Design, synthesis, fungicidal activity and molecular docking studies of novel 2-((2-hydroxyphenyl)methylamino)acetamide derivatives

Article abstract of DOI:10.1016/j.bmc.2019.03.040

A series of novel 2-hydroxyphenyl substituted aminoacetamides was designed by molecular hybridization of the aminoacetamide scaffold and 2-hydroxyphenyl motif. The target compounds were synthesized and their fungicidal activities were evaluated. Some of the target compounds showed excellent antifungal activities against S. sclerotiorum and P. capsici. Significantly, compounds 5e displayed the most potent activity against S. sclerotiorum with EC₅₀ = 2.89 μg/mL, which was lower than that of commercial chlorothalonil. The systematic studies provided strong confidence that the hydroxyl group and the carbonyl group are crucial for the fungicidal activity. Molecular docking studies suggest that SDH enzyme could be one of the potential action targets of our compounds.

Full text of DOI:10.1016/j.bmc.2019.03.040

Accepted Manuscript
Design, Synthesis, Fungicidal Activity and Molecular Docking Studies of Novel
2-((2-Hydroxyphenyl)methylamino)acetamide Derivatives
Zilong Tang, Xinxing Li, Yuan Yao, Yongcun Qi, Ming Wang, Ningning Dai,
Yuhao Wen, Yichao Wan, Lifen Peng
PII:
S0968-0896(19)30160-9
https://doi.org/10.1016/j.bmc.2019.03.040
BMC 14832
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 January 2019
17 March 2019
19 March 2019
Please cite this article as: Tang, Z., Li, X., Yao, Y., Qi, Y., Wang, M., Dai, N., Wen, Y., Wan, Y., Peng, L., Design,
Synthesis,
Fungicidal
Activity
and
Molecular
Docking
Studies
of
Novel
2-((2-
Hydroxyphenyl)methylamino)acetamide Derivatives, Bioorganic & Medicinal Chemistry (2019), doi: https://
doi.org/10.1016/j.bmc.2019.03.040
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Design, Synthesis, Fungicidal Activity and Molecular Docking
Studies of Novel 2-((2-Hydroxyphenyl)methylamino)acetamide
Derivatives
Zilong Tanga,b,*, Xinxing Lib, Yuan Yaob, Yongcun Qib, Ming Wangb,
Ningning Daib, Yuhao Wenb, Yichao Wana, Lifen Penga
a Key Laboratory of Theoretical Organic Chemistry and Functional Molecular,
Ministry of Education, Hunan University of Science and Technology, Xiangtan
411201, People’s Republic of China
b Hunan Provincial key Laboratory of Controllable Preparation and Functional
Application of Fine Polymers, School of Chemistry and Chemical Engineering,
Hunan University of Science and Technology, Xiangtan 411201, People’s Republic of
China
Abstract: A series of novel 2-hydroxyphenyl substituted aminoacetamides was
designed by molecular hybridization of the aminoacetamide scaffold and
2-hydroxyphenyl motif. The target compounds were synthesized and their fungicidal
activities were evaluated. Some of the target compounds showed excellent antifungal
activities against S. sclerotiorum and P. capsici. Significantly, compounds 5e
displayed the most potent activity against S. sclerotiorum with EC50 = 2.89 µg/mL,
which was lower than that of commercial chlorothalonil. The systematic studies
provided strong confidence that the hydroxyl group and the carbonyl group are crucial
for the fungicidal activity. Molecular docking studies suggest that SDH enzyme could
be one of the potential action targets of our compounds.
Keywords: aminoacetamide; synthesis; fungicidal activity; succinate dehydrogenase
inhibitor; molecular docking
*Corresponding author at: Key Laboratory of Theoretical Organic Chemistry and
Functional Molecular, Ministry of Education, Hunan University of Science and
Technology, Xiangtan, 411201, PR China (Z. Tang).
1

E-mail addresses: zltang67@aliyun.com
1. Introduction
Fungal pathogens can not only cause significant yield reductions but also greatly
affect food security.1 For example, some fungal pathogens such as Fusarium species
can produce terrible mycotoxins like fumonisins, trichothecenes and zearalenone in
cereal crops.2 To guard against fungal pathogens, one traditional way is to use
synthetic fungicides, which are both economical and effective tool for controlling
most fungal pathogens in agriculture. Therefore, the development of new fungicides
to efficiently control plant fungi is in great demand.
Since the first succinate dehydrogenase inhibitor (SDHI) fungicide [Fungicide
Resistance Action Committee (FRAC)]3 Carboxin was commercialized in 1966, SDHI
fungicides have been widely employed to control various destructive plant fungi,
including those effecting cereals, grape, stone fruit, kiwifruit, strawberry, apple and
cucurbit, and have become the fastest growing in view of new compounds produced
and launched into the market.4 SDHI fungicides, most belonging to amide
compounds,5 interfere the respiration of plant pathogens by inhibiting the activity of
complex II enzymes.6 But, as is well-known, many fungal pathogens have trend to
develop resistance to fungicides, particularly to those compounds acting at a single
defined target site.4,7 The situation of drug resistances become more and more serious
along with the use of fungicides. Recently, it is reported that the widespread and
frequent utilization of SDHI fungicides over the past several decades has given rise to
the occurrence of resistance in fungi.3,5,8 As a consequence, the discovery of new
SDHI fungicides to overcome the resistance of fungal pathogens is highly desirable.
Various aminoacetamide derivatives (Fig. 1) have been documented in the past
decades with a wide range of biological property, such as inhibitors of
acetylcholinesterase (AChE),9 AChE and butyrylcholinesterase (BChE),10
porcupine,11 cholestery ester transfer;12 opioid receptor agonists,13
anti-inflammatory,14 bacterial and fungicidal,15 antiprion,16 anticonvulsant,17
antimalarial activity,18 anticancer19 and anti-HIV-1 activity.20 On the other hand,
2

Wuest et al.21 reported that promysalin (3, Fig. 1), a Pseudomonad secondary
metabolite, displayed selective inhibition of Pseudomonas aeruginosa by targeting
succinate dehydrogenase. The results showed that the 2-hydroxyphenyl moiety within
the promysalin structure played a very important role in its bacterial activity. Likely,
fungicide antimycin A (4), which inhibits the activity of complex III of the
mitochondrial electron transport chain by engaging the ubiquinone-binding site,
contains a 2-hydroxyphenyl group.21,22 Stokker et al.23 found that
2-(hydroxyphenyl)methylamines possessed antihypertensive, saluretic as well as
antiinflammatory activity. In our previous paper we also reported that
2-hydroxyphenyl substituted 1,3,4-thiadiazoles exhibited fungicidal activity.24
Molecular hybridization which involves the combination of two or more distinct
bioactive units is one of the successful strategies for the development of drug
discovery.25,26 Hence, as our continuous program24,27,28 aimed at the discovery and
development of novel SDHI fungicides with high fungicidal potency, we designed a
series of novel 2-hydroxyphenyl substituted aminoacetamides hybrids (5) (Fig. 1) by
combining the aminoacetamide scaffold and 2-hydroxyphenyl moiety. Herein, we
present the synthesis, fungicidal activity, and molecular docking studies about these
hybrid compounds. The synthetic route to the target compounds 5 is shown in Scheme
1.
Fig. 1. Representative examples of aminoamides, promysalin, antimycin A, and the
design of the target compounds.
3

Scheme 1. Synthesis of compounds 5 and 7. Reagents and conditions: (a) Et3N, dry
CH2Cl2, 0 °C, 1 h; (b) K2CO3, DMF/THF (v:v = 1:1), 65 °C, 4 h.
2. Results and discussion
2.1.Chemistry
According to Scheme 1, the intermediates 2-bromoacetamides 6 were firstly
prepared by reaction of arylamines with 2-bromoacetyl bromide in 70-97% yields.
Then, the target compounds 5a-5v were synthesized by selective N-alkylation of
2-hydroxylbenzylamine with 2-bromoacetamides 6. Furthermore, to elucidate the
effect of the hydroxyl and the carbonyl group on the fungicidal activity, compounds
7a-7b were similarly produced in 58-64% yields. Compounds 8a-8b were synthesized
by reduction of 5e-f with LiAlH4 in THF (Scheme 2).
Scheme 2. Synthesis of compound 8.
2.2. Antifungal activity
According to standard method NY/T1156.5–2006,28 the in vitro fungicidal
activities of the prepared compounds 5a–5v against G. zeae , P. capsici , S.
sclerotiorum, B. cinerea, R. solani and M. oryzae were evaluated at the concentration
of 50 µg/mL or 25 µg/mL, adopting the mycelium growth rate test method, and using
4

chlorothalonil 6 as the reference compound. The activities were expressed as
inhibition rate (%) and summarized in Table 1. All compounds showed activities
against the tested fungi, and some of them exhibited excellent activities. Both
compounds 5e and 5f showed 100% activities against S. sclerotiorum at 25 µg/mL,
which are higher than that of chlorothalonil (84.9%). Compounds 5e displayed 100%
activity against P. capsici at 25 µg/mL and 100% activity against M. oryzae at 50
µg/mL, and both are higher than that of the reference compound. Compounds 5f
showed 100% activity against P. capsici and B. cinerea at 50 µg/mL, which are all
higher than that of chlorothalonil. It also exhibited 94.4% and 87.2% activities against
M. oryzae and R. solani, respectively. So, it can be seen that compounds 5e and 5f
have broad activities. Compounds 5n displayed 87.7% activity against S. sclerotiorum
at 50 µg/mL. Compounds 5v demonstrated 81.0% and 79.2% activities against G.
zeae and P. capsici, respectively. In addition, generally speaking, the compounds with
the amide nitrogen atom connected with a benzyl group (n = 1) were more active than
those with an aryl group (n = 0). The logP of the compounds has effect on the
antifungal activities. The compounds with smaller logP, like 5e, 5f, 5g (n = 1), and 5n,
5o, 5p (n = 0) show relatively higher activities than those of the corresponding type
compounds. It indicates that the less lipophilic compounds are more active. The
methoxy group on the phenyl ring showed the highest activity and abided the order of
ortho > para > meta for both n = 1 and n = 0. Also, chloride impacted the effect on
the activity followed the order of para > ortho for both cases. The influence of the
methyl group followed the order of para > meta > ortho for n = 1, whereas para >
ortho > meta for n = 0.
Table 1
Fungicidal activities of compounds 5a-5v
Inhibition rate (%)a
Compd.
5a
n
1
1
Ar
LogP
1.93
Gz
Pc
Ss
Bc
Rs
Mo
13.9
(9.8)
16.7
16.7
(11.5)
22.2
37.0
(12.3)
18.5
50.0
(19.4)
38.1
23.3
(9.3)
22.1
Ph
33.3
16.7
5b
2-CH3C6H4
2.42
5

(7.3)
33.3
(22.0)
17.6
66.7
(46.3)
47.2
(24.4)
27.8
(7.3)
32.4
23.5
41.7
(12.2)
33.3
(12.2)
41.7
(19.5)
10.7
33.3
(9.8)
27.8
(19.5)
10.7
48.1
12.0
48.4
22.2
22.6
81.0
(7.7)
38.9
(6.2)
30.9
(13.9)
26.2
(11.1)
32.3
64.3
(38.9)
100.0
(83.3)
33.3
(11.1)
32.3
22.6
38.1
(13.9)
61.9
(27.8)
73.8
(27.8)
33.3
64.3
(36.1)
14.3
(8.3)
33.3
38.1
9.5
(5.8)
29.1
(4.7)
37.9
75.6
(34.9)
87.2
(68.6)
19.8
(5.8)
29.3
12.1
17.4
(5.8)
23.3
(5.8)
23.3
(8.1)
10.0
29.1
(17.4)
17.4
(4.7)
12.5
21.3
8.2
5c
5d
5e
1
1
1
4-CH3C6H4
3-CH3C6H4
2-CH3OC6H4
2.42
2.42
1.81
16.7
25.0
100.0
(15.4)
25.1
(6.2)
42.9
100.0
(100.0)
100.0
(76.9)
33.3
100.0
(100.0)
100.0
(100.0)
37.0
5f
1
1
4-CH3OC6H4
3-CH3OC6H4
1.81
1.81
94.4
22.2
5g
(15.4)
42.9
(7.4)
42.9
5h
5i
1
1
4-ClC6H4
2-ClC6H4
2.49
2.49
28.6
14.3
7.1
28.6
27.8
18.5
5j
0
0
Ph
1.87
2.35
22.2
27.8
(19.2)
33.3
(12.3)
18.5
5k
2-CH3C6H4
(23.1)
50.0
(12.3)
32.1
5l
0
0
0
4-CH3C6H4
3-CH3C6H4
2-CH3OC6H4
2.35
2.35
1.74
38.9
31.7
44.4
(34.6)
12.5
(17.3)
22.6
5m
5n
50.0
87.7
(23.1)
33.3
(42.3)
12.3
5o
0
4-CH3OC6H4
1.74
22.2
(19.2)
8.3
(7.3)
22.6
5p
5q
5r
5s
5t
0
0
0
0
0
0
0
3-CH3OC6H4
3-CH3CH2C6H4
3,4-(CH3)2C6H3
4-ClC6H4
1.74
2.77
2.84
2.42
2.42
2.86
2.86
24.4
9.1
40.0
38.1
46.7
19.0
18.2
18.8
6.3
50.0
25.0
2.8
12.7
7.0
2-ClC6H4
3.8
25.0
5.6
5u
5v
1-C10H7
7.7
50.0
11.1
21.1
12.5
25.0
37.5
2-C10H7
79.2
43.8
33.3
/
89.3
96.2
94.6
92.6
53.8
6c
(67.6)
(78.6)
(84.9)
(92.9)
(85.2)
(46.2)
a The value measured at the concentration of 50 µg/mL. The value in bracket
measured at concentration of 25 µg/mL. Gz: G. zeae ; Pc: P. capsici ; Ss: S.
sclerotiorum ; Bc: B. cinerea; Rs: R. solani; Mo: M. oryzae .
b LogP: oil-water partition coefficient.
c Chlorothalonil 6 used as reference compound.
As shown in Table 2, the results clearly indicated that the hydroxyl group and the
carbonyl group were crucial for the fungicidal activity. The inhibitory effect against P.
6

capsici, S. sclerotiorum and M. oryzae dropped sharply when the carbonyl group of
compounds (5e, 5f) was reduced to form compounds 8a and 8b. Similarly,
compounds (7a, 7b) resulted from compounds (5e, 5f) by removing the hydroxyl
group showed much lower activity, even lower than those of compounds 8a and 8b. It
seems that the hydroxyl group impact relatively greater effect on the activity than the
carbonyl group. These results validated our hypothesis of the designation of the target
compound. In addition, there exist apparent relationship between the antifungal
activities and logP of the compounds. The compounds 5e, 5f with smaller logP show
relatively higher activities than those of compounds 7a, 7b, 8a and 8b, which
indicates that the less lipophilic compounds are more active.
Table 2
Fungicidal activities of compounds 5e-5f, 7a-7b, 8a-8b (inhibition rate/%a)
Compound
LogPb Gz
Pc
Ss
Bc
Rs
Mo
1.81
1.81
2.20
2.20
66.7
100.0
100.0
64.3
75.6
100.0
5e
47.2
27.6
10.3
100.0
21.4
28.6
100.0
67.6
37.2
100.0
18.2
31.8
87.2
47.2
37.7
94.4
44.4
33.3
5f
7a
7b
2.44
2.44
31.0
24.1
25.0
25.0
46.5
39.5
63.6
50.0
70.5
39.6
55.6
44.4
8a
8b
a The value measured at concentration of 50 µg/mL. Gz: G. zeae ; Pc: P. capsici ; Ss: S.
sclerotiorum ; Bc: B. cinerea; Rs: R. solani; Mo: M. oryzae .
b LogP: oil-water partition coefficient.
7

Table 3 was the second screening of compounds 5e and 5f with excellent activities
against P. capsici, S. sclerotiorum and M. oryzae, and the activities were expressed as
EC50. The EC50 values of 5e and 5f against S. sclerotiorum and M. oryzae were all
lower than chlorothalonil. In particular, compound 5e displayed the best antifungal
activity against S. sclerotiorum, whose EC50 value (2.89 µg/mL) was much lower than
chlorothalonil (5.79 µg/mL). Moreover, considering that chlorothalonil molecule
contains four chorine atoms, we believe that there exist obvious problems of pesticide
halogen residues.4 Therefore, the compounds 5e and 5f we synthesized have obvious
advantages for their high antifungal activity and halogen-free residue, and especially
compounds 5e could be a potential fungicidal candidate against S. sclerotiorum.
Table 3
EC50 value of compounds 5e-5f
EC50 (µg/mL)
Compd.
P. capsici
S. sclerotiorum
M. oryzae
11.78
5e
5f
6a
9.49
2.89
5.34
5.79
7.02
9.25
3.00
33.56
a Chlorothalonil 6 used as reference compound.
2.3. Molecular docking
More recently, Hu4 employed molecular docking method to prove SDH enzyme
to be one of the action targets for their synthesized compound A4 using Carboxin, a
reported SDH inhibitor, as a reference compound. Also, Wuest21 adopted a similar
method to identify SDH enzyme as the action target of promysalin. Hence, to verify
the reasonability of our design of SDHI fungicides, we chose the most active
compound 5e to dock with SDH enzyme29 in the active site using Carboxin as the
reference. Surflex-Dock was used for simulating and evaluating the interactions
between compound 5e and the target protein by an empirical scoring function.30 The
docking results showed that Carboxin and compound 5e could both insert into the
active pocket of SDH adopting similar conformations and locations. Carboxin formed
8

two hydrogen bonds with Tyr58 and Try173 (Fig. 2a, 2b). Beside two hydrogen bonds
formed with Tyr 58 and Try173, compound 5e generated extra three hydrogen bonds
with Arg43, His42 and Hem143 (Fig. 2c, 2d), which were not exhibited in the binding
model of Carboxin with SDH. Among these hydrogen bonds, one was formed by the
hydrogen atom of the hydroxyl group with His42, and another produced by the
oxygen atom with Hem143. This fact may explain the loss of activities of compounds
7a-7b without hydroxyl group. Apparently, these results suggested that SDH enzyme
could be one of the potential action targets for compound 5e, as well as the title
compounds.
Fig. 2. (a) Connolly surface of SDH enzyme complex Ⅱ with Carboxin shown as a
stick model. (b) Hydrogen-bond interaction of Carboxin and amino acid residues near
the ligand. (c) Connolly surface of compound 5e with SDH enzyme complex Ⅱ
shown as a stick model. (d) Hydrogen-bond interaction of compound 5e and amino
acid residues near the ligand.
3. Results and discussion
9

In summary, a class of novel 2-((2-hydroxyphenyl)methylamino)acetamide
derivatives were synthesized, and their fungicidal activities were evaluated in this
study. The bioassay results indicated that some target compounds showed excellent
antifungal activities against S. sclerotiorum and P. capsici . Compounds 5e displayed
the most potent activity against S. sclerotiorum, which was far superior to the
commercial chlorothalonil. The logP of the compounds has effect on the antifungal
activities, and the less lipophilic compounds are more active. In addition, molecular
docking studies suggested that SDH enzyme could be one of the potential action
targets of the title compounds, and thus validated the rationality of our design.
4. Experimental section
4.1 Material and measurements
1H and 13C NMR spectra were recorded on Bruker Avance-500 MHz
spectrometer (500 MHz for 1H and 125 MHz for 13C), using tetramethylsilane (TMS)
as the internal standard. Chemical shift (δ) and coupling constants (J) are given in
ppm and Hertz (Hz), respectively. HRMS were recorded on Waters
UPLC/XEVOQ-TOF LC/MS instrument. Melting points were determined on a
WRS-1B digital melting point instrument and were uncorrected. Column
chromatography was carried out using silica gel (200-300 mesh). Reagents were
purchased from MERYER and Energy Chemical Company (Shanghai, China) as
analytical grades and used without further purification. All anhydrous solvents were
dried by standard procedure.
4.2. General procedure for the synthesis of compounds (5a-5v) and (7a-7b)
Under nitrogen atmosphere, into a 150 mL three-necked round botton flask
equipped with a condenser, 2-bromo-N-phenylacetamide (4.26 g, 20 mmol),
2-(aminomethyl)phenol (2.953 g, 24 mmol), K2CO3 (4.14 g, 30 mmol), DMF/THF
(50 mL, v/v = 1:1) were added with stirring bar. The solution was heated at 65 °C for
4 h (checked by TLC). Then, the solvent was evaporated under reduced pressure.
Water (30 mL) was added to the residue, and the mixture was extracted with ethyl
acetate (30 mL×3). The combined organic solution washed sequentially with water (2
× 40 mL) and saturated brine (2× 40 mL). The organic phase was dried over Na2SO4,
10

filtered. The solvent was evaporated under reduced pressure, and the obtained residue
was purified by silica gel flash chromatography affording product 5j as a white solid.
4.2.1. N-benzyl-2-((2-hydroxybenzyl)amino)acetamide (5a)
White solid, M.p: 107.6-108.4 °C, yield: 69%. 1H NMR (500 MHz, CDCl3) δ:
7.31 (t, J = 7.2 Hz, 2H), 7.23 (t, J = 7.7 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 6.94 (d, J =
7.3 Hz, 1H), 6.74-6.80 (m, 2H), 6.46 (s, 1H), 4.40 (d, J = 5.7 Hz, 2H), 3.90 (s, 2H),
3.22 (s, 2H). 13C NMR (125 MHz, CDCl3) δ: 170.1, 157.4, 137.7, 128.9, 128.9, 128.7
(2C), 127.7 (2C), 127.6, 122.2, 119.3, 116.2, 51.7, 50.4, 43.4. HRMS (ESI) calcd for
C16H19N2O2 [M+H]+ 271.1447, found 271.1441.
4.2.2. 2-((2-hydroxybenzyl)amino)-N-(2-methylbenzyl)acetamide (5b)
White solid, M.p: 142.2-143.8 °C, yield: 64%. 1H NMR (500 MHz, CDCl3) δ:
7.21 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.06-7.03
(m, 2H), 6.95 (d, J = 7.2 Hz, 1H), 6.77-6.81 (m, 2H), 6.27 (brs, 1H, NH), 4.39 (d, J =
5.7 Hz, 2H), 3.93 (s, 2H), 3.25 (s, 2H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ:
170.2, 157.0, 136.1, 135.3, 130.3, 128.9, 128.8, 128.1, 127.6, 125.9, 122.4, 119.2,
115.9, 51.2, 50.1, 41.3, 18.8. HRMS (ESI) calcd for C17H21N2O2 [M+H]+ 285.1603,
found 285.1598.
4.2.3. 2-((2-hydroxybenzyl)amino)-N-(4-methylbenzyl)acetamide (5c)
White solid, M.p: 122.6-123.5 °C, yield: 67%. 1H NMR (500 MHz, CDCl3) δ:
7.29 (s, 1H), 7.19 (d, J = 9.1 Hz, 4H), 6.99 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 8.1 Hz,
1H), 6.81 (t, J = 7.3 Hz, 1H), 5.95 (brs, 1H, NH), 4.46 (d, J = 5.5 Hz, 2H), 4.01 (s,
2H), 3.31 (s, 2H), 2.37 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 169.7, 157.6, 137.5,
134.5, 129.4 (2C), 129.0, 128.8, 127.8 (2C), 121.9, 119.3, 116.4, 51.98, 50.5, 43.4,
21.1. HRMS (ESI) calcd for C17H21N2O2 [M+H]+ 285.1603, found 285.1610.
4.2.4. 2-((2-hydroxybenzyl)amino)-N-(3-methylbenzyl)acetamide (5d)
White solid, M.p: 102.0-102.1 °C, yield: 57%. 1H NMR (500 MHz, CDCl3) δ:
7.22 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.04-7.05
(m, 2H), 6.96 (d, J = 7.3 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.77 (t, J = 7.4 Hz, 1H),
6.28 (brs,1H, NH), 4.40 (s, 2H), 3.94 (d, J = 6.5 Hz, 2H), 3.26 (d, J = 5.1 Hz, 2H),
2.34 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 169.9, 157.5, 138.5, 137.6, 128.9, 128.9,
11

128.6, 128.5, 128.4, 124.8, 122.1, 119.3, 116.3, 51.9, 50.5, 43.5, 21.3. HRMS (ESI)
calcd for C17H21N2O2 [M+H]+ 285.1603, found 285.1597.
4.2.5. 2-((2-hydroxybenzyl)amino)-N-(2-methoxybenzyl)acetamide (5e)
White solid, M.p: 104.7-105.1 °C, yield: 62%. 1H NMR (500 MHz, CDCl3) δ:
7.21 (d, J = 5.3 Hz, 2H), 7.10-7.15 (m), 6.98 (s, 1H), 6.86 (d, J = 5.2 Hz, 2H), 6.76 (d,
J = 5.6 Hz, 1H), 4.38 (s, 2H), 3.93 (s, 2H), 3.80 (s, 3H), 3.29 (s, 2H). 13C NMR (125
MHz, CDCl3) δ: 169.8, 157.5, 157.4, 129.6, 128.9, 128.8, 128.8, 125.7, 122.3, 120.5,
119.1, 116.1, 110.2, 55.2, 51.7, 50.5, 39.3. HRMS (ESI) calcd for C17H21N2O3
[M+H]+ 301.1552, found 301.1557.
4.2.6. 2-((2-hydroxybenzyl)amino)-N-(4-methoxybenzyl)acetamide (5f)
White solid, M.p: 142.4-143.6 °C, yield: 65%. 1H NMR (500 MHz, CDCl3) δ:
7.15 (d, J = 5.3 Hz, 2H), 7.04-7.09 (m, 2H), 6.92 (s, 1H, NH), 6.80 (d, J = 5.2 Hz,
2H), 6.76 (d, J = 4.7 Hz, 1H), 6.70 (d, J = 5.6 Hz, 1H), 4.32 (s, 2H), 3.87 (s, 2H),
3.74 (s, 3H), 3.23 (s, 2H). 13C NMR (125 MHz, DMSO-d6) δ 170.5, 158.2, 156.4,
131.4, 129.0, 128.6 (2C), 127.9, 124.8, 118.6, 115.2, 113.7 (2C), 55.0, 50.8, 49.3,
41.4. HRMS (ESI) calcd for C17H21N2O3 [M+H]+ 301.1552, found 301.1544.
4.2.7. 2-((2-hydroxybenzyl)amino)-N-(3-methoxybenzyl)acetamide (5g)
White solid, M.p: 86.7-88.4 °C, yield: 54%. 1H NMR (500 MHz, CDCl3) δ: 7.22
(d, J = 5.3 Hz, 2H), 7.11-7.16 (m, 2H), 6.99 (s, 1H), 6.87 (d, J = 5.2 Hz, 2H), 6.77 (d,
J = 5.6 Hz, 1H), 4.39 (s, 2H), 3.94 (s, 3H), 3.81 (s, 2H), 3.30 (s, 2H). 13C NMR (125
MHz, DMSO-d6) δ: 170.7, 159.3, 156.5, 141.1, 129.3, 129.0, 127.9, 124.8, 119.4,
118.6, 115.2, 112.8, 112.2, 54.9, 50.8, 49.3, 41.9. HRMS (ESI) calcd for C17H21N2O3
[M+H]+ 301.1552, found 301.1547.
4.2.8. 2-((2-hydroxybenzyl)amino)-N-(4-chlorobenzyl)acetamide (5h)
Pale yellow solid, M.p: 117.0-118.6 °C, yield: 43%. 1H NMR (500 MHz, CDCl3)
δ: 7.28 (d, J = 8.2 Hz, 2H), 7.14-7.18 (m, 3H), 6.96 (d, J = 7.4 Hz, 1H), 6.76-6.81 (m,
2H), 6.38 (brs, 1H, NH), 4.39 (d, J = 5.9 Hz, 2H), 3.93 (s, 2H), 3.26 (s, 2H). 13C NMR
(125 MHz, CDCl3) δ 170.2, 157.3, 136.3, 133.4, 129.0 (2C), 129.0, 128.9, 128.8 (2C),
122.1, 119.4, 116.2, 51.8, 50.5, 42.8. HRMS (ESI) calcd for C16H18ClN2O2 [M+H]+
305.1057, found 305.1051.
12

4.2.9. 2-((2-hydroxybenzyl)amino)-N-(2-chlorobenzyl)acetamide (5i)
White solid, M.p: 109.4-111.0 °C, yield: 52%. 1H NMR (500 MHz, CDCl3) δ:
7.33-7.37 (m, 2H), 7.22-7.24 (m, 2H), 7.15 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 7.3 Hz,
1H), 6.81 (d, J = 8.1 Hz, 1H), 6.77 (t, J = 7.4 Hz, 1H), 6.47 (brs, 1H, NH), 4.53 (d, J =
5.9 Hz, 2H), 3.92 (s, 2H), 3.26 (s, 2H). 13C NMR (125 MHz, CDCl3) δ: 170.2, 157.4,
135.1, 133.6, 130.2, 129.56, 129.1, 128.9, 128.9, 127.1, 122.1, 119.3, 116.2, 51.8,
50.4, 41.4. HRMS (ESI) calcd for C16H18ClN2O2 [M+H]+ 305.1057, found 305.1052.
4.2.10. 2-((2-hydroxybenzyl)amino)-N-phenylacetamide (5j)
White solid, M.p: 124.7-127.6 °C, yield: 71%. 1H NMR (500 MHz, CDCl3) δ: 8.48 (s,
1H, OH), 7.50 (d, J = 7.8 Hz, 2H), 7.27 (t, J = 7.6 Hz, 2H), 7.11-7.14 (m, 2H), 6.98
(d, J = 7.1 Hz, 1H), 6.78-6.83 (m, 2H), 5.26 (s, 1H, NH), 3.89 (s, 2H), 3.31 (s, 2H).
13C NMR (125 MHz, CDCl3) δ: 168.9, 156.9, 137.2, 129.2, 129.0 (2C), 128.9 (2C),
124.6, 122.6, 120.0, 119.6, 116.1, 53.4, 51.5, 51.1. HRMS (ESI) calcd for
C15H17N2O2 [M+H]+ 257.1290, found 257.1282.
4.2.11. 2-((2-hydroxybenzyl)amino)-N-(2-methylphenyl)acetamide (5k)
White solid, M.p: 111.0-113.6 °C, yield: 61%. 1H NMR (500 MHz, DMSO-d6) δ:
9.80 (s, 1H, OH), 7.47 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.19-7.24 (m,
3H), 7.11 (t, J = 7.3 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 7.4 Hz, 1H), 4.09
(s, 2H), 3.77 (s, 2H), 2.21 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 168.9, 156.9, 134.9,
130.5, 129.4, 129.2, 129.0, 126.7, 125.5, 123.0, 122.5, 119.6, 116.2, 51.5, 51.2, 17.7.
HRMS (ESI) calcd for C16H19N2O2 [M+H]+ 271.1447, found 271.1440.
4.2.12. 2-((2-hydroxybenzyl)amino)-N-(4-methylphenyl)acetamide (5l)
White solid, M.p: 127.0-128.8 °C, yield: 67%. 1H NMR (500 MHz, CDCl3) δ:
8.24 (s, 1H, OH), 7.39 (s, 2H), 7.09-7.15 (m, 3H), 6.99 (s, 1H), 6.79-6.84 (m, 2H),
3.91 (s, 2H), 3.32 (s, 2H), 2.29 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 168.8, 157.0,
134.6, 134.3, 129.5 (2C), 129.2, 128.9, 122.5, 120.0 (2C), 119.6, 116.1, 51.5, 51.0,
20.8. HRMS (ESI) calcd for C16H19N2O2 [M+H]+ 271.1447, found 271.1442.
4.2.13. 2-((2-hydroxybenzyl)amino)-N-(3-methylphenyl)acetamide (5m)
Yellow oil, yield: 60%. 1H NMR (500 MHz, CDCl3) δ: 7.44 (s, 1H), 7.40 (s,
1H), 7.16 (dt, J = 8.9, 4.5 Hz, 2H), 7.02 (d, J = 7.1 Hz, 1H), 6.92 (t, J = 9.1 Hz, 2H),
13

6.81 (t, J = 7.3 Hz, 1H), 3.87 (s, 2H), 3.36 (s, 2H), 2.30 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ: 169.4, 156.6, 138.4, 137.2, 129.1, 128.6, 128.4, 124.9, 122.9, 120.5, 119.1,
116.9, 115.7, 50.8, 36.3, 21.1. HRMS (ESI) calcd for C16H19N2O2 [M+H]+ 271.1447,
found 271.1438.
4.2.14. 2-((2-hydroxybenzyl)amino)-N-(2-methoxyphenyl)acetamide (5n)
White solid, M.p: 100.6-103.5 °C, yield: 68%. 1H NMR (500 MHz, CDCl3) δ: 8.36 (d,
J = 7.7 Hz, 1H), 8.17 (s, 1H, OH), 7.19 (t, J = 7.4 Hz, 1H), 7.04-7.07 (m, 1H), 7.01 (d,
J = 7.2 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.88-6.84 (m, 2H), 6.80 (t, J = 7.2 Hz, 1H),
4.00 (s, 2H), 3.85 (s, 3H), 3.45 (s, 2H). 13C NMR (125 MHz, CDCl3) δ: 168.1, 157.5,
147.8, 128.9, 128.9, 126.8, 124.1, 122.2, 120.9, 119.7, 119.3, 116.3, 109.9, 55.5, 51.8,
51.4. HRMS (ESI) calcd for C16H19N2O3 [M+H]+ 287.1396, found 287.1390.
4.2.15. 2-((2-hydroxybenzyl)amino)-N-(4-methoxyphenyl)acetamide (5o)
White solid, M.p: 114.3-116.7 °C, yield: 70%. 1H NMR (500 MHz, CDCl3) δ:
7.41 (d, J = 8.9 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 6.79-6.85
(m, 4H), 3.94 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.34 (d, J = 6.4 Hz, 2H). 13C NMR
(125 MHz, CDCl3) δ 168.5, 157.1, 156.5, 130.3, 129.2, 129.0, 122.5, 121.8, 121.8,
119.6, 116.2, 114.1 (2C), 55.4, 51.6, 51.0. HRMS (ESI) calcd for C16H19N2O3
[M+H]+ 287.1396, found 287.1391.
4.2.16. 2-((2-hydroxybenzyl)amino)-N-(3-methoxyphenyl)acetamide (5p)
White solid, M.p: 90.5-93.1 °C, yield: 63%. 1H NMR (500 MHz, CDCl3) δ: 9.15
(s, 1H, OH), 7.27 (s, 1H), 7.08-7.12 (m, 2H), 7.04 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 7.2
Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.75 (t, J = 7.3 Hz, 1H), 6.60 (dd, J = 8.1, 1.8 Hz,
1H), 3.80 (s, 2H), 3.67 (s, 3H), 3.28 (s, 2H). 13C NMR (125 MHz, CDCl3) δ: 169.4,
159.7, 156.5, 138.5, 129.4, 129.2, 128.7, 123.1, 119.3, 115.7, 112.1, 109.8, 105.8,
54.9, 50.93, 50.90. HRMS (ESI) calcd for C16H19N2O3 [M+H]+ 287.1396, found
287.1389.
4.2.17. 2-((2-hydroxybenzyl)amino)-N-(3-ethylphenyl)acetamide (5q)
Pale yellow solid, M.p: 78.7-79.9 °C, yield: 62%. 1H NMR (500 MHz, CDCl3) δ:
8.27 (s, 1H, OH), 7.39 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H),
7.17-7.15 (m, 1H), 7.01-7.00 (m, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 8.0 Hz,
14

1H), 6.82-6.79 (m,1H), 3.94 (s, 2H), 3.35 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.21 (t, J =
7.6 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 168.9, 156.9, 145.3, 137.2, 129.2, 129.0,
128.9, 124.2, 122.5, 119.6, 119.5, 117.3, 116.1, 51.5, 51.1, 28.7, 15.4. HRMS (ESI)
calcd for C17H21N2O2 [M+H]+ 285.1603, found 285.1597.
4.2.18. 2-((2-hydroxybenzyl)amino)-N-(3,4-dimethylphenyl)acetamide (5r)
White solid, M.p: 106.0-106.4 °C, yield: 58%. 1H NMR (500 MHz, CDCl3) δ:
8.07 (s, 1H, OH), 7.30 (d, J = 1.6 Hz, 1H), 7.22-7.24 (m,1H), 7.16-7.19 (m, 1H), 7.06
(d, J = 8.1 Hz, 1H), 7.00 (d, J = 6.6 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.82 (t, J = 7.4
Hz, 1H), 3.94 (s, 2H), 3.34 (s, 2H), 2.21 (s, 6H). 13C NMR (125 MHz, CDCl3) δ:
168.7, 157.1, 137.3, 134.8, 133.0, 129.9, 129.1, 128.9, 122.4, 121.3, 119.5, 117.5,
116.1, 51.6, 51.0, 19.8, 19.2. HRMS (ESI) calcd for C17H21N2O2 [M+H]+ 285.1603,
found 285.1599.
4.2.19. 2-((2-hydroxybenzyl)amino)-N-(4-chlorophenyl)acetamide (5s)
Yellow solid, M.p: 143.8-144.5 °C, yield: 46%. 1H NMR (500 MHz, CDCl3) δ:
8.06 (s, 1H, OH), 7.48 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.19 (t, J = 7.6
Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.85-6.81 (m, 2H), 3.99 (s, 2H), 3.48 (s, 1H, NH),
3.40 (s, 2H). 13C NMR (125 MHz, DMSO-d6) δ: 169.9, 156.4, 137.6, 129.2, 128.6
(2C), 128.0, 126.8, 124.8, 120.6 (2C), 118.6, 115.2, 51.4, 49.3. HRMS (ESI) calcd for
C15H16ClN2O2 [M+H]+ 291.0900, found 291.0895.
4.2.20. 2-((2-hydroxybenzyl)amino)-N-(2-chlorophenyl)acetamide (5t)
Yellow oil, yield: 45%. 1H NMR (500 MHz, CDCl3) δ: 8.37 (d, J = 8.1 Hz, 1H),
8.19 (s, 1H, OH), 7.37-7.39 (m, 1H), 7.27-7.29 (m, 1H), 7.18-7.22 (m, 1H), 7.04-7.07
(m, 2H), 6.86-6.88 (m, 1H), 6.81-6.84 (m, 1H), 4.04 (s, 2H), 3.52 (s, 2H). 13C NMR
(125 MHz, CDCl3) δ: 168.7, 157.1, 133.9, 129.2, 129.1, 129.1, 127.8, 125.0, 122.9,
122.2, 121.6, 119.6, 116.3, 51.7, 51.6. HRMS (ESI) calcd for C15H16ClN2O2 [M+H]+
291.0900, found 291.0893.
4.2.21. 2-((2-hydroxybenzyl)amino)-N-(1-naphthalenyl)acetamide (5u)
White solid, M.p: 144.6-145.2 °C, yield: 41%. 1H NMR (500 MHz, CDCl3) δ:
8.37 (s, 1H, OH), 7.90 (d, J = 7.4 Hz, 1H), 7.84-7.87 (m, 1H), 7.77-7.81 (m, 1H), 7.69
(d, J = 8.2 Hz, 1H), 7.47-7.51 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.20 (t, J = 7.5 Hz,
15

1H), 7.06 (d, J = 7.2 Hz, 1H), 6.84 (dd, J = 14.6, 7.6 Hz, 2H), 4.03 (s, 2H), 3.53 (s,
2H). 13C NMR (125 MHz, DMSO-d6) δ 170.2, 156.3, 133.7, 133.1, 129.4, 128.2,
128.1, 127.0, 126.0, 125.9, 125.6, 124.9, 124.8, 122.0, 120.3, 118.7, 115.2, 51.3, 49.0.
HRMS (ESI) calcd for C19H19N2O2 [M+H]+ 307.1447, found 307.1441.
4.2.22. 2-((2-hydroxybenzyl)amino)-N-(2-naphthalenyl)acetamide (5v)
White solid, M.p, 155.1-155.4 °C, yield: 53%. 1H NMR (500 MHz, CDCl3) δ:
8.20 (d, J = 1.3 Hz, 1H), 8.00 (s, 1H, OH), 7.78 (d, J = 7.4 Hz, 3H), 7.45-7.47 (m, 2H),
7.41 (t, J = 7.6 Hz, 1H), 7.18-7.21 (m, 1H), 7.03 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 8.0
Hz, 1H), 6.82 (t, J = 7.4 Hz, 1H), 4.02 (s, 2H), 3.46 (s, 2H). 13C NMR (125 MHz,
DMSO-d6) δ 170.1, 156.5, 136.3, 133.4, 129.8, 129.2, 128.4, 128.0, 127.4, 127.2,
126.4, 124.9, 124.5, 119.9, 118.7, 115.2, 115.1, 51.5, 49.3. HRMS (ESI) calcd for
C19H19N2O2 [M+H]+ 307.1447, found 307.1442.
4.2.23. 2-(benzylamino)-N-(2-methoxybenzyl)acetamide (7a)
Yellow oil, yield: 58%. 1H NMR (500 MHz, CDCl3) δ: 7.58 (s, 1H, NH),
7.27-7.15 (m, 7H), 6.83 (d, J = 8.3 Hz, 2H), 4.33 (d, J = 5.7 Hz, 2H), 3.73 (s, 3H),
3.68 (s, 2H), 3.25 (s, 2H), 2.23 (brs, 1H, NH). 13C NMR (125 MHz, CDCl3) δ: 170.9,
157.4, 139.3, 129.3, 128.6, 128.3 (2C), 127.9 (2C), 127.1, 126.1, 120.5, 110.1, 55.1,
53.6, 51.8, 38.7. HRMS (ESI) calcd for C17H21N2O2 [M+H]+ 285.1603, found
285.1593.
4.2.24. 2-(benzylamino)-N-(4-methoxybenzyl)acetamide (7b)
Yellow oil, yield: 64%. 1H NMR (500 MHz, CDCl3) δ: 7.49 (s, 1H, NH), 7.30 (t,
J = 7.2 Hz, 2H), 7.26 (d, J = 6.9 Hz, 1H), 7.23 (d, J = 7.4 Hz, 2H), 7.19 (d, J = 8.5 Hz,
2H), 6.86 (d, J = 8.5 Hz, 2H), 4.37 (d, J = 5.9 Hz, 2H), 3.78 (s, 3H), 3.73 (s, 2H), 3.32
(s, 2H), 1.96 (s, 1H, NH). 13C NMR (125 MHz, CDCl3) δ 171.2, 158.8, 139.1, 130.3,
128.9 (2C), 128.5 (2C), 128.0 (2C), 127.2, 113.9 (2C), 55.2, 53.8, 51.8, 42.3. HRMS
(ESI) calcd for C17H21N2O2 [M+H]+ 285.1603, found 285.1595.
4.3. Biological assay
The in vitro inhibition of mycelium in the agar culture medium caused by the title
compounds against six phytopathogenic fungi: Sclerotonia sclerotiorum, Botrytis
cinerea, Rhizoctonia solani, Gibberella zeae, Phytophythora capsic and Magnaporthe
16

oryzae was performed. Referring to the standard method NY/T1156.5–2006,
antifungal activity assays adopted the mycelium growth rate test method.
Chlorothalonil was used as a reference compound. A stock solution of every test
compound was prepared in acetone and then diluted to the required test concentrations
(500 µg/mL) with sorporl-144 (concentration: 200 µg/mL). Solutions of the test
compounds (1 mL) were added to potato dextrose agar (PDA) medium (9 mL, 45 °C)
to provide the final concentration of 25 µg/mL or 50 µg/mL. The mixed medium
without sample was used as the blank control. The inocula, 4 mm in diameter, were
removed from the margins of actively growing colonies of mycelium and placed in
the centers of the above plates. Percentages of growth inhibition were calculated by
comparing the mean value of the diameters of the mycelia in the test plates after
placement in a 24 °C biochemical incubator thermostat for 3 days. The inhibition
percent was calculated according to the following equation:
I = [(D1 –D0)/D1-4]×100%
Where I is the inhibition rate, D1 is the average diameter of mycelia in blank test, and
D0 is the average diameter of mycelia in the presence of compounds. Three replicates
were performed for each compounds. The results are given in Table 1 and Table 2.
4.4. Molecular Docking
The docking study was conducted based on the Surflex-Dock program in Sybyl
X-2.1. The parameters were set at default values except that the structure of
compound 5e was added Gasteiger-Hückel charges. The crystal structure of SDH
enzyme (PDB code: 2FBW) was downloaded from the Protein Data Bank (PDB)29.
Surflex-Dock was used for simulating and evaluating the interactions between
compound 5e and the target protein by an empirical scoring function.30
Conflicts of interest
Acknowledgments
This work was supported by the National Natural Science Foundation of China
17

(21877034, 21372070) and the Scientific Research Fund of Hunan Provincial
Education Department (17A066).
to this article can be found online at
https://doi.org/10.1016/j.bmc. These data include the general procedure for the
synthesis of compounds 8a, 8b and 1H NMR and 13C NMR spectra of the obtained
compounds (PDF).
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