4 and Table 1. To synthesize target compounds 17a-17i, 18a-18i
and 19a-19i, two classes of important intermediates were prepared. One class was
compound 4 and another class was compounds 8 and 13. Compound 4 was prepared
in two steps as previously described [31,32]. First, compound 2 was allowed to react
with compound 1 under KOH by condensation reaction to produce compound 3. Then
it was reduced by the combined action of iron and concentrated HCl to produce
compound 4. However, compound 8 was prepared in three steps [33,34]. First,
compound 5 was reacted with chloroactone under C2H5ONa to afford compound 6,
before ring closing under dilute H2SO4 to produce compound 7. Finally, compound 8
was prepared by saponification of compound 7 under dilute NaOH, before being
acidized under dilute HCl.
Another intermediate, compound 13, was prepared in four steps [35]. First,
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compound 10 was prepared by compound 9 reacting with Br2 prior to a reaction with
compound 5 under C2H5ONa to produce compound 11. Subsequently, ring closing
under dilute H2SO4 produced compound 12. Compound 13 was produced by
saponification of compound 12 under dilute NaOH, before being acidized under dilute
HCl.
Finally, furoic acid, compound 8 or 13 was reacted with SOCl2 to obtain
compound 14, 15 or 16 respectively [36]. Then compound 14, 15 or 16 was reacted
with compound 4 by amidation to gain the target compounds 17a-17i, 18a-18i or
19a-19i respectively [37,38].
2.2. Antifungal activities
The results of the in vitro antifungal activity of compounds 17a-17i, 18a-18i,
19a-19i, Boscalid and Carbendazim at 20 mg L-1 against fungus R. solani, V. mali, S.
ampelimum and B. cirerea were listed in Table 2, in which the antifungal activity was
expressed as inhibition percentage.
The results in Table 2 showed that target compounds were active against nearly
four fungi to various extents. Most of the furancarboxamide derivatives showed very
strong activity against R. solani and S. ampelimum. Compounds 18a-18i and 19a-19i
showed the best activity against R. solani and S. ampelimum than the compounds
17a-17i. As could be seen from Scheme 4, there was difference between the two
structures (compounds 18 and 19) with respect to one CH3 group position. However,
the two classes of compounds’ activity was highly comparable indicating that the
influence of the CH3 group in furan ring’ fourth position on antifungal activity is poor
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in the tested strains. Structural differences between group 17 and 18/19 were more
than only presence of CH3 group (two to three, not one). The amide group was at
second position in group 17 where as it was at third position in group 18/19. This
indicated that positioning of amide group in addition to presence of CH3 group/s
affected the antifungal activity. Due to compounds in group 18 and 19’s superior
antifungal activities, with 100 % inhibition of growth at 20 mg L-1 these compounds
,
were selected for further analysis.
As seen in Table 3, some compounds had higher antifungal activity against S.
ampelimum than Boscalid or Carbendazim, and their EC50 values were much smaller
than Boscalid or Carbendazim. For example, compound 18e, with two chlorine atoms
in benzene ring’s second and fourth position, had the greatest antifungal activity in the
group. While in the 19 group, compound 19b, with one fluorine atom in benzene
ring’s fourth position, showed the greatest antifungal activity.
3. Conclusions
In summary, twenty seven furancarboxamide derivatives 17a-17i, 18a-18i and
19a-19i were synthesized and evaluated for their antifungal activity against four plant
pathogenic fungi (R. solani, V. mali, S. ampelimum and B. cirerea). The biological test
results showed that some of the synthesized target compounds exhibited strong
antifungal activity at 20 mg L-1. Most of the furancarboxamide derivatives showed
excellent activity against R. solani and S. ampelimum. Specifically, compounds 18
and 19 (with the exception of 19h) displayed exceptional activity against S.
ampelimum with 100 % growth inhibition. Among them, compound 18e had the
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strongest activity against S. ampelimum (EC50 = 0.020 mg L-1), even stronger than
commercially available Boscalid or Carbendazim. Furthermore, these preliminary
results can aid future development of new and more effective agrochemical fungicides.
Further design and biological evaluation of these compounds is ongoing in our
laboratory.
4. Experimental
4.1. Materials and methods
All the reagents used were commercial and were used without further purification
unless otherwise indicated. Analytical thin-layer chromatography and preparative
thin-layer chromatography were performed with silica gel plates using silica gel 60
GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, Shandong Province, China).
1H NMR spectra were recorded in deuterochloroform solution on a Bruker 400 MHz
spectrometer, using tetramethylsilane (TMS) as an internal standard. IR data were
obtained on a TENSOR Infrared Spectrometer (Bruker) and MS data were obtained
on a MALDI-TOF/TOF Mass Spectrometer (Bruker).
4.2. Synthesis
4.2.1. Synthesis of 2-amine-aryloxybenzenes (4a-4i)
4.2.1.1. Synthesis of 2-nitro-aryloxybenzenes (3a–3i)
KOH (66 mmol) was added to compound 1 (66 mmol) at 90 ℃, and the mixture
was stirred for 15 min. Then compound 2 (60 mmol) was added slowly. The mixture
was stirred for another 2 h at 150 ℃. Finally, the reaction mixture was extracted with
ethyl acetate, and the solvent was removed in vacuum to give compounds 3a-3i in
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yields of 86-98 %.
4.2.1.2. Synthesis of 2-amine-aryloxybenzenes (4a-4i)
To a slurry mixture of iron powder (150 mmol) and compound 3 (50 mmol) in
absolute alcohol (40 mL), a solution of concentrated HCl (5 mL) in absolute alcohol
(10 mL) was added dropwise in 10 min at 80 ℃. Then the mixture was stirred for
another 2 h at 80 ℃. Finally, the reaction mixture was alkalized by NaOH solution
and filtered. The solvent in the collected filtrate was removed in a vacuum to give the
crude product. The crude product was purified using a silica gel chromatography
column to give compounds 4a-4i in yields of 38-51%.
4.2.2. Synthesis of 2, 5-dimethylfuran-3-carboxylic acid (8)
4.2.2.1. Synthesis of ethyl 2-acetyl-4-oxo-pentanoate (6)
After dissolving Na (150 mmol) in absolute alcohol (50 mL), compound 5 (150
mmol) was added and the solution was brought to refluxing temperature and
chloroacetone (150 mmol) was then added over 1 h. After refluxing for another 1 h,
the mixture was cooled, NaCl filtered off and the filtrate distilled and the crude
compound 6 was obtained.
4.2.2.2. Synthesis of ethyl 2,5-dimethylfuran-3-carboxylate (7)
A mixture of compound 6 (100 mmol) and H2SO4 (10 %, 120 mL) were refluxed
for 6 h. Then it was cooled and extracted with diethyl ether. The organic layer was
washed with NaHCO3 solution, dried over anhydrous Na2SO4 and the solvent was
removed in vacuum to afford the crude compound 7.
4.2.2.3. Synthesis of 2,5-dimethylfuran-3-carboxylic acid (8)
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NaOH solution (10 %, 50 mL) was added to compound 7 (50 mmol) and the
mixture was refluxed for 30 min. Then it was cooled, acidized, filtered, washed and
dried to afford compound 8. The pure product was obtained by recrystallization in
petroleum/absolute ethanol (3:2).
4.2.3. Synthesis of 2, 4, 5-trimethylfuran-3-carboxylic acid (13)
4.2.3.1. Synthesis of 3-bromo-2-butanone (10)
To a solution of compound 9 (860 mmol), H2O (500 mL) and KClO3 (120 mmol)
were added Br2 (500 mmol) at 37℃. Then the reaction mixture was stirred at 37℃
for another 1 h. The mixture was extracted with ethyl acetate, and the organic layer
was washed, dried and distillated to afford compound 10.
4.2.3.2. Synthesis of ethyl 2-acetyl-3-methyl-4-oxo-pentanoate (11)
After dissolving Na (150 mmol) in absolute alcohol (50 mL), compound 5 (150
mmol) was added and the solution was brought to refluxing temperature. Compound
10 (150 mmol) was then added over 1 h. After refluxing for another 1 h, the mixture
was cooled, the NaCl filtered off and the filtrate was distilled to obtain the crude
compound 11.
4.2.3.3. Synthesis of ethyl 2,4,5-trimethylfuran-3-carboxylate (12)
A mixture of compound 11 (100 mmol) and H2SO4 (10 %, 120 mL) were refluxed
for 6 h. Then it was cooled and extracted with diethyl ether. The organic layer was
washed, dried and the solvent was removed in vacuum to afford the crude compound
12.
4.2.3.4. Synthesis of 2,4,5-trimethylfuran-3-carboxylic acid (13)
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NaOH solution (10 %, 50 mL) was added to compound 12 (50 mmol) and the
mixture was refluxed for 30 min. Then it was cooled, acidized, filtered, washed and
dried to afford compound 13. The pure product was obtained by recrystallization in
petroleum/absolute ethanol (3:2).
4.2.4. General procedure for the synthesis of carboxylic acid chlorides (14, 15 and
16)
Thionyl chloride (15 mL) was added to furoic acid, compound 8 or 13 (10 mmol),
and the mixture was refluxed for 1 h. Then excess thionyl chloride was removed in
vacuum. The crude product 14, 15 or 16 was obtained and used in the subsequent
reaction without further purification.
4.2.5. General procedure for the synthesis of furancarboxamide derivatives
A mixture of NaOH solution (2 mol L-1, 20 mL), 1,4-dioxane (2 mL) and
compound 4 (5 mmol) was dissolved and cooled to 0 ℃ in an ice bath. While
stirring the mixture, compound 14, 15 or 16 was added slowly. Afterwards, the
mixture was stirred for another 5 h at room temperature. The mixture was then
extracted with ethyl acetate, and the solvent was removed in vacuum. The crude
product was purified by column chromatography on silica gel to give compounds
17a-17i, 18a-18i or 19a-19i in yields of 30–73%. All the compounds were list in
Table 1 and the spectral parameters for 1H NMR, IR and MS were as follows.
4.2.5.1. N-(2-phenoxyphenyl)-2-furancarboxamide (17a). yellow solid, yield: 86.3 %;
1H NMR (400 MHz, CDCl3): δ 8.77 (s, H = 1), 8.57 (dd, J = 8.0 Hz, J = 4.0 Hz, H = 1),
7.46-7.47 (m, H = 1), 7.7.35-7.40 (m, H = 2), 7.22 (d, J = 4.0 Hz, H=1), 7.13-7.18 (m,
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H=2), 7.07-7.10 (m, H = 2), 7.01-7.05 (m, H=1), 6.53 (m, H=1); 13C NMR (400 MHz,
CDCl3): δ 156.42, 156.06, 147.92, 145.98, 144.40, 130.04, 129.36, 124.17, 124.10,
124.04, 120.75, 119.00, 117.59, 115.27, 112.54. IR (KBr, cm-1) νmax: 3407.24 (NH
str.), 1671.38 (C=O str.), 1580.72, 1536.74 (C=C Ar str.), 1209.56 (C-O-C str.); MS
(EI) m/z 280.1 (M+1).
4.2.5.2. N-(2-(4-fluorophenoxy)phenyl)-2-furancarboxamide (17b). yellow solid, yield:
1
81.1 %; H NMR (400 MHz, CDCl3): δ 8.76 (s, H=1), 8.56 (dd, J=8.0 Hz, H=1),
7.48-7.49 (m, H = 1), 7.23 (d, J = 4.0 Hz, H = 1), 7.12-7.16 (m, H=1), 7.00-7.07 (m,
H = 5), 6.81 (dd, J = 8.0 Hz, H = 1), 6.53-6.55 (m, H=1); 13C NMR (400 MHz,
CDCl3): δ 160.45, 158.04, 156.04, 152.06, 152.04, 147.88, 146.40, 144.40, 129.00,
124.19, 123.96, 120.82, 120.71, 120.62, 116.81, 116.73, 116.50, 115.34, 112.58. IR
(KBr, cm-1) νmax: 3396.63 (NH str.), 1665.94 (C=O str.), 1579.59, 1536.28 (C=C Ar
str.), 1202.62 (C-O-C str.); MS (EI) m/z 298.1 (M+1).
4.2.5.3. N-(2-(4-chlorophenoxy)phenyl)-2-furancarboxamide (17c). light yellow solid,
yield: 78.2 %; 1H NMR (400 MHz, CDCl3): δ 8.68 (s, H=1), 8.56 (d, J=8.0 Hz, H=1),
8.47 (d, J=0.8 Hz, H=1), 7.32-734 (m, H=2), 7.23 (d, J=3.6 Hz, H=1), 7.17 (t, H=1),
7.00-7.07 (m, H=3), 6.87 (d, J=8.0 Hz, H=1), 6.54-6.55 (m, H=1); IR (KBr, cm-1) νmax
3406.21 (NH str.), 1670.33 (C=O str.), 1607.47, 1522.83 (C=C Ar str.), 1217.33
(C-O-C str.); MS (EI) m/z 314.1 (M+1).
:
4.2.5.4. N-(2-(2-chlorophenoxy)phenyl)-2-furancarboxamide (17d). light yellow solid,
yield: 80.8 %; 1H NMR (400 MHz, CDCl3): δ 8.82 (s, H =1), 8.58 (d, J = 8.0 Hz, H =
1), 8.48-8.50 (m, H = 2), 7.23-7.29 (m, H = 2), 7.14-7.18 (m, H = 2), 7.07-7.09 (m, H
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= 1), 7.03 (t, H = 1), 6.76 (d, J = 8.0 Hz, H = 1), 6.54-6.55 (m, H = 1); IR (KBr, cm-1)
νmax: 3397.35 (NH str.), 1671.31 (C=O str.), 1587.53, 1537.39 (C=C Ar str.), 1232.02
(C-O-C str.); MS (EI) m/z 314.1 (M+1).
4.2.5.5. N-(2-(2,4-dichlorophenoxy)phenyl)-2-furancarboxamide (17e). pink solid,
yield: 78.4 %; 1H NMR (400 MHz, CDCl3): δ 8.74 (s, H=1), 8.56 (dd, J = 8.0 Hz, J =
1.2 Hz, H = 1), 7.51 (d, J = 2.0 Hz, H = 2), 7.16-7.25 (m, H = 3), 6.99-7.06 (m, H = 2),
6.76 (d, J = 8.0 Hz, H = 1), 6.54-6.56 (m, H = 1); IR (KBr, cm-1) νmax: 3407.35 (NH
str.), 1668.40 (C=O str.), 1585.87, 1525.40 (C=C Ar str.), 1224.89 (C-O-C str.); MS
(EI) m/z 348.1 (M+1).
4.2.5.6. N-(2-(2-tolyloxy)phenyl)-2-furancarboxamide (17f). light brown solid, yield:
79.8 %; 1H NMR (400 MHz, CDCl3): δ 8.88 (s, H=1), 8.58 (dd, J1=8.0 Hz, J2=1.6 Hz,
H=1), 7.49 (s, H=1), 7.29 (dd, J1=8.0 Hz, J2=0.8 Hz, H=1), 7.24 (dd, J1=3.2 Hz,
J2=0.8 Hz, H=1), 7.20 (dd, J1=8.0 Hz, J2=1.2 Hz, H=1), 7.14 (dd, J1=7.6 Hz, J2=1.2
Hz, H=1), 7.11 (dd, J1=7.6 Hz, J2=1.2 Hz, H=1), 6.96-7.00 (m, H=2), 6.66 (dd, J1=8.0
Hz, J2=1.6 Hz, H=2), 2.28 (s, H=3); IR (KBr, cm-1) νmax: 3407.29 (NH str.), 1669.35
(C=O str.), 1586.56, 1525.07 (C=C Ar str.), 1225.76 (C-O-C str.); MS (EI) m/z 294.2
(M+1).
4.2.5.7. N-(2-(3-tolyloxy)phenyl)-2-furancarboxamide (17g). light brown solid, yield:
66.3 %; 1H NMR (400 MHz, CDCl3): δ 8.77 (s, H=1), 8.57 (dd, J1=8.0 Hz, J2=1.6 Hz,
H=1), 7.46 (d, J=0.8 Hz, H=1), 7.25 (t, J=8.0 Hz, H=1), 7.21 (d, J=3.2 Hz, H=1), 7.13
(t, J=8.0 Hz, H=1), 7.03 (t, J=8.0 Hz, H=1), 6.87 (d, J=8.0 Hz, H=1), 6.86-6.89 (m,
H=3), 6.52-6.53 (m , H=1), 2.35 (s, H=3); IR (KBr, cm-1) νmax: 3407.26 (NH str.),
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1672.57 (C=O str.), 1580.69, 1536.31 (C=C Ar str.), 1224.93 (C-O-C str.); MS (EI)
m/z 294.2 (M+1).
4.2.5.8. N-(2-(4-methoxyphenoxy)phenyl)-2-furancarboxamide (17h). orange solid,
yield: 31.2 %; 1H NMR (400 MHz, CDCl3): δ 8.84 (s, H=1), 8.55 (d, J=8.0 Hz, H=1),
7.49 (s, H=1), 7.23 (d, J=3.6 Hz, H=1), 7.10 (t, H=1), 6.98-7.05 (m, H=3), 6.91-6.94
(m, H=2), 6.76 (d, J=8.0 Hz, H=1), 6.53 (m, H=1), 3.82 (s, H=3); IR (KBr, cm-1) νmax
:
3410.49 (NH str.), 1669.69 (C=O str.), 1581.80, 1526.72 (C=C Ar str.), 1207.65
(C-O-C str.); MS (EI) m/z 310.1 (M+1).
4.2.5.9. N-(2-(2-methoxyphenoxy)phenyl)-2-furancarboxamide (17i). light yellow
solid, yield: 71.1 %; 1H NMR (400 MHz, CDCl3): δ 8.97 (s, H=1), 8.53 (d, J=8.0 Hz,
H=1), 7.49 (s, H=1), 7.17-7.24 (m, H=2), 7.07-7.11 (m, H=2), 6.94-6.99 (m, H=3),
6.74 (d, J=8.0 Hz, H=1), 6.54 (m, H=1), 3.82 (s, H=3); IR (KBr, cm-1) νmax: 3418.54
(NH str.), 1685.87 (C=O str.), 1585.17, 1537.06 (C=C Ar str.), 1229.86 (C-O-C str.);
MS (EI) m/z 310.1 (M+1).
4.2.5.10. 2,5-dimethyl-N-(2-phenoxyphenyl)-3-furancarboxamide (18a). brown solid,
yield: 35.5 %; 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J=8.0 Hz, H=1), 7.98 (s, H=1),
7.37 (t, H=2), 7.15 (t, H=2), 7.00-7.05 (m, H=3), 6.88 (d, J=8.0 Hz, H=1), 5.97 (s,
H=1), 2.44 (s, H=3), 2.23 (s, H=3); IR (KBr, cm-1) νmax: 3437.86 (NH str.), 1675.21
(C=O str.), 1584.80, 1524.79 (C=C Ar str.), 1201.23 (C-O-C str.); MS (EI) m/z 308.2
(M+1).
4.2.5.11. N-(2-(4-fluorophenoxy)phenyl)-2,5-dimethyl-3-furancarboxamide (18b).
1
brown solid, yield: 71.2 %; H NMR (400 MHz, CDCl3): δ 8.54 (dd, J1=8.0 Hz,
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J2=1.2 Hz, H=1), 7.97 (s, H=1), 7.35-7.39 (m, H=2), 7.13 (t, H=2), 6.99-7.05 (m,
13
H=3), 6.88 (d, J=8.0 Hz, H=1), 2.55 (s, H=3), 2.23 (s, H=3); C NMR (400 MHz,
CDCl3): δ 162.03, 160.27, 157.86, 155.90, 152.12, 152.10, 150.23, 145.79, 129.70,
124.08, 123.67, 120.65, 120.16, 120.08, 117.04, 116.67, 116.58, 116.44, 103.89. IR
(KBr, cm-1) νmax: 3437.73 (NH str.), 1674.00 (C=O str.), 1584.55, 1524.07 (C=C Ar
str.), 1200.66 (C-O-C str.); MS (EI) m/z 326.1 (M+1).
4.2.5.12. N-(2-(4-chlorophenoxy)phenyl)-2,5-dimethyl-3-furancarboxamide (18c).
1
yellow solid, yield: 68.4 %; H NMR (400 MHz, CDCl3): δ 8.54 (d, J=8.0 Hz, H=1),
7.90 (s, H=1), 7.32 (d, J=8.8 Hz, H=2), 7.17 (t, H=1), 7.03 (t, H=1), 6.98 (d, J=8.8 Hz,
H=2), 6.87 (d, J=8.0 Hz, H=1), 5.97 (s, H=1), 2.56 (s, H=3), 2.24 (s, H=3); 13C NMR
(400 MHz, CDCl3): δ 162.22, 156.14, 155.33, 150.47, 145.18, 130.28, 130.17, 129.14,
124.82, 123.98, 121.01, 119.77, 118.12, 116.73, 104.05, 13.74, 13.46. IR (KBr, cm-1)
νmax: 3440.65 (NH str.), 1675.92 (C=O str.), 1585.41, 1523.30 (C=C Ar str.), 1225.58
(C-O-C str.); MS (EI) m/z 342.1 (M+1).
4.2.5.13. N-(2-(2-chlorophenoxy)phenyl)-2,5-dimethyl-3-furancarboxamide (18d).
1
yellow solid, yield: 64.2 %; H NMR (400 MHz, CDCl3): δ 8.57 (dd, J1=8.0 Hz,
J2=0.8 Hz, H=1), 8.06 (s, H=1), 7.49 (dd, J1=8.0 Hz, J2=1.2 Hz, H=1), 7.23-7.25 (m
H=1), 7.11-7.18 (m, H=2), 6.99-7.04 (m, H=2), 6.79-6.84 (m, H=1), 6.09 (s, H=1),
2.58 (s, H=3), 2.26 (s, H=3); IR (KBr, cm-1) νmax: 3306.50 (NH str.), 1663.62 (C=O
str.), 1585.73, 1532.93 (C=C Ar str.), 1226.29 (C-O-C str.); MS (EI) m/z 342.1 (M+1).
4.2.5.14. N-(2-(2,5-dichlorophenoxy)phenyl)-2,5-dimethyl-3-furancarboxamide (18e).
1
yellow solid, yield: 79.3 %; H NMR (400 MHz, CDCl3): δ 8.55 (d, J=8.0 Hz, H=1),
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7.97 (s, H=1), 7.50 (s, J=2.0 Hz, H=1), 7.20-7.24 (m, H=2), 7.00-7.08 (m, H=1), 6.35
(d, J=8.4 Hz, H=1), 6.75-6.78 (m, H=1), 6.07 (s, H=1), 2.58 (s, H=3), 2.26 (s, H=3);
IR (KBr, cm-1) νmax: 3449.09 (NH str.), 1675.72 (C=O str.), 1584.17, 1523.15 (C=C Ar
str.), 1251.11 (C-O-C str.); MS (EI) m/z 398.1 (M+23).
4.2.5.15. N-(2-(2-tolyloxy)phenyl)-2,5-dimethyl-3-furancarboxamide (18f). brown
1
solid, yield: 73.8 %; H NMR (400 MHz, CDCl3): δ 8.63 (dd, J1=8.0 Hz, J2=0.8 Hz,
H=1), 7.12 (s, H=1), 7.24-7.29 (m, H=1), 7.18 (t, H=1), 7.10 (t, H=1), 6.95-7.02 (m,
H=1), 6.85-6.92 (m, H=3), 5.98 (s, H=1), 2.58 (s, H=3), 2.39 (s, H=3), 2.28 (s, H=3);
IR (KBr, cm-1) νmax: 3449.79 (NH str.), 1674.56 (C=O str.), 1583.89, 1524.28 (C=C Ar
str.), 1252.10 (C-O-C str.); MS (EI) m/z 322.2 (M+1).
4.2.5.16. N-(2-(3-tolyloxy)phenyl)-2,5-dimethyl-3-furancarboxamide (18g). brown
1
solid, yield: 70.2 %; H NMR (400 MHz, CDCl3): δ 8.55 (dd, J1=8.0 Hz, J2=0.8 Hz,
H=1), 7.09 (s, H=1), 7.21-7.24 (m, H=1), 7.14 (t, H=1), 7.01 (t, H=1), 6.91-6.97 (m,
H=1), 6.83-6.89 (m, H=3), 5.97 (s, H=1), 2.56 (s, H=3), 2.37 (s, H=3), 2.26 (s, H=3);
IR (KBr, cm-1) νmax: 3437.94 (NH str.), 1675.64 (C=O str.), 1585.10, 1520.99 (C=C Ar
str.), 1250.86 (C-O-C str.); MS (EI) m/z 322.2 (M+1).
4.2.5.17. N-(2-(4-tolyloxy)phenyl)-2,5-dimethyl-3-furancarboxamide (18h). yellow
1
solid, yield: 42.1 %; H NMR (400 MHz, CDCl3): δ 8.53 (dd, J1=8.0 Hz, J2=1.2 Hz,
H=1), 8.08 (s, H=1), 7.07-7.11 (m, H=1), 6.95-6.99 (m, H=3), 6.89-6.92 (m, H=2),
6.76-6.78 (m, H=1), 6.05 (s, H=1), 3.81 (s, H=3), 2.58 (s, H=3), 2.25 (s, H=3); IR
(KBr, cm-1) νmax: 3445.20 (NH str.), 1672.38 (C=O str.), 1584.89, 1525.20 (C=C Ar
str.), 1259.10 (C-O-C str.); MS (EI) m/z 338.2 (M+1).
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4.2.5.18. N-(2-(2-tolyloxy)phenyl)-2,5-dimethyl-3-furancarboxamide (18i). brown
solid, yield: 59.4 %; 1H NMR (400 MHz, CDCl3): δ 8.52 (s, J=8.0 Hz, H=1), 8.25 (s,
H=1), 7.14-7.18 (m, H=1), 6.97-7.18 (m, H=3), 6.92-6.95 (m, H=2), 6.78 (d, J=8.0 Hz,
H=1), 6.11 (s, H=1), 3.82 (s, H=3), 2.59 (s, H=3), 2.25 (s, H=3); IR (KBr, cm-1) νmax
:
3444.25 (NH str.), 1671.38 (C=O str.), 1585.76, 1524.97 (C=C Ar str.), 1258.42
(C-O-C str.); MS (EI) m/z 338.2 (M+1).
4.2.5.19. 2,4,5-trimethyl-N-(2-phenoxyphenyl)-3-furancarboxamide (19a). yellow
1
solid, yield: 77.2 %; H NMR (400 MHz, CDCl3): δ 8.61 (dd, J1=8.0 Hz, J2=0.8 Hz,
H=1), 8.07 (s, H=1), 7.34 (t, H=2), 7.10-7.18 (m, H=2), 7.01-7.05 (m, H=3), 6.92 (d,
J=8.0 Hz, H=1), 2.55 (s, H=3), 2.14 (s, H=3), 2.04 (s, H=3); IR (KBr, cm-1) νmax
:
3441.54 (NH str.), 1674.10 (C=O str.), 1588.98, 1523.51 (C=C Ar str.), 1215.09
(C-O-C str.); MS (EI) m/z 322.2 (M+1).
4.2.5.20. N-(2-(4-fluorophenoxy)phenyl)-2,4,5-trimethyl-3-furancarboxamide (19b).
1
yellow solid, yield: 61.0 %; H NMR (400 MHz, CDCl3): δ 8.59 (dd, J1=8.0 Hz,
J2=1.2 Hz, H=1), 8.06 (s, H=1), 7.15 (t, H=1), 6.99-7.06 (m, H=3), 6.95-6.98 (m,
H=2), 6.84 (dd, J1=8.0 Hz, J2=1.2 Hz, H=1), 2.49 (s, H=3), 2.16 (s, H=3), 2.06 (s,
H=3); IR (KBr, cm-1) νmax: 3450.70 (NH str.), 1664.76 (C=O str.), 1576.85, 1528.48
(C=C Ar str.), 1199.51 (C-O-C str.); MS (EI) m/z 340.2 (M+1).
4.2.5.21. N-(2-(4-chlorophenoxy)phenyl)-2,4,5-trimethyl-3-furancarboxamide (19c).
1
brown solid, yield: 84.6 %; H NMR (400 MHz, CDCl3): δ 8.60 (d, J=8.0 Hz, H=1),
7.99 (s, H=1), 7.29-7.33 (m, H=2), 7.19 (t, H=1), 7.04 (t, H=1), 6.88-6.96 (m, H=3),
2.56 (s, H=3), 2.16 (s, H=3), 2.04 (s, H=3); IR (KBr, cm-1) νmax: 3445.76 (NH str.),
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1672.61 (C=O str.), 1573.95, 1521.58 (C=C Ar str.), 1221.51 (C-O-C str.); MS (EI)
m/z 356.1 (M+1).
4.2.5.22. N-(2-(2-chlorophenoxy)phenyl)-2,4,5-trimethyl-3-furancarboxamide (19d).
1
yellow solid, yield: 57.9 %; H NMR (400 MHz, CDCl3): δ 8.62 (dd, J1=8.4 Hz,
J2=1.2 Hz, H=1), 8.11 (s, H=1), 7.48 (dd, J1=8.0 Hz, J2=1.6 Hz, H=1), 7.23 (dd,
J1=8.0 Hz, J2=1.6 Hz, H=1), 7.10-7.19 (m, H=2), 6.97-7.03 (m, H=2), 6.78 (dd, J1=8.0
Hz, J2=0.8 Hz, H=1), 2.52 (s, H=3), 2.16 (s, H=3), 2.10 (s, H=3); IR (KBr, cm-1) νmax
:
3444.69 (NH str.), 1675.11 (C=O str.), 1582.89, 1520.59 (C=C Ar str.), 1229.24
(C-O-C str.); MS (EI) m/z 356.1 (M+1).
4.2.5.23.
N-(2-(2,4-dichlorophenoxy)phenyl)-2,4,5-trimethyl-3-furancarboxamide
(19e). yellow solid, yield: 65.0 %; 1H NMR (400 MHz, CDCl3): δ 8.61 (dd, J1=8.0 Hz,
J2=0.8 Hz, H=1), 8.03 (s, H=1), 7.48-7.50 (m, H=1), 7.16-7.22 (m, H=2), 7.00-7.07
(m, H=1), 6.90-6.93 (m, H=1), 6.79-6.82 (m, H=1), 2.57 (s, H=3), 2.17 (s, H=3), 2.10
(s, H=3); IR (KBr, cm-1) νmax: 3446.84 (NH str.), 1676.15 (C=O str.), 1582.53,
1519.71 (C=C Ar str.), 1229.82 (C-O-C str.); MS (EI) m/z 390.1 (M+1).
4.2.5.24. N-(2-(2-tolyloxy)phenyl)-2,4,5-trimethyl-3-furancarboxamide (19f). brown
solid, yield: 60.3 %; 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J=8.0 Hz, H=1), 8.09 (s,
H=1), 7.26 (t, H=1), 7.18 (t, H=1), 7.04 (t, H=1), 6.88-6.99 (m, H=2), 6.80-6.88 (m,
H=2), 2.49 (s, H=3), 2.38 (s, H=3), 2.14 (s, H=3), 2.08 (s, H=3); IR (KBr, cm-1) νmax
:
3445.20 (NH str.), 1676.47 (C=O str.), 1581.45, 1522.30 (C=C Ar str.), 1251.23
(C-O-C str.); MS (EI) m/z 336.2 (M+1).
4.2.5.25. N-(2-(3-tolyloxy)phenyl)-2,4,5-trimethyl-3-furancarboxamide (19g). brown
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solid, yield: 57.4 %; 1H NMR (400 MHz, CDCl3): δ 8.61 (d, J=8.0 Hz, H=1), 8.07 (s,
H=1), 7.22 (t, H=1), 7.16 (t, H=1), 7.02 (t, H=1), 6.88-6.97 (m, H=2), 6.79-6.85 (m,
H=2), 2.47 (s, H=3), 2.34 (s, H=3), 2.17 (s, H=3), 2.05 (s, H=3); IR (KBr, cm-1) νmax
:
3444.54 (NH str.), 1675.25 (C=O str.), 1581.28, 1521.23 (C=C Ar str.), 1250.72
(C-O-C str.); MS (EI) m/z 336.2 (M+1).
4.2.5.26. N-(2-(4-methoxyphenoxy)phenyl)-2,4,5-trimethyl-3-furancarboxamide (19h).
light brown solid, yield: 70.8 %; 1H NMR (400 MHz, CDCl3): δ 8.58 (dd, J1=8.0 Hz,
J2=0.8 Hz, H=1), 8.15 (s, H=1), 7.08-7.12 (m, H=1), 6.99-7.07 (m, H=1), 6.93-6.96
(m, H=2), 6.87-6.90 (m, H=2), 6.77-6.79 (m, H=1), 3.81 (s, H=3), 2.58 (s, H=3), 2.16
(s, H=3), 2.08 (s, H=3); IR (KBr, cm-1) νmax: 3452.37 (NH str.), 1665.34 (C=O str.),
1576.35, 1521.57 (C=C Ar str.), 1211.15 (C-O-C str.); MS (EI) m/z 352.2 (M+1).
4.2.5.27. N-(2-(2-methoxyphenoxy)phenyl)-2,4,5-trimethyl-3-furancarboxamide (19i).
yellow solid, yield: 53.5 %.6; 1H NMR (400 MHz, CDCl3): δ 8.56 (d, J=8.0 Hz, H=1),
8.26 (s, H=1), 7.03-7.17 (m, H=2), 6.96-7.02 (m, H=2), 6.91-6.95 (m, H=2),
6.76-6.78 (m, H=1), 3.82 (s, H=3), 2.57 (s, H=3), 2.16 (s, H=3), 2.10 (s, H=3); IR
(KBr, cm-1) νmax: 3440.71 (NH str.), 1671.36 (C=O str.), 1602.48, 1520.45 (C=C Ar
str.), 1256.57 (C-O-C str.); MS (EI) m/z 352.2 (M+1).
4.3. Biological assay
All synthesized compounds 17a-17i, 18a-18i and 19a-19i were evaluated for their
in vitro antifungal activity. For preliminary screening the antifungal tests of R. solani,
B. cirerea, S. ampelimum and V. mali were carried by using plate growth rate method
[39]. The fungi were obtained from the Institute of Pesticide and Crop Protection,
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ACCEPTED MANUSCRIPT
Sichuan University.
Each tested compound firstly was dissolved in acetone. Then the solution was
diluted with 1‰ Tween 80 solution, added to the sterile PDA medium, mixed to
homogeneity and transferred to sterile Petri dishes to solidify. For primary screening,
compound was used at a concentration of 20 mg L-1. Afterwards, a mycelium agar
disc of the target fungi was placed in the center of PDA plates, and then the plates
were incubated at 26 ℃ in the dark. Inhibition of radial growth was measured after
several days. Growth inhibition was calculated as the percentage of inhibition of
radial growth relative to the control.
Acknowledgments
This work was supported by National Natural Science Foundation of China
(31272068), Hi-Tech Research and Development of China (2011AA10A202-3),
National Key Technology R&D Program of China (2011BAE06B01-23) and Applied
Basic Research Program of Sichuan Province (2014JY0063). We also thank Sichuan
University Analytical and Testing Center for NMR spectroscopic analysis.
Appendix A . Supplementary data
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Table Legends
Table 1. Synthesized furancarboxamide derivatives.
Table 2. Antifungal activities of furancarboxamide derivatives at 20 mg L-1.
Table 3. EC50 values (mg L-1) of compounds 18a-18i and 19a-19i against S.
ampelimum.
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Table 1
Synthesized furancarboxamide derivatives.
Compound
17a
R
Compound R
Compound R
C6H5
18a
18b
18c
18d
C6H5
19a
19b
19c
19d
C6H5
17b
4-FC6H4
4-ClC6H4
2-ClC6H4
4-FC6H4
4-ClC6H4
2-ClC6H4
4-FC6H4
17c
4-ClC6H4
17d
2-ClC6H4
17e
2,4-Cl2C6H3 18e
2,4-Cl2C6H3 19e
2,4-Cl2C6H3
2-CH3C6H4
3-CH3C6H4
4-OCH3C6H4
2-OCH3C6H4
17f
2-CH3C6H4
3-CH3C6H4
18f
2-CH3C6H4
3-CH3C6H4
19f
17g
18g
19g
17h
4-OCH3C6H4 18h
2-OCH3C6H4 18i
4-OCH3C6H4 19h
2-OCH3C6H4 19i
17i
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Table 2
Antifungal activities of furancarboxamide derivatives at 20 mg L-1.
Inhibition of growth (%)
Compound
R. solani
59
V. mali
58
48
58
15
5
S. ampelimum
B. cirerea
42
47
17a
17b
17c
17d
17e
17f
65
43
34
73
53
32
33
70
13
29
23
12
16
12
33
5
10
15
44
74
21
17g
17h
17i
9
2
5
69
30
39
34
29
30
17
51
26
91
100
100
100
100
100
56
18a
18b
18c
18d
18e
18f
88
56
80
28
88
38
92
23
89
85
45
59
100
100
25
31
18g
18h
18i
78
94
83
84
78
90
88
26
43
39
26
24
31
7
100
100
100
100
100
100
100
47
32
19
34
31
22
18
19a
19b
19c
19d
19e
19f
78
80
46
54
100
100
24
33
19g
19h
80
92
88
94
26
35
13
91
96
25
100
100
38
20
19i
Boscalid
74
Carbendazim
100
3 / 4

ACCEPTED MANUSCRIPT
Table 3
EC50 values (mg L-1) of compounds 18a-18i and 19a-19i against S. ampelimum.
S. ampelimum
EC50(mg L-1)
S. ampelimum
EC50(mg L-1)
Compound
Compound
0.050
0.230
18a
18b
19a
19b
0.160
0.200
0.170
0.030
0.020
-
0.300
0.060
0.030
-
18c
19c
18d
19d
18e
19e
18f
19f
0.210
0.510
0.280
0.740
0.070
-
18g
19g
18h
19h
0.250
33.540
18i
19i
Boscalid
Carbendazim
4 / 4