Combinatorial synthesis of benzimidazole-azo-phenol derivatives as antifungal agents

Article abstract of DOI:10.2174/13862073113166660058

A chemically diverse library of benzimidazole-azo-phenol derivatives was efficiently prepared and screened for their antifungal activities against five phytopathogenic fungi. Some compounds exhibited potent antifungal activities. As compared with a commercially available agricultural fungicide, hymexazol, especially compound V-5 showed the most promising broad-spectrum antifungal activities against five phytopathogenic fungi. The EC50 values of V-5 against F. graminearum, A. solani, V. mali, B. cinerea, and C. lunata were 0.09, 0.08, 0.06, 0.07, and 0.11 mol/mL, respectively.

Full text of DOI:10.2174/13862073113166660058

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Combinatorial Chemistry & High Throughput Screening, 2014, 17, 89-95
89
Combinatorial Synthesis of Benzimidazole-Azo-Phenol Derivatives as
Antifungal Agents
Yazhen Ke§, Xiaoyan Zhi§, Xiang Yu, Guodong Ding, Chun Yang and Hui Xu*
Laboratory of Pharmaceutical Design & Synthesis, College of Sciences, Northwest A&F University, Yangling 712100,
China
Abstract: A chemically diverse library of benzimidazole-azo-phenol derivatives was efficiently prepared and screened for
their antifungal activities against five phytopathogenic fungi. Some compounds exhibited potent antifungal activities. As
compared with a commercially available agricultural fungicide, hymexazol, especially compound V-5 showed the most
promising broad-spectrum antifungal activities against five phytopathogenic fungi. The EC50 values of V-5 against F.
graminearum, A. solani, V. mali, B. cinerea, and C. lunata were 0.09, 0.08, 0.06, 0.07, and 0.11 μmol/mL, respectively.
Keywords: Antifungal activity, benzimidazole-azo-phenol, phytopathogenic fungi, synthesis.
1. INTRODUCTION
reaction of I-1 or I-2 gave II-1 or II-2, while 2-phenyl-5-
nitro-1H-benzimidazole (II-3) was obtained by the reaction
of benzoic acid with 4-nitro-o-phenylenediamine. Subsequently,
reduction of II-1-II-3 in the presence of SnCl2·2H2O
afforded III-1-III-3. Finally, III-1-III-3 reacted with
concentrated hydrochloric acid and sodium nitrite at 0-5 oC
to give the corresponding benzenediazonium chlorides,
which further reacted with the different phenols (IV-1-IV-
The benzimidazole subunits, existing in many biologi-
cally active natural products and synthetic compounds, have
recently gained widespread interest due to their key role in
medically important species, such as those displaying
anticancer activity [1,2], antimicrobial activity [3-5],
inhibitors of hepatitis C virus NS5B polymerase [6], and p38
kinase inhibitory and anti-inflammatory activity [7]. On the
other hand, phenol derivatives including those isolated from
the plants displayed the antifungal activities. It suggested
that the hydroxyl group of phenol analogs was required for
their antifungal activities, that is, removal of the phenolic
hydroxyl group would sharply lead to loss of activities [8-
10]. To our knowledge, the phytopathogenic fungi, which
are hard to control, easily infect many crops. Therefore the
development of bioactive compounds for effective control of
those agricultural diseases is highly desirable. In the
meantime, combinatorial synthesis that makes possible to
prepare a large number of compounds in a single process,
has recently gained widespread interest [11-16]. In
continuation of our program aimed at the discovery and
development of compounds with superior bioactivity [17-
o
10) at 0-5 C for 3-6 h to give benzimidazole-azo-phenol
derivatives (V-1-V-28). The structures of the target
1
compounds were well characterized by H NMR, MS, and
mp.
HO
HO
R2
N
N
CH3
N
R1
N
O
N
H
hymexazol
V
Fig. (1). Chemical structures of benzimidazole-phenol hybrids (V)
and hymexazol.
20], here we combinatorially prepared
a series of
2.2. Antifungal Activities
benzimidazole-phenol hybrids (V, Fig. 1) as antifungal
agents by incorporating the benzimidazole fragment with
phenol moieties into a single molecular framework via the
-N=N- bond.
As described in Table 1, a series of benzimidazole-azo-
phenol derivatives V-1-V-28 were screened in vitro for their
antifungal activities at 100 μg/mL against five
phytopathogenic fungi such as Fusarium graminearum,
Alternaria solani, Valsa mali, Botrytis cinerea, and
Curvularia lunata. Hymexazol (Fig. 1), a commercial
agricultural fungicide, was used as a positive control.
Compounds V-4-V-6, V-10, V-11, V-18, V-22, and V-24-V-
26 showed good antifungal activity against A. solani;
compounds V-4, V-5, V-8-V-11, V-19-V-22, and V-24-V-26
showed good antifungal activity against V. mali; compounds
V-5, V-6, V-10, V-11, V-19, and V-22-V-26 showed good
antifungal activity against C. lunata; compounds V-4 and V-
5 showed good antifungal activity against B. cinerea;
compounds V-4, V-5, V-8, and V-9 showed good antifungal
activity against F. graminearum. Among them, compound
V-5 exhibited a good and broad-spectrum of antifungal
2. RESULTS AND DISCUSSION
2.1. Chemistry
As shown in Scheme 1, firstly, 1H-benzimidazoles (I-1
and I-2) were prepared by the reaction of formic acid or
acetic acid with o-phenylenediamine. Then nitrification
*Address correspondence to this author at the Laboratory of Pharmaceutical
Design & Synthesis, College of Sciences, Northwest A&F University,
Yangling 712100, China; Tel: (86) 029-87091952; Fax: (86) 029-87091952;
E-mail: orgxuhui@nwsuaf.edu.cn
§These authors contributed equally to this work.
1875-5402/14 $58.00+.00
© 2014 Bentham Science Publishers

90 Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 1
Ke et al.
N
x
u
l
NO2
f
e
N
N
H
r
2H,
R1
conc.H2SO4
KNO3, 0oC
HCO
I-1
%
4
H2N
H2N
9
N
H
8 h,
CH
.
4M H
Cl
SnCl2 2H2O
3
4
,
NH2
II-1: R1 = H 88%
N
re
3CO
2H
flu
EtOAc, reflux
78% - 92%
x
,
N
8 h
5
II-2: R1 = CH3 80%
R1
, 65
%
2
N
H
H3C
III-1: R1 = H
III-2: R1 = CH3
III-3: R1 = Ph
1
N
H
III-1~III-3
I-2
O
NO2
H2N
NO2
N
OH
0-5 oC
PPA
NaNO2, HCl
+
Ph
140 oC, 8 h, 94%
N
H
H2N
II-3
HO
OH
IV-10
N2+Cl-
N
N
N
N
R1
R1
N
H
N
H
NaOH, EtOH
0-5 oC, 80%-95%
V-1~V-3
V-1: R1 = H; V-2: R1 = CH3;
V-3: R1 = Ph
HO
NaOH/EtOH
0-5 oC
R2
IV-1: R2 = H; IV-2: R2 = 2-CH3;
IV-3: R2 = 3-CH3; IV-4: R2 = 2-Cl;
IV-5: R2 = 2-Br; IV-6: R2 = 4-CH3;
IV-7: R2 = 4-Cl; IV-8: R2 = 4-C(CH3)3;
IV-9: R2 = 3-CH3,4-OCH3;
IV-1~IV-9
11%-66%
37-92%
HO
R2
OH
N
N
N
R1
N
N
N
H
N
R2
V-4~V-14
R1
N
H
V-15~V-28
V-4: R1 = H, R2= 4-CH3;
V-5: R1 = H, R2 = 4-C(CH3)3;
V-6: R1 = H, R2 = 4-OCH3,5-CH3;
V-7: R1 = H, R2 = 4-Cl;
V-15: R1 = H, R2 = 2-CH3; V-16: R1 = H, R2 = 3-CH3;
V-17: R1 = H, R2 = 2-Cl; V-18: R1 = H, R2 = 2-Br;
V-19: R1 = CH3, R2 = H; V-20: R1 = CH3, R2 = 2-CH3;
V-8: R1 = CH3, R2 = 4-CH3;
V-9: R1 = CH3, R2 = 4-C(CH3)3;
V-21: R1 = CH3, R2 = 3-CH3; V-22: R1 = CH3, R2 = 2-Cl;
V-23: R1 = CH3, R2 = 2-Br; V-24: R1 = Ph, R2 = H;
V-25: R1 = Ph, R2 = 2-CH3; V-26: R1 = Ph, R2 = 3-CH3;
V-27: R1 = Ph, R2 = 2-Cl; V-28: R1 = Ph, R2 = 2-Br.
V-10: R1 = CH3, R2 = 4-OCH3,5-CH3;
V-11: R1 = CH3, R2 = 4-Cl;
V-12: R1 = Ph, R2 = 4-C(CH3)3;
V-13: R1 = Ph, R2 = 4-OCH3,5-CH3;
V-14: R1 = H, R2 = H.
Scheme 1. The synthetic route of compounds V-1-V-28.
activities against five phytopathogenic fungi at the
concentration of 100 μg/mL. The benzimidazole-azo-
naphthol derivatives (V-1-V-3) generally exhibited less
potent antifungal activities than benzimidazole-azo-phenol
ones (V-4-V-28). To V-4-V-14, R1 as the hydrogen atom is
an important factor for their antifungal activities. For
example, the inhibition rates of V-9 and V-12 at 100 μg/mL
against A. solani, V. mali, C. lunata, B. cinerea, and F.
whereas the inhibition rates of V-5 at 100 μg/mL against A.
solani, V. mali, C. lunata, B. cinerea, and F. graminearum
were 66.8%, 76.2%, 68.1%, 86%, and 84.6%, respectively.
When R1 = H, introduction of R2 as the electron-donating
groups could lead to the potent compounds (V-4-V-6 vs
V-7). To V-15-V-28, introduction of R1 as the phenyl group,
and R2 as the hydrogen atom or the electron-donating groups
could generally result in the potent compounds (V-24-V-26).
graminearum
were
40.2%/21.5%,
58.5%/29.4%,
39.2%/21.9%, 47.4%/21.5%, and 57.4%/3.9%, respectively;

Combinatorial Synthesis of Benzimidazole-Azo-Phenol Derivatives
Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 1 91
Table 1. Antifungal Activities of Compounds V-1-V-28 Against Five Phytopathogenic Fungi at 100 μg/mLa
Antifungal Activities (Inhibition %)
Compounds
A. solani
V. mali
C. lunata
B. cinerea
F. graminearum
V-1
V-2
13.6 ( 0.8)
16.8 ( 1.6)
25.2 ( 0.8)
50.5 ( 1.6)
66.8 ( 0.8)
58.4 ( 2.1)
33.2 ( 0.8)
35.1 ( 0.8)
40.2 ( 1.6)
51.4 ( 1.6)
54.7 ( 1.6)
21.5 ( 1.4)
25.2 ( 1.6)
42.5 ( 1.4)
41.6 ( 0.8)
43.0 ( 1.6)
19.2 ( 1.6)
57.5 ( 1.6)
38.3 ( 2.4)
45.3 ( 1.4)
35.5 ( 1.4)
54.2 ( 0.8)
41.1 ( 1.4)
57.7 ( 4.1)
70.1 ( 0.8)
58.4 ( 0.8)
29.5 ( 0.8)
29.5 ( 0.8)
79.7 ( 0.8)
25.4 ( 0.6)
35.0 ( 1.1)
14.8 ( 0.6)
70.6 ( 0.5)
76.2 ( 0.9)
47.7 ( 0.5)
46.8 ( 0.5)
57.9 ( 0.5)
58.5 ( 0.9)
52.9 ( 0.5)
65.3 ( 1.4)
29.4 ( 1.8)
33.0 ( 1.8)
49.7 ( 1.8)
19.7 ( 1.5)
26.5 ( 1.0)
20.6 ( 1.5)
26.7 ( 1.0)
55.6 ( 1.0)
67.5 ( 1.5)
66.6 ( 0.6)
57.6 ( 1.9)
45.3 ( 1.5)
60.8 ( 0.6)
60.1 ( 0.6)
49.8 ( 0.0)
36.7 ( 0.6)
41.5 ( 0.6)
43.5 ( 0.9)
8.1 ( 0.7)
14.6 ( 0.7)
1.2 ( 0.7)
10.0 ( 0.5)
13.8 ( 0.5)
0.0 ( 0.5)
5.4 ( 0.7)
12.8 ( 0.4)
1.4 ( 0.4)
V-3
V-4
22.6 ( 1.6)
68.1 ( 1.2)
53.1 ( 1.8)
44.1 ( 1.2)
22.9 ( 2.1)
39.2 ( 1.6)
67.0 ( 1.6)
74.0 ( 1.0)
21.9 ( 1.0)
20.8 ( 1.0)
35.1 ( 1.6)
42.0 ( 1.6)
25.4 ( 0.6)
31.2 ( 1.4)
47.0 ( 1.9)
75.7 ( 1.2)
26.7 ( 0.7)
34.0 ( 1.9)
79.8 ( 0.7)
72.9 ( 0.7)
74.9 ( 1.4)
81.8 ( 0.0)
62.8 ( 0.7)
44.9 ( 0.7)
15.8 ( 0.7)
70.5 ( 0.6)
73.1 ( 0.6)
86.0 ( 1.1)
15.6 ( 1.1)
35.1 ( 1.1)
42.5 ( 1.0)
47.4 ( 1.7)
21.4 ( 2.0)
44.8 ( 1.1)
21.5 ( 1.2)
29.9 ( 0.8)
24.7 ( 0.5)
19.2 ( 1.6)
18.1 ( 0.8)
12.9 ( 1.1)
24.8 ( 1.6)
6.3 ( 1.4)
51.4 ( 1.3)
84.6 ( 0.6)
36.6 ( 0.9)
41.0 ( 0.4)
51.9 ( 1.2)
57.4 ( 0.6)
45.3 ( 0.7)
31.7 ( 0.7)
3.9 ( 0.9)
V-5
V-6
V-7
V-8
V-9
V-10
V-11
V-12
V-13
V-14
V-15
V-16
V-17
V-18
V-19
V-20
V-21
V-22
V-23
V-24
V-25
V-26
V-27
V-28
Hymb
11.5 ( 0.7)
34.2 ( 0.9)
17.1 ( 0.9)
5.8 ( 0.9)
6.8 ( 0.8)
11.1 ( 0.6)
22.8 ( 0.6)
36.6 ( 1.3)
36.4 ( 0.6)
44.9 ( 0.7)
18.9 ( 0.7)
42.0 ( 1.2)
38.5 ( 0.4)
37.5 ( 0.7)
2.1 ( 0.7)
30.1 ( 0.5)
30.4 ( 1.9)
33.6 ( 0.5)
10.7 ( 0.9)
32.0 ( 1.4)
42.0 ( 0.5)
22.6 ( 0.5)
7.2 ( 1.1)
5.7 ( 0.5)
8.4 ( 0.4)
79.9 ( 0.6)
69.0 ( 0.7)
aValues are means S.D. of three replicate.
bHymexazol was used as a positive control.
Finally, the EC50 values of V-5, V-6, V-11, V-24, and
V-25 were further calculated against five phytopathogenic
fungi as shown in Table 2. Among them, compound V-5
exhibited the most promising broad-spectrum antifungal
activities against five fungi. The EC50 values of V-5 against
F. graminearum, A. solani, V. mali, B. cinerea, and C. lunata
were 0.09, 0.08, 0.06, 0.07, and 0.11 μmol/mL, respectively.
Whereas the EC50 values of hymexazol against F.
graminearum, A. solani, V. mali, B. cinerea, and C. lunata
were 0.42, 0.21, 1.33, 0.16, and 0.43 μmol/mL, respectively.
It is noteworthy that V-5 exhibited the most potent
antifungal activity against V. mali with the EC50 value of
0.06 μmol/mL, which was more than 22-fold more potent
than that of hymexazol (1.33 μmol/mL). In addition, V-6,
V-11, V-24, and V-25 were also showed more potent
antifungal activity against V. mali and C. lunata as compared
with hymexazol. For example, the EC50 values of V-6, V-11,
V-24, and V-25 against V. mali and C. lunata were
0.40/0.20, 0.25/0.20, 0.20/0.08, and 0.24/0.05 μmol/mL,
respectively; whereas the EC50 values of hymexazol V. mali
and C. lunata were 1.33, and 0.43 μmol/mL, respectively.
3. CONCLUSIONS
In summary,
a
chemically diverse library of
benzimidazole-azo-phenol derivatives was efficiently
prepared and screened for their antifungal activities against
five phytopathogenic fungi. Some compounds exhibited

92 Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 1
Ke et al.
Table 2. EC50 Values of Compounds V-5, V-6, V-11, V-24, and V-25 Against Five Phytopathogenic Fungi
EC50 (µmol/mL) a
Compounds
A. solani
V. mali
C. lunata
B. cinerea
F. graminearum
hymexazol
V-5
0.21
0.08
0.13
0.28
0.24
0.13
1.33
0.06
0.40
0.25
0.20
0.24
0.43
0.11
0.20
0.20
0.08
0.05
0.16
0.07
－
0.42
0.09
－
V-6
V-11
－
－
V-24
－
－
V-25
－
－
a50% effective concentration: concentration of compound that inhibits the fungi growth by 50%.
potent antifungal activities. As compared with
a
MHz, DMSO-d6) δ: 12.20 (s, 1H), 7.43-7.45 (m, 2H), 7.08-
7.12 (m, 2H), 2.48 (s, 3H); MS (ESI): m/z (%) 133 ([M+H]+,
100).
commercially available agricultural fungicide, hymexazol,
especially compound V-5 showed the most promising broad-
spectrum antifungal activities against five phytopathogenic
fungi. It implied that V-5 might be considered as a new
promising lead candidate for further design and synthesis of
agricultural fungicide.
4.4. General Procedure for Synthesis of 5-Nitro-1H-
Benzimidazole
(II-1)
and
2-Methyl-5-Nitro-1H-
Benzimidazole (II-2)
To a mixture of compound I-1or I-2 (7 mmol) in
o
4. MATERIALS AND METHODS
4.1. General Remarks
concentrated sulfuric acid (5 mL) at 0 C, a solution of
KNO3 (7 mmol) in concentrated sulfuric acid (5 mL) was
added dropwise for 20 min. After stirring continuously for
105 min, the reaction mixture was poured slowly to ice-
water (100 mL) with stirring. The precipitated product was
filtered, washed with cold water, dried over anhydrous
Na2SO4, concentrated, and purified by PTLC to give product
II-1 in 88% yield or II-2 in 80% yield.
All reagents and solvents were of reagent grade or
purified according to standard methods before use.
Analytical thin-layer chromatography (TLC) and preparative
thin-layer chromatography (PTLC) were performed with
silica gel plates using silica gel 60 GF254 (Qingdao Haiyang
Chemical Co., Ltd.). Melting points were determined on a
digital melting-point apparatus and were uncorrected. Proton
nuclear magnetic resonance spectra (1H NMR) were
recorded on a Bruker Avance 400 MHz instrument in CDCl3
or DMSO-d6 using TMS (tetramethylsilane) as the internal
standard. Electrospray iontrap mass spectrometry (ESI-
TRAP-MS) was carried out with Bruker ESI-TRAP Esquire
6000 plus mass spectrometry instrument.
1
Data for II-1: Yellow solid, m.p. 202-204°C; H NMR
(400 MHz, DMSO-d6) δ: 8.55 (s, 1H), 8.52 (d, J = 2.0 Hz,
1H), 8.23 (dd, J = 8.8, 2.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H);
MS (ESI): m/z (%) 164 ([M+H]+, 100).
1
Data for II-2: White solid, m.p. 222-224°C; H NMR
(400 MHz, DMSO-d6) δ: 12.92 (s, 1H), 8.36 (d, J = 2.4 Hz,
1H), 8.04 (dd, J = 8.8, 2.4 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H),
2.57 (s, 3H); MS (ESI): m/z (%) 178 ([M+H]+, 100).
4.2. Synthesis of 1H-Benzimidazole (I-1)
4.5. Synthesis of 2-Phenyl-5-Nitro-1H-Benzimidazole (II-3)
A
mixture of formic acid (11 mmol) and o-
A mixture of 4-nitro-o-phenylenediamine (10 mmol),
benzoic acid (11 mmol) and polyphosphoric acid (PPA, 20
g) was reacted at 140°C for 8 h. Then the reaction mixture
was cooled to room temperature and neutralized with 5 N aq.
NaOH. The resulting solid was filtered, and washed with
water. Finally, 2-phenyl-5-nitro-1H-benzimidazole (II-3)
was obtained by recrystallization from ethanol in 94% yield.
phenylenediamine (10 mmol) was refluxed for 8 h. Then the
reaction mixture was cooled to room temperature and
neutralized with 5N aq. NaOH. The precipitate was formed,
filtered, and washed with water. Finally, 1H-benzimidazole
(I-1) was obtained by recrystallization from water in 94%
1
yield. White solid, m.p. 168-170°C; H NMR (400 MHz,
DMSO-d6) δ: 12.49 (s, 1H), 8.23 (s, 1H), 7.58-7.61 (m, 2H),
1
7.17-7.21 (m, 2H); MS (ESI): m/z (%) 119 ([M+H]+, 100).
White solid, m.p. 196-198°C; H NMR (400 MHz, DMSO-
d6) δ: 8.48 (d, J = 2.0 Hz, 1H), 8.26 (m, 2H), 8.10 (dd, J =
8.8, 2.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.54-7.63 (m, 3H);
MS (ESI): m/z (%) 240 ([M+H]+, 100).
4.3. Synthesis of 2-Methyl-1H-benzimidazole (I-2)
A
mixture of acetic acid (11 mmol) and o-
phenylenediamine (10 mmol) in 9 mL of 4 N HCl was
refluxed for 8 h. Then the reaction mixture was cooled to
room temperature. The precipitate was formed, filtered, and
washed with water. Finally, 2-methyl-1H-benzimidazole (I-
2) was obtained by recrystallization from 10% aq. ethanol in
4.6. General Procedure for Synthesis of Phenol-Azo-
Benzimidazole Derivatives (V-1~V-28)
A mixture of compound II-1, II-2 or II-3 (2 mmol),
SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for
12 h. When the reaction was complete according to TLC
analysis, the resulting reaction mixture was cooled to room
1
65% yield. White solid, m.p. 176-177°C; H NMR (400

Combinatorial Synthesis of Benzimidazole-Azo-Phenol Derivatives
Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 1 93
temperature. Subsequently, the reaction mixture was
adjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).
Then the mixture was extracted with EtOAc (2 × 150 mL).
The combined organic phase was washed with brine (200
mL), dried over anhydrous Na2SO4, and concentrated to
afford compounds III-1, III-2 or III-3, which were used
directly for the next step without further purification. To a
mixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,
2 mmol), water (5 mL) and concentrated HCl (12 mol/L,
0.51 mL) at 0°C, a solution of sodium nitrite (NaNO2, 2.1
mmol) in water (10 mL) was added dropwise while
maintaining the temperature below 5°C. After stirring for 20
min, a solution of diazonium chloride was prepared.
Subsequently, a solution of diazonium chloride was added
gradually to a mixture of phenols (IV-1-IV-10, 2 mmol),
sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) and
water (25 mL) at 0-5°C. After the addition of the above
diazonium solution, the mixture was continued to stir for 3-6
h until a lot of precipitate was produced. The solid was
collected, washed with water (3×10 mL), dried and purified
by PTLC to give the target products V-1~V-28.
7.30 (s, 1H), 6.89 (s, 1H), 3.82 (s, 3H), 2.20. (s, 3H); MS
(ESI): m/z (%) 283.2 ([M+H]+, 100).
Data for V-7: Yellow solid, yield: 11%, m.p. 239-241 oC;
IR cm-1: 3415, 3023, 2956, 2867, 1622, 1585, 1482, 1285,
1
1183, 819, 656; H NMR (400 MHz, DMSO-d6) δ: 8.40 (s,
1H), 8.29 (s, 1H), 7.95 (dd, J = 8.8, 2.0 Hz, 1H), 7.72 (d, J =
8.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.40 (dd, J = 8.8, 2.8
Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H); MS (ESI): m/z (%) 273.2
([M+H]+, 100).
Data for V-8: Yellow solid, yield: 44%, m.p. 202-204 oC;
IR cm-1: 3388, 3025, 2974, 2866, 1624, 1625, 1593, 1498,
1
1279, 1025, 816; H NMR (400 MHz, DMSO-d6) δ: 12.59
(s, 1H), 11.15 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.83 (dd, J =
8.8, 2.0 Hz, 1H), 7.58-7.60 (m, 2H), 7.18 (dd, J = 8.8, 2.0
Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 2.54 (s, 3H), 2.31 (s, 3H));
MS (ESI): m/z (%) 267.3 ([M+H]+, 100).
o
Data for V-9: Orange solid, yield: 28%, m.p. 186-88 C;
IR cm-1: 3452, 3175, 2964, 2871, 1623, 1591, 1498, 1271,
1181, 822; 1H NMR (400 MHz, DMSO-d6) δ: 12.56 (s, 1H),
11.41 (s, 1H), 8.10 (s, 1H), 7.83 (dd, J = 8.8, 2.0 Hz, 1H),
7.78 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.43 (dd, J
= 8.8, 2.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 2.54 (s, 3H),
1.32 (s, 9H); MS (ESI): m/z (%) 309.3 ([M+H]+, 100).
Data for V-1: Dark red solid, yield: 80%, m.p. 204-206
oC; IR cm-1: 3425, 3036, 2954, 2851, 1619, 1481, 1250,
1129, 824, 745; 1H NMR (400 MHz, DMSO-d6) δ: 15.34 (s,
1H), 12.79 (s, 1H), 8.73 (d, J = 8.0 Hz, 1H), 8.40 (s, 1H),
8.24 (s, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.87 (m, 2H), 7.79 (s,
1H), 7.65-7.69 (m, 1H), 7.47-7.51 (m, 1H), 7.13 (d, J = 9.2
Hz, 1H); MS (ESI): m/z (%) 289 ([M+H]+, 100).
o
Data for V-10: Red solid, yield: 45%, m.p. 194-196 C;
IR cm-1: 3496, 3179, 2935, 2840, 1626, 1582, 1494, 1237,
1
1031, 874, 874; H NMR (400 MHz, CDCl3) δ: 7.99 (d, J =
1.6 Hz, 1H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.61 (d, J = 8.8
Hz, 1H), 7.31 (s, 1H), 6.82 (s, 1H), 3.88 (s, 3H), 2.68 (s,
3H), 2.26 (s, 3H); MS (ESI): m/z (%) 297.3 ([M+H]+, 100).
Data for V-2: Red solid, yield: 86%, m.p. 152-154 oC; IR
cm-1: 3444, 3177, 3054, 2921, 2849, 1620, 1550, 1494, 1211,
1
1129, 825, 750; H NMR (400 MHz, DMSO-d6) δ: 15.28(s,
Data for V-11: Orange solid, yield: 66%, m.p. 138-140
1
oC; H NMR (400 MHz, DMSO-d6) δ: 12.56 (s, 1H), 11.00
1H), 12.55 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H),
7.98 (d, J = 9.2 Hz, 1H), 7.83-7.90 (m, 2H), 7.62-7.69 (m,
2H), 7.47-7.51 (m, 1H), 7.14 (d, J = 9.2 Hz, 1H), 2.55 (s,
3H); MS (ESI): m/z (%) 302.3 ([M+H]+, 100).
(s, 1H), 7.95 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.77 (dd, J =
8.8, 2.4 Hz, 1H), 7.72 (d, J = 8.8, 2.0 Hz, 1H), 7.57 (d, J =
8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 2.54 (s, 3H); MS
(ESI): m/z (%) 287.2 ([M+H]+, 100), 289.2 ([M+H]+, 34).
Data for V-3: Dark red solid, yield: 95%, m.p. 182-184
1
oC; H NMR (400 MHz, DMSO-d6) δ: 15.35 (s, 1H), 13.27
Data for V-12: Yellow solid, yield: 39%, m.p. 160-162
oC; IR cm-1: 3415, 3061, 2960, 2867, 1622, 1503, 1498,
(s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.22-8.24 (m, 3H), 7.99 (d,
J = 9.2 Hz, 1H), 7.87-7.93 (m, 2H), 7.79 (s, 1H), 7.66-7.70
(m, 1H), 7.47-7.62 (m, 4H), 7.13 (d, J = 8.8 Hz, 1H); MS
(ESI): m/z (%) 364.4 ([M+H]+, 100).
1
1265, 1180, 874; H NMR (400 MHz, DMSO-d6) δ: 12.81
(s, 1H), 10.08 (s, 1H), 8.10-8.12 (m, 2H), 8.06 (s, 1H), 7.90
(d, J = 2.4 Hz, 1H), 7.87 (dd, J = 8.8, 1.6 Hz, 1H), 7.71(d, J
= 8.8 Hz, 1H), 7.47-7.49 (m, 3H), 7.36 (dd, J = 8.4, 2.4 Hz,
1H), 6.95 (d, J = 8.8 Hz, 1H), 1.37 (s, 9H); MS (ESI): m/z
(%) 370.4 ([M+H]+, 100).
Data for V-4: Yellow solid, yield: 65%, m.p. 258-260 oC;
IR cm-1: 3443, 3022, 2959, 2867, 1624, 1595, 1498, 1284,
1136, 817; 1H NMR (400 MHz, DMSO-d6) δ: 12.82 (s, 1H),
11.90 (s, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 7.92 (dd, J = 8.8,
2.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 2.0 Hz,
1H), 7.20 (dd, J = 8.4, 2.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H),
2.31 (s, 3H); MS (ESI): m/z (%) 352.2 ([M+H]+, 100).
Data for V-13: Yellow solid, yield: 64%, m.p. 116-118
1
oC; H NMR (400 MHz, DMSO-d6) δ: 8.24-8.26 (m, 2H),
8.20 (d, J = 1.2 Hz, 1H), 7.92 (dd, J = 8.4, 2.0 Hz, 1H), 7.71
(d, J = 8.4 Hz, 1H), 7.53-7.63 (m, 3H), 7.31 (s, 1H), 6.90 (s,
1H); MS (ESI): m/z (%) 359.3 ([M+H]+, 100).
Data for V-5: Yellow solid, yield: 63%, m.p. 196-198 oC;
IR cm-1: 3448, 3039, 2957, 2863, 1619, 1495, 1266, 1178,
Data for V-14: Yellow solid, yield: 66%, m.p. 268-270
1
1
oC; IR cm-1: 3434, 3174, 1583, 1464, 1271, 1139, 837; H
834; H NMR (400 MHz, DMSO-d6) δ: 11.35 (s, 1H), 8.41
(s, 1H), 8.25 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 8.8, 2.0 Hz,
1H), 7.79 (d, J =2.4 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.45
(dd, J = 8.4, 2.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 1.32 (s,
9H); MS (ESI): m/z (%) 295.3 ([M+H]+, 100).
NMR (400 MHz, DMSO-d6) δ: 12.75 (s, 1H), 10.22 (s, 1H),
8.36 (s, 1H), 8.00-8.12 (m, 1H), 7.66-7.82 (m, 4H), 6.94 (d, J
= 8.4 Hz, 2H); MS (ESI): m/z (%) 239.2 ([M+H]+, 100).
Data for V-15: Yellow solid, yield: 60%, m.p. 234-236
oC; IR cm-1: 3442, 3272, 1614, 1591, 1474, 1266, 1126, 817;
1H NMR (400 MHz, DMSO-d6) δ: 8.34 (s, 1H), 8.04 (s, 1H),
7.76 (dd, J = 8.4, 1.6 Hz, 1H), 7.69-7.71 (m, 2H), 7.73 (d, J
= 8.8 Hz, 1H), 7.63 (dd, J = 8.4, 2.0 Hz, 1H), 6.95 (d, J = 8.4
Data for V-6: Dark red solid, yield: 51%, m.p. 210-212
oC; IR cm-1: 3450, 3037, 2949, 1625, 1582, 1495, 1236,
1127, 868; 1H NMR (400 MHz, DMSO-d6) δ: 12.80 (s, 1H),
10.91 (s, 1H), 8.32-8.38 (m, 2H), 7.92 (s, 1H), 7.73 (s, 1H),

94 Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 1
Ke et al.
Hz, 1H), 2.22 (s, 3H); MS (ESI): m/z (%) 253.2 ([M+H]+,
Data for V-25: Orange solid, yield: 92%, m.p. 192-194
100).
oC; IR cm-1: 3399, 3098, 2954, 2854, 1700, 1594, 1503,
1
1274, 1098, 820; H NMR (400 MHz, DMSO-d6) δ: 13.20
Data for V-16: Orange solid, yield: 61%, m.p. 270-272
(s, 1H), 10.20 (s, 1H), 8.21-8.23 (m, 2H), 8.04 (s, 1H), 7.79
(dd, J = 8.4, 2.0 Hz, 1H), 7.72 (d, J = 1.6 Hz, 2H), 7.65-7.68
(m, 1H), 7.54-7.61 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 2.24 (s,
3H); MS (ESI): m/z (%) 329.3 ([M+H]+, 100).
1
oC; IR cm-1: 3442, 3224, 1591, 1469, 1241, 1105, 849; H
NMR (400 MHz, DMSO-d6) δ: 12.72 (s, 1H), 10.08 (s, 1H),
8.36 (s, 1H), 7.99-8.11 (m, 1H), 7.78 (s, 2H), 7.61 (d, J = 8.8
Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 8.8, 2.8 Hz,
1H), 2.65 (s, 3H); MS (ESI): m/z (%) 253.2 ([M+H]+, 100).
Data for V-26: Orange solid, yield: 83%, m.p. 184-185
oC; IR cm-1: 3408, 3062, 2957, 2851, 1596, 1475, 1364,
Data for V-17: Yellow solid, yield: 64%, m.p. 278-280
oC; IR cm-1: 3425, 3278, 1621, 1590, 1484, 1297, 1139, 819,
711; 1H NMR (400 MHz, DMSO-d6) δ: 12.79 (s, 1H), 11.03
(s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H),
7.71-7.81 (m, 3H), 7.16 (d, J = 8.8 Hz, 1H); MS (ESI): m/z
(%) 273.2 ([M+H]+, 100).
1
1237, 1106, 862; H NMR (400 MHz, DMSO-d6) δ: 13.21
(s, 1H), 10.08 (s, 1H), 8.21-8.23 (m, 2H), 8.03 (s, 1H), 7.80
(m, 1H), 7.73 (s, 1H), 7.53-7.65 (m, 4H), 6.80 (d, J = 2.4 Hz,
1H), 6.72 (dd, J = 8.4, 2.4 Hz, 1H), 2.66 (s, 3H); MS (ESI):
m/z (%) 329.3 ([M+H]+, 100).
Data for V-27: Orange solid, yield: 44%, m.p. 156-158
Data for V-18: Orange solid, yield: 40%, m.p. 270-272
oC; 1H NMR (400 MHz, DMSO-d6) δ: 12.75 (s, 1H), 8.37 (s,
1H), 8.09 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.79-7.85 (m,
2H), 7.71 (s, 1H), 7.14 (d, J = 8.8 Hz, 1H); MS (ESI): m/z
(%) 317.2 ([M+H]+, 100), 319.2 ([M+H]+, 92).
1
oC; H NMR (400 MHz, DMSO-d6) δ: 13.27 (s, 1H), 8.21-
8.23 (m, 2H), 8.08 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.79-
7.83 (m, 2H), 7.68-7.73 (m, 1H), 7.54-7.61 (m, 3H), 7.16 (d,
J = 8.8 Hz, 1H); MS (ESI): m/z (%) 349.3 ([M+H]+, 100),
351.3 ([M+H]+, 33).
Data for V-19: Yellow solid, yield: 61%, m.p. 264-266
Data for V-28: Yellow solid, yield: 62%, m.p. 220-222
oC; IR cm-1: 3485, 3180, 3063, 2923, 1742, 1585, 1508,
1
oC; H NMR (400 MHz, DMSO-d6) δ: 13.31 (s, 1H), 8.22-
1
1281, 1150, 840; H NMR (400 MHz, DMSO-d6) δ: 12.49
8.24 (m, 2H), 8.05-8.07 (m, 2H), 7.80-7.85 (m, 2H), 7.71-
7.74 (m, 1H), 7.54-7.61 (m, 3H), 7.13 (d, J = 8.4 Hz, 1H);
MS (ESI): m/z (%) 393.3 ([M+H]+, 99), 395.3 ([M+H]+, 98).
(s, 1H), 10.19 (s, 1H), 7.70-7.81 (m, 5H), 6.93-6.96 (m, 2H),
2.53 (s, 3H); MS (ESI): m/z (%) 253.2 ([M+H]+, 100).
Data for V-20: Yellow solid, yield: 39%, m.p. 256-258
oC; IR cm-1: 3380, 3059, 2924, 1595, 1502, 1274, 1029, 819;
1H NMR (400 MHz, DMSO-d6) δ: 12.49 (s, 1H), 10.13 (s,
1H), 7.90 (s, 1H), 7.68-7.71 (m, 2H), 7.62 (dd, J = 8.4, 2.4
Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H),
2.53 (s, 3H), 2.22 (s, 3H); MS (ESI): m/z (%) 267.2
([M+H]+, 100).
4.7. Antifungal Activities Assay
A series of benzimidazole-azo-phenol derivatives V-1-V-
28 were screened in vitro for their antifungal activities
against five phytopathogenic fungi by poisoned food
technique. Five phytopathogenic fungi such as Fusarium
graminearum, Alternaria solani, Valsa mali, Botrytis
cinerea, and Curvularia lunata, were used for the assays.
Potato dextrose agar (PDA) medium was prepared in the
flasks and sterilized. Compounds V-1-V-28 were dissolved
in acetone before mixing with PDA, and the concentration of
test compounds in the medium was fixed at 100 μg/mL.
Subsequently, 50% effective concentration (EC50) values of
V-5, V-6, V-11, V-24, and V-25 were further calculated. The
medium was then poured into sterilized Petri dishes. All
types of fungi were incubated in PDA at 28 1°C for 5 days
to get new mycelium for the antifungal assays, and a mycelia
disk of approximately 5 mm diameter cut from culture
medium was picked up with a sterilized inoculation needle
and inoculated in the center of the PDA Petri dishes. The
o
Data for V-21: Red solid, yield: 53%, m.p. 270-272 C;
IR cm-1: 3439, 3193, 3063, 2921, 2829, 1736, 1587, 1446,
1
1244, 1021, 825; H NMR (400 MHz, DMSO-d6) δ: 10.06
(s, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.70 (dd, J = 8.8, 1.6 Hz,
1H), 7.59 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 6.78
(d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.4, 2.8 Hz, 1H), 2.63 (s,
3H), 2.50 (s, 3H); MS (ESI): m/z (%) 267.2 ([M+H]+, 100).
Data for V-22: Yellow solid, yield: 37%, m.p. 196-197
oC; IR cm-1: 3426, 3074, 2995, 2863, 1640, 1581, 1468,
1
1299, 1131, 829, 658; H NMR (400 MHz, DMSO-d6) δ:
12.52 (s, 1H), 11.60 (s, 1H), 7.95 (s, 1H), 7.88 (d, J = 2.4
Hz, 1H), 7.77 (dd, J = 8.8, 2.8 Hz, 1H), 7.72 (dd, J = 8.4, 2.0
Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H),
1.32 (s, 3H); MS (ESI): m/z (%) 287.2 ([M+H]+, 100).
inoculated Petri dishes were incubated at 28
1°C for 4
days. Acetone without any compounds mixed with PDA was
served as a control, while hymexazol, a commercial
agricultural fungicide, was used as a positive control. For
each treatment, three replicates were conducted. The radial
growths of the fungal colonies were measured and the data
were statistically analyzed. The inhibitory effects of the test
compounds on these fungi in vitro were calculated by the
formula: Inhibition rate (%) = (C-T) × 100/C, where C
represents the diameter of fungi growth on untreated PDA,
and T represents the diameter of fungi on treated PDA.
Finally, the linear regressions of inhibition rates (%) versus
seven concentrations of V-5, V-6, V-11, V-24, V-25 and
hymexazol were obtained, and the EC50 values were
calculated against five phytopathogenic fungi.
Data for V-23: Yellow solid, yield: 37%, m.p. 142-144
1
oC; H NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 11.05
(s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.95 (s, 1H), 7.81 (dd, J =
8.8, 2.4 Hz, 1H), 7.72 (dd, J = 8.4, 1.6 Hz, 1H), 7.57 (d, J =
8.4 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 2.54 (s, 3H); MS
(ESI): m/z (%) 331.2 ([M+H]+, 99), 333.2 ([M+H]+, 100).
Data for V-24: Orange solid, yield: 77%, m.p. 238-240
oC; IR cm-1: 3404, 3061, 2923, 1586, 1503, 1242, 1143, 870;
1H NMR (400 MHz, DMSO-d6) δ: 13.22 (s, 1H), 10.23(s,
1H), 8.21 (d, J = 7.2 Hz, 1H), 8.04 (s, 1H), 7.80-7.83 (m,
4H), 7.54-7.59 (m, 3H), 6.95 (d, J = 8.8 Hz, 2H). MS (ESI):
m/z (%) 315.3 ([M+H]+, 100).

Combinatorial Synthesis of Benzimidazole-Azo-Phenol Derivatives
Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 1 95
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CONFLICT OF INTEREST
The authors confirm that they do not have any conflicts
of interest.
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ACKNOWLEDGEMENTS
This work was financially in part supported by National
Natural Science Foundation of China (No. 31171896), and
the Special Funds of Central Colleges Basic Scientific
Research Operating Expenses (YQ2013008). We are deeply
grateful to Prof. H. L. Zhang for the NMR experiments.
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Received: July 17, 2013
Revised: September 19, 2013
Accepted: October 11, 2013