Synthesis and bioactive evaluation of a novel series of coumarinazoles

Article abstract of DOI:10.1016/j.bmcl.2014.05.029

A series of novel coumarinazoles were designed, synthesized, and characterized by IR, NMR, MS and HRMS spectra. The bioactive assay for the newly prepared compounds against six bacteria and five fungi manifested that most new compounds exhibited good or even stronger antibacterial and antifungal activities in comparison with reference drugs Chloromycin, Norfloxacin and Fluconazole. Bis-azole alcohols 7a and 7d-e showed better anti-Candida utilis activity than mono-azole derivatives 4a and 4d-e at the tested concentrations, and they were more potent than the clinical Fluconazole. While triazole alcohol 7a gave comparable anti-Candida albicans and anti-Candida mycoderma activity to Fluconazole and better anti-MRSA activity than mono-triazole one 4a and clinical Norfloxacin. 1H-Benzoimidazol-2-ylthio coumarin derivatives 4e and 7e gave the strongest anti-Escherichia coli JM109 efficacy. Oxiran-2-ylmethoxy moiety was found to be a beneficial fragment to improve antibacterial and antifungal activity to some extent.

Full text of DOI:10.1016/j.bmcl.2014.05.029

Accepted Manuscript
Synthesis and bioactive evaluation of a novel series of coumarinazoles
Guri L.V. Damu, Sheng-Feng Cui, Xin-Mei Peng, Qin-Mei Wen, Gui-Xin Cai,
Cheng-He Zhou
PII:
S0960-894X(14)00529-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.05.029
BMCL 21643
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
24 January 2014
23 April 2014
10 May 2014
Please cite this article as: Damu, G.L.V., Cui, S-F., Peng, X-M., Wen, Q-M., Cai, G-X., Zhou, C-H., Synthesis and
bioactive evaluation of a novel series of coumarinazoles, Bioorganic & Medicinal Chemistry Letters (2014), doi:
http://dx.doi.org/10.1016/j.bmcl.2014.05.029
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Synthesis and bioactive evaluation of a novel series
of coumarinazoles
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Guri L V Damu , Sheng-Feng Cui , Xin-Mei Peng , Qin-Mei Wen, Gui-Xin Cai* and Cheng-He Zhou*
§
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
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Synthesis and bioactive evaluation of a novel series of coumarinazoles
Guri L V Damu , Sheng-Feng Cui , Xin-Mei Peng , Qin-Mei Wen, Gui-Xin Cai and Cheng-He Zhou
§†
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*
∗
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Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China
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ARTICLE INFO
ABSTRACT
Article history:
Received
A series of novel coumarinazoles were designed, synthesized, and characterized by IR, NMR,
MS and HRMS spectra. The bioactive assay for the newly prepared compounds against six
bacteria and five fungi manifested that most new compounds exhibited good or even stronger
antibacterial and antifungal activities in comparison with reference drugs Chloromycin,
Norfloxacin and Fluconazole. Bis-azole alcohols 7a and 7d−e showed better anti-C. utilis
activity than mono-azole derivatives 4a and 4d−e at the tested concentrations, and they were
more potent than the clinical Fluconazole. While triazole alcohol 7a gave comparable anti-C.
albicans and anti-C. mycoderma activity to Fluconazole and better anti-MRSA activity than
mono-triazole one 4a and clinical Norfloxacin. 1H-Benzoimidazol-2-ylthio coumarin derivatives
Revised
Accepted
Available online
Keywords:
Coumarin
Azole
Antibacterial
Antifungal
log p
4e and 7e gave the strongest anti-E .coli JM109 efficacy. Oxiran-2-ylmethoxy moiety was found
to be a beneficial fragment to improve antibacterial and antifungal activity to some extent.
2
013 Elsevier Ltd. All rights reserved.
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3
0
Azole compounds have been attracting increasing interest due
1
Important group to bind enzymes and receptors:
Azole ring: bind with the prosthetic group iron(II) of cytochrome P450
Hydroxyl group: Form hydrogen bond with H310 in the active site
1to their large potentiality in medicinal chemistry. Azole
2heterocycles are able to easily bind with the enzymes and
3receptors in organisms through weak interactions such as
4coordination bonds, hydrogen bonds, ion-dipole, cation-π, π-π
5stacking and hydrophobic effect as well as van der Waals force
6etc. A number of azole drugs such as Fluconazole, Itraconazole,
7Voriconazole, Posaconazole and so on have been prevalently
N
N
N
N
N
N
N
N
2
8used in the anti-infective therapy. Successful usage of these
N
OH
N
9drugs in clinic inspires more research towards azole antimicrobial
0drugs. Although the extensively clinical use of triazole anti-
1infective agents has ever revolutionized the treatment of many
2infectious diseases, some of them are still limited by poor
3activities towards intractable fungi, high frequency of renal
4toxicity and several adverse effects as well as emergence of
5increasing resistant microbes, which are becoming one of the
6most paramount public health threats. These situations force
7researchers to develop structurally new antimicrobial agents.
8Much literature work has shown that the introduction of triazolyl 34 Fig. 1. Design of coumarin-derived azole alcohols as analogs of Fluconazole
9ethanol moiety can play an important role in exerting
0antimicrobial action, which not only remarkably enhances the
1antimicrobial activities, but also broadens the antimicrobial
OH
OH
N
N
O
O
Change
Different azoles
F
R
Regulate
physicochemical
properties and affinity
O
F
Target compounds
3
Clinical Fluconazole
O
3
3
3
3
3
3
3
4
4
4
4
4
5
Coumarin derivatives exhibit extensive potentiality in
6medicinal chemistry with the latent ability to exert noncovalent
7interactions with various active sites in organisms. Related fields
8have been increasingly attracting special interest due to their
9potential outstanding contributions in the prevention and
0treatment of diseases, such as antibacterial, antifungal,
1anticancer, antiviral, anti-HIV, anti-psoriasis, anti-coagulant,
2anti-tubercular, anti-malarial, anti-inflammatory, antioxidant
4
2spectrum.
5
3agents and so on. Numerous efforts have been focusing on the
4research and development of coumarin derivatives as potential
—
§
——
These authors contributed equally to this work
Postdoctoral fellow from Indian Institute of Chemical Technology (IICT), India
Corresponding author: Tel/Fax: +86 23 68254967; e-mail: zhouch@swu.edu.cn (Cheng-He Zhou), gxcai@swu.edu.cn (Gui-Xin Cai).
†
*
5

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5drugs. So far some coumarin derivatives, for example, Warfarin, 55skeleton and changed different kinds of azole rings including
6Acenocoumarol, Armillarisin A, Hymecromone, Cyclocumarol, 56triazole, benzotriazole, benzimidazole and thiol-benzimidazole to
7Carbochromen, Dicoumarol, and Ensaculin have been approved 57generate a novel class of coumarin-derived azole alcohols as
8for therapeutic purposes in clinic. Currently there is a huge 58novel analogs of Fluconazole (Fig. 1). The newly synthesized
9scientific and commercial interest in the discovery of potent and 59coumarinazoles might be expected to show potentiality against
0safe coumarin-based agents in the treatment of infective diseases 60bacterial and fungal strains, especially drug-resistant
6
1for their special ability against resistant strains.
61microorganism. Therefore, their antibacterial and antifungal
2activities were evaluated in vitro against six bacteria and five
63fungi. The lipophilicity/hydrophilicity and structure-activity
6
5
5
5
2
In continuation of our ongoing interest in the development of
7
3new antimicrobial agents, herein we incorporated triazolyl
6
4relationship (SAR) were also discussed.
4ethanol, an important fragment in Fluconazole, into coumarin
R1
CH
CH3
CH3
Im
3
O
ii
iv
OH
iii
1
R = H
HO
OH
HO
O
O
O
O
O
O
O
O
1
2
3
4a−
Im
e
1
i
R = OH
O
CH3
CH3
O
O
OH CH3
OH
iii
iv
O
O
O
O
Im
O
N
O
N
O
N
HO
O
O
6
7a−
e
OH
5
N
N
b =
N
N c =
d =
N
N
e =
S
4
,7 Im, a =
N
N
N
H
H C
3
CH3
6
5
6
6
6
6
7
6Scheme 1. Reagents and conditions: (i) ethyl acetoacetate, oxalic acid, 80−100 °C, 8−10 h; (ii) ethyl acetoacetate, piperidine, -5−30 °C, 8−10 h; (iii) 2-
2 3 2 3
7(chloromethyl)oxirane, K CO , reflux, 4−6 h; (iv) triazole, benzotriazole, benzimidazole or thiol-benzimidazole, K CO , EtOH, 50−70 °C, 6−8 h.
8
9
The target coumarinazoles were prepared from commercially 99for benzimidazole derivatives 4c and 7c. It seemed that the
0available phenols, and the synthetic route was outlined in 100combination of benzimidazole and coumarin was not beneficial
1Scheme 1. The cyclization of resorcinol and phloroglucinol 101to exert their antimicrobial behavior. The fungal C. utilis was
2respectively with ethyl acetoacetate in the presence of oxalic 102more sensitive to mono-azole coumarins 4a and 4d−e and bis-
3acid to form the corresponding 7-hydroxy coumarin 2 with 103azole derivatives 7a and 7d−e at the concentrations of 2–4
4excellent yield of 93% and 5,7-dihydroxy-coumarin 5 in 90% 104µg/mL than the reference Fluconazole (MIC = 8 µg/mL), while
5yield. The latter was further O-alkylated by commercial 2- 105coumarin triazole alcohol 7a gave comparable anti-C. albicans
6(chloromethyl)oxirane to yield racemic 5,7- and 7-(oxiran-2- 106and anti- C. mycoderma activity to reference Fluconazole (MIC
7ylmethoxy)-2H-chromen-2-one derivatives 3 and 6 in high yields 107= 1 and 4 µg/mL). It was noticeable that mono-substituted
8(80−91%), and subsequently the later were opened ring by 108oxiran-2-ylmethoxy coumarin 3 (MIC = 1 µg/mL) and its double
9different azoles in ethanol using sodium bicarbonate as base to 109derivative 6 (MIC = 16 and 8 µg/mL) exhibited much superior
0produce racemates 4a−e and 7a−e with excellent yields. All the 110activities against A. flavus and B. yeast to reference drug
7
7
7
7
7
7
7
7
7
8
8
8
1
13
1new compounds were confirmed by H NMR, C NMR, IR, MS 111Fluconazole (MIC
2and HRMS spectra. 112intermediates 3 and 6 showed good antifungal activity against
= 256 and 16 µg/mL). Furthermore,
1
1
13other tested fungal strains. These might suggested this fragment
14was beneficial to improve antifungal activity to some extent.
8
8
8
8
8
8
8
9
9
9
9
9
9
3
All the newly synthesized coumarinazoles were evaluated in
4vitro for their antimicrobial activities against two Gram-positive
5bacteria (Micrococcus luteus ATCC 4698 and Methicillin 115 The antibacterial assay showed that most prepared coumarin
6Resistant Staphylococcus aureus N315), four Gram-negative 116azole alcohols exhibited moderate to weak activities against
7bacteria (Pseudomonas aeruginosa, Bacillus subtilis, Shigella 117Gram-positive bacteria in comparison with clinical Norfloxacin
8dysenteriae and Escherichia coli JM109), and five fungi 118and Chloromycin. However, bis-triazole coumarin 7a gave better
9(Candida utilis, Aspergillus flavus, Beer yeast, Candida 119anti-MRSA activity (MIC = 8 µg/mL) than mono-triazole one 4a
0albicans, and Candida mycoderma) by two folds serial dilution 120(MIC = 32 µg/mL) even better than Norfloxacin (MIC = 16
1technique recommended by National Committee for Clinical 121µg/mL), which suggested that triazole alcohol fragment should
2Laboratory Standards (NCCLS) with the positive control of 122be helpful for anti-MASR. The biological activities against
3clinically antimicrobial drugs Fluconazole, Norfloxacin and 123Gram-negative bacteria showed that bis-1H-benzoimidazol-2-
4Chloromycin. The antimicrobial tests were carried out for three 124ylthio coumarin 7e displayed similar anti-E .coli JM109 ability
8
5times.
125to mono-one 4e (MIC = 0.5 µg/mL), which was much better than
1
1
1
1
26references Norfloxacin (MIC = 32 µg/mL) and Chloromycin
27(MIC = 16 µg/mL). It was noticed that intermediates 3 and 6
28showed comparable or superior antibacterial activities against B.
29Subtilis, S. dysenteriae and E .coli JM109 to standard
9
9
9
6
The obtained results as depicted in Table 1 revealed that most
7of coumarin azole alcohols could effectively inhibit the growth
8of the tested bacterial and fungal strains to some extent, except
6

1
1
30Norfloxacin and Chloromycin. These results confirmed that the 132antimicrobial activities. Surprisingly, oxiran-2-ylmethoxy
31incorporation of azole alcohol moiety was helpful for the 133fragment exerted great effect on the bioactivity to some extent.
a
1
34Table 1. In vitro antimicrobial data as MIC (µg/mL) for compounds 3, 4a−e, 6, 7a−e
Fungi
B.
yeast
1
Gram-positive bacteria
Gram-negative bacteria
B. S.
aeruginosa Subtilis dysenteriae JM109
Compds
C.
utilis
32
4
16
512
4
0.5
16
4
A.
flavus
1
C. C.
albicans mycoderma
P.
E .coli
M. luteus
MRSA
3
16
4
4
8
16
16
128
16
16
8
4
16
32
512
128
16
8
128
32
16
512
64
32
64
8
8
4
2
32
16
128
128
32
4
4
32
64
512
64
64
4
0.5
64
16
4
4
a
b
6
32
8
256
>512
128
16
32
>512
64
64
8
4
c
512
32
64
8
128
16
32
8
128
128
0.5
0.5
1
4
d
4
e
6
16
32
7
7
a
32
32
1
4
16
32
16
32
32
16
64
16
64
b
16
256
8
32
32
7
c
512
4
512
64
>512
16
>512
16
64
32
128
64
512
32
128
16
>512
128
>512
16
>512
32
7
d
7
e
2
8
-
64
256
-
16
16
-
8
1
-
16
4
-
32
-
64
-
16
-
64
-
32
-
0.5
-
Fluconazole
Chloromycin
Norfloxacin
8
2
16
8
32
1
32
16
32
4
32
16
-
-
-
-
-
a
1
1
1
1
35 C. utilis, Candida utilis; A. flavus, Aspergillus flavus; B. yeast, Beer yeast; C. albicans, Candida albicans; C. mycoderma, Candida mycoderma; M. luteus,
36Micrococcus luteus ATCC 4698; MRSA, Methicillin-Resistant Staphylococcus aureus N315; P. aeruginosa, Pseudomonas aeruginosa; B. Subtili, Bacillus
37subtilies; S. dysenteriae, Shigella dysenteriae; E. Coli JM109, Escherichia coli
38
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
39 Lipophilicity/hydrophilicity governs various biological 173derivatives 4e and 7e showed the strongest anti-E .coli JM109
40processes such as the transportation, distribution, metabolism 174efficacy, which were much better than Norfloxacin and
41and secretion of biological molecules. A good knowledge of the 175Chloromycin. It was found that oxiran-2-ylmethoxy moiety
42lipophilicity/hydrophilicity is essential to predict the 176seemed to be especially beneficial fragment to improve
43transportation and activity of drugs. Therefore, the 177antifungal activity against fungal strains A. flavus and B. yeast to
44lipophilicity/hydrophilicity expressed as octanol/water partition 178some extent. Other related work, including the thermodynamic
45coefficient (log P) was calculated experimentally by traditional 179properties, the antibacterial and antifungal action mechanism, the
46saturation shake flask method combining with UV-vis 180interactions between highly active compounds and HSA, the
47spectrophotometric approach (Supplementary Information). The 181effect factors on anti-microbial activities of the target
48obtained log P values of compounds 4a−e and 7a−e given in 182compounds such as different kinds of substituted coumarin
49Table 2 indicated that compounds 4a, 4e and 7b with low log P 183derivatives, other heterocyclic azoles (imidazole, tetrazole and
50values showed good antibacterial activities in comparison with 184their derivatives, etc.), as well as the toxicity investigation along
51other target compounds with high log P values. These might be 185with in vivo bioactive evaluation are active in progress in our
52explained by the possibility that higher lipophilic compounds 186group. All these will be reported in the future full paper.
53were unfavorable for being delivered to the binding sites in
54organism, and indicated the significant role of suitable 187Acknowledgments
55lipophilicity in drug design.
1
1
1
1
1
1
1
1
1
88 This work was partially supported by National Natural
89Science Foundation of China [No. 21372186, 21172181,
9081350110338, 81250110089, 81350110523 (The Research
91Fellowship for International Young Scientists from the
92International (Regional) Cooperation and Exchange Program)],
93the key program from Natural Science Foundation of Chongqing
94(CSTC2012jjB10026), the Specialized Research Fund for the
95Doctoral Program of Higher Education of China (SRFDP
9620110182110007).
1
56Table 2. The values of log P for compounds 4a–e and 7a–e
Compds
Log P
4a
4b
4c
4d
4e
0
.45
0.60
7b
0.55
7c
0.61
7d
0.49
7e
Compds
Log P
7
a
0
.65
0.48
0.49
0.61
0.58
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
57 In summary, a series of coumarinazoles as novel type of
58antimicrobial agents were successfully prepared through an easy,
59convenient and economic synthetic procedure. Their structures 198
1
97References and notes
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2
2
2
2
00
01
02
03
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65gave comparable anti-C. utilis activity to mono-azole derivatives 205
2
2
2
2
2
06
07
08
09
10
664a and 4d−e, which were more potent than the clinical
67Fluconazole. Moreover, triazole alcohol coumarin 7a also
68exhibited comparable anti-C. albicans and anti- C. mycoderma
69activity to Fluconazole. In particular, bis-triazole coumarin 7a
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71even better than clinical Norfloxacin. Among all the prepared
72coumarin azole alcohols, 1H-benzoimidazol-2-ylthio coumarin
2
7

2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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58
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64
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2H, benzoimidazole-2-thiol 4,8-H), 6.97-6.94 (d, 1H,
benzoimidazole-2-thiol 5,6-H), 6.20 (s, 1H, coumarin olefin 3-H),
5.78 (s, 2H, OH), 4.19−4.17 (m, 2H, S-CH
2
), 4.13 (s, 2H, chiral-
H), 3.58−3.55 (m, 2H, -OCH ), 2.38 (s, 3H, coumarin 4-CH )
3
2
+
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ppm; ESI-MS (m/z): [M+H] , 383; HRMS (TOF) calcd. for
+
21 19 4 4
C H N O S[M+H] , 383.1066; found, 383.1061.
Synthesis of 5,7-bis(2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)-
4-methyl-2H-chromen-2-one (7a). To a stirred suspension of
potassium carbonate (0.151 g, 1.2 mmol) in ethanol was added
1,2,4-triazole (1.382 g, 2.0 mmol). The mixture was stirred at 60
o
C for 1 h. The reaction was cooled to room temperature,
compound 6 (0.302 g, 1.0 mmol) was added at the room
temperature and stirred for another 10 h under reflux. After the
reaction came to end, solvent was evaporated and the residue was
extracted with chloroform (3 × 20 mL). The combined organic
extracts were dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The crude product was
2010, 20, 1881.
309
8.
Experimental: melting points were recorded on X-6 melting point 310
apparatus and uncorrected. TLC analysis was done using pre- 311
coated silica gel plates. FT-IR spectra were carried out on Bruker 312
RFS100/S spectrophotometer (Bio-Rad, Cambridge, MA, USA) 313
purified
by
column
chromatography
(eluent,
chloroform/methanol, 60/5, V/V) to afford white solid 0.365 g.
1
6
Yield: 82 %; H NMR (300 MHz, DMSO-d ) δ: 8.50, 8.49 (s, 2H,
triazole 3-H), 8.00, 7.99 ( s, 2H, triazole 5-H), 6.62−6.61 (d, 1H, J
= 3 Hz, coumarin 8-H), 6.51−6.50 (d, 1H, J = 3 Hz, coumarin 6-
H), 6.05 (s, 1H, coumarin 3-H), 5.61−5.57 (bs, 2H, OH),
-1
using KBr pellets in the 400–4000 cm range. NMR spectra were 314
recorded on a Bruker AV 300 spectrometer using TMS as an 315
internal standard. The chemical shifts were reported in parts per 316
million (ppm), the coupling constants (J) are expressed in hertz 317
(Hz) and singlet (s), doublet (d) and triplet (t), broad (br) as well 318
as multiplet (m). The mass spectra (MS) were recorded on 319
LCMS–2010A and the high-resolution mass spectra (HRMS) 320
were recorded on an IonSpec FT-ICR mass spectrometer with ESI 321
2
4.37−4.29 (m, 4H, phenyl-OCH ), 4.27−4.25 (bs, 2H, CHOH),
4.08−4.01 (m, 4H, triazole-CH ), 2.59 (s, 3H, coumarin 4-CH )
2
3
1
3
ppm; C NMR (75 MHz, DMSO-d
6
) δ: 162.3 (coumarin 2-C),
160.2 (coumarin 7-C), 158.6 (coumarin 5-C), 156.9 (coumarin 9-
C), 154.9 (coumarin 4-C), 152.0, 151.9 (triazole 3-C), 145.5,
145.4 (triazole 5-C), 111.4 (coumarin 3-C), 104.7 (coumarin 10-
C), 97.1 (coumarin 6-C), 94.9 (coumarin 8-C), 71.5, 70.8
resource.
322
Synthesis of 4-methyl-7-(oxiran-2-ylmethoxy)-2H-chromen-2-one 323
(3). A mixture of 7-hydroxy-4-methyl coumarin 2 (1.76 g, 10 324
mmol), potassium carbonate (2.07 g, 15 mmol) and 325
epichlorohydrin (15 mL, 200 mmol) was refluxed for 3−4 h. After 326
the reaction was completed (monitored by TLC, eluent, 327
chloroform/methanol, 200−50/1, V/V), the mixture was cooled to 328
(coumarin 7-OCH
3
CH ), 24.7 (coumarin-CH ) ppm; ESI-MS (m/z): 443.1 [M+H] ,
+
2
), 67.8, 67.7 (CHOH), 52.6, 52.4 (triazole-
+
2
+
414.1 [M-CO] ; HRMS (TOF) calcd. for C20
443.1634; found, 443.1680.
22 6 6
H N O [M+H] ,
9.
National Committee for Clinical Laboratory Standards Approved
standard Document. M27-A2, Reference Method for Broth
Dilution Antifungal Susceptibility Testing of Yeasts, National
Committee for Clinical Laboratory Standards, Wayne, PA, 2002.
room temperature. The excess 2-(chloromethyl) oxirane was
evaporated under reduced pressure, and then water was added.
The residue was extracted with chloroform (3 × 20 mL), and the
combined organic phase was dried over anhydrous sodium sulfate.
The crude product was purified by column chromatography
(eluent, chloroform/methanol, 200/1, V/V) to give the desired
compound 3 (0.294 g) as white solid. Yield: 68.9%; mp: 124−125
3
3
29
30
-
1
ºC; IR (KBr) cm : 3407 (OH), 3129, 2964 (Ar-H), 2931, 2810
(CH ), 1722 (C=O), 1629, 1512 (aromatic frame), 1442, 1394,
1373, 1281, 1202, 1155, 1026, 984, 962, 830, 762, 730 cm ; H
NMR (300 MHz, DMSO-d ) δ: 8.49 (s, 1H, triazole 3-H), 7.99 (s,
2
–
1
1
6
1H, triazole 5-H), 7.72−7.69 (d, 1H, J = 9 Hz, coumarin 5-H),
7.00−6.98 (m, 2H, coumarin 6,8-H), 6.23 (s, 1H, coumarin 3-H),
5.60−5.58 (d, 1H, J = 6 Hz, OH), 4.38−4.31 (m, 2H, phenyl-
OCH
2.40 (s, 3H, coumarin 4-CH
δ: 161.9 (coumarin 2-C), 160.5 (coumarin 7-C), 155.1
2
), 4.18 (bs, 1H, CHOH), 4.09−4.04 (m, 2H, triazole-CH
2
),
1
3
3
) ppm; C NMR (75 MHz, DMSO-
6
d )
(coumarin 9-C), 153.8 (coumarin 4-C), 151.8 (triazole 3-C), 145.4
(triazole 5-C), 126.9 (coumarin 5-C), 113.7 (coumarin 3-C), 112.8
(coumarin 10-C), 111.7 (coumarin 6-C), 101.7 (coumarin 8-C),
2 2
70.7 (coumarin 7-OCH ), 67.6 (CHOH), 52.2 (triazole-CH ), 18.6
+ +
(coumarin-CH ) ppm; ESI-MS (m/z): 301.5 [M] , 273.1 [M-CO] ;
3
+
HRMS (TOF) calcd. for C15
302.1143.
15 3 4
H N O [M+H] , 302.1096; found,
Synthesis of 7-(3-(1H-benzo[d]imidazol-2-ylthio)-2-hydroxy pro-
poxy)-4-methyl-2H-chromen-2-one (4e). To a stirred suspension
of potassium carbonate (0.151 g, 1.2 mmol) in ethanol was added
1H-benzo[d]imidazole-2-thiol (0.150 g, 1.0 mmol). The mixture
o
was stirred at 60 C for 1 h. The reaction was cooled to room
temperature, compound 3 (0.302 g, 1.0 mmol) was added at the
room temperature and stirred for 10 h under reflux. After the
reaction came to end, solvent was evaporated and the residue was
extracted with chloroform (3 × 20 mL). The combined organic
extracts were dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The crude product was
purified
by
column
chromatography
chloroform/methanol, 20−10/1, V/V) to afford white solid (0.168
(eluent,
g). Yield: 56%; mp:168−169 °C; IR (KBr) ν: 3419 (OH), 3210
2
(NH), 2970 (Ar-H), 2658 (CH ), 1698 (C=O), 1630, 1610
(aromatic frame), 1455, 1390, 1349, 1267, 1287, 1204, 1148,
–
1
1
6
1109, 1071, 980, 744 cm ; H NMR (300 MHz, DMSO-d ) δ:
12.58 (s, 2H, benzoimidazole-2-thiol N-H), 7.65−7.63 (m, 2
coumarin 8-H), 7.35−7.33 (m, 2H, coumarin 5,6-H), 7.09-7.06 (d,
8