Synthesis and Activity of New Schiff Bases of Furocoumarin

Article abstract of DOI:10.1515/hc-2020-0115

Furocoumarins, such as 8-MOP, are the most common medications used to relieve the symptoms of vitiligo clinically. Some furocoumarins also showed excellent performance in an anti-bacterial assay. This paper describes the synthesis of a series of novel Schiff bases (6a-6k), and their promotion in melanogenesis and anti-bacterial properties were studied in vitro. The pigment production of B16 cells and bacterial inhibition ring assay were applied for the bioactivity of 6a-6k. According to the results, a stronger promotion on pigment content was observed, when six compounds co-cultured with cells, compared with positive control (8-MOP). Significantly, compound 6k (237%) as the most active was found to increase the amount of melanin more than 1.7 times compared with 8-MOP activation rate (136%). All the compounds could moderately retard C. albicans growth. Interestingly, aldehyde 5, which possessed a broader antibacterial spectrum, showed the highest inhibition against C. albicans as well and much better than the positive control (Amphotericin B). Studies of 6k in animal models of vitiligo and related molecular mechanism are presently under way, with the aim of discovering an anti-vitiligo leading compound.

Full text of DOI:10.1515/hc-2020-0115

Heterocycl. Commun. 2020; 26: 176–184
Research Article
Open Access
Huijun Xie, Chao Niu, Zeyang Chao, Nuramina Mamat, Haji Akber Aisa*
Synthesis and Activity of New Schiff Bases
of Furocoumarin
https://doi.org/10.1515/hc-2020-0115
Received August 12, 2020; accepted November 04, 2020.
Interestingly, aldehyde 5, which possessed a broader anti-
bacterial spectrum, showed the highest inhibition against
C. albicans as well and much better than the positive
control (Amphotericin B).
Studies of 6k in animal models of vitiligo and related
molecular mechanism are presently under way, with the
aim of discovering an anti-vitiligo leading compound.
Abstract: Furocoumarins, such as 8-MOP, are the most
common medications used to relieve the symptoms of viti-
ligo clinically. Some furocoumarins also showed excellent
performance in an anti-bacterial assay. This paper descri-
bes the synthesis of a series of novel Schiff bases (6a-6k),
and their promotion in melanogenesis and anti-bacterial
properties were studied in vitro.
The pigment production of B16 cells and bacterial inhi-
bition ring assay were applied for the bioactivity of 6a-6k.
According to the results, a stronger promotion on pigment
content was observed, when six compounds co-cultured
with cells, compared with positive control (8-MOP). Sig-
nificantly, compound 6k (237%) as the most active was
found to increase the amount of melanin more than 1.7
times compared with 8-MOP activation rate (136%). All the
compounds could moderately retard C. albicans growth.
Keywords: vitiligo, furocoumarin, melanin synthesis,
anti-bacterial activity, SAR
Introduction
Vitiligo clinical features are irregular white spots of skin
and mucous membrane often accompanied by gray-white
hair, with the typical acquired cutaneous abnormalities
[
[
1,2] (Figure 1). It affects 50 million patients worldwide
3]. The disease can affect people of any gender or ethnic
group and it is more likely to start during adolescence
4]. So far the mechanism of disease is still unclear, and
*
Corresponding author: Haji Akber Aisa, State Key Laboratory
[
Basis of Xinjiang Indigenous Medicinal Plants Resource
Utilization and Key Laboratory of Plant Resources and Chemistry
of Arid Zone, Xinjiang Technical Institute of Physics and
Chemistry, Chinese Academy of Sciences, Urumqi 830011, China;
University of Chinese Academy of Sciences, Beijing, China;
e-mail: aisa@ms.xjb.ac.cn
people are much more likely to believe the autoimmune
and inflammatory theory after considerable research.
The melanin pigments in skin, which was synthesized
in human melanosomes, play an important role in the pre-
vention of UV rays [6]. There are lots of factors (enzyme,
cytokines, protein kinases) which may regulate this
process through various signal pathways, such as tyrosi-
nase (TYR), α-MSH (α-melanocyte stimulating hormone),
MITF (microphthalmia-associated transcription factor),
MAPK (mitogen-activated protein kinase), etc [7-9].
Current clinical drugs for vitiligo include furocouma-
rins, prednisone, tacrolimus, calcipotriol, khellin and,
more recently, ruxolitinib [10,11]. As photosensitizers [12],
derivatives of furocoumarin (Figure 2) were always orally
or topically dosed and then combined with the UVB [13]. It
was proved in many clinical cases that the furocoumarins
were the most efficacious and led to cure or alleviate the
vitiligo, although some side-effects were reported [14,15].
At present, there is little comprehensive and systema-
tic research for new anti-vitiligo drug discovery. Our team
Huijun Xie, State Key Laboratory Basis of Xinjiang Indigenous
Medicinal Plants Resource Utilization and Key Laboratory of
Plant Resources and Chemistry of Arid Zone, Xinjiang Technical
Institute of Physics and Chemistry, Chinese Academy of Sciences,
Urumqi 830011, China; University of Chinese Academy of Sciences,
Beijing, China.
Chao Niu, State Key Laboratory Basis of Xinjiang Indigenous
Medicinal Plants Resource Utilization and Key Laboratory of Plant
Resources and Chemistry of Arid Zone,Xinjiang Technical Institute
of Physics and Chemistry, Chinese Academy of Sciences, Urumqi
8
30011, China; University of Chinese Academy of Sciences, Beijing,
China; Nantong ChanyooPharmatech Co.,Ltd.,Nantong 226407,
China
Zeyang Chao and Nuramina Mamat, State Key Laboratory Basis of
Xinjiang Indigenous Medicinal Plants Resource Utilization and Key
Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang
Technical Institute of Physics and Chemistry, Chinese Academy of
Sciences, Urumqi 830011, China
Open Access. © 2020 Haji Akber Aisa et al., published by De Gruyter.ꢀ
Attribution alone 4.0 License.
ꢀThis work is licensed under the Creative Commons

Huijun Xie et al.: Synthesis and Activity of New Schiff Bases of Furocoumarinꢁ
ꢁ177
Figure 1ꢀThe main symptoms of vitiligo [1,2]
Figure 2ꢂThe clinically used furocoumarins for vitiligo
Figure 3ꢂStructure of furocoumarins with anti-bacterial activity
are dedicated to search for leading compounds, which autoinducer inhibitors targeting microbial cell signaling
possess excellent potential development, from nature or processes [26] (Figure 3).
synthesis over the years [16-22]. Based on previous experi-
In this research, eleven derivatives of Schiff bases
ences, introduction of substituted phenyl to C-5 provided (6a-6k) were prepared, aiming to exploit new leadsas
us an approach of discovering new active molecules. We anti-vitiligo drugs, and potential anti-bacterial agents
next modified the structure by constructing imineswith that had wide spectrum and high-performance. We then
different anilines.
evaluated these compounds for the enhancing effect on
In addition, naturally occurring and synthetic furo- melanin synthesis at cell level, and bacteriostatic action
coumarins were demonstrated to show anti-bacterial on three different strains. After that, preliminary SAR was
and anti-fungal activity [23-25], since they may act as summarized as well.

ꢁ
Huijun Xie et al.: Synthesis and Activity of New Schiff Bases of Furocoumarin
1
78ꢁ
Scheme 1ꢂSynthesis for Schiff bases 6a-6k
Figure 4ꢀCytotoxicity of Schiff bases 6a-6k
Result and discussion
A route to synthesize 6a-6k was illustrated below at -78 °C with high yields. Cyclization of 3, dissolving in a
acetone gave 2. After that, aldehyde 3 was obtained by
an optimized Swern Oxidation using DMSO and (COCl)2
(
Scheme 1). Resorcin was treated with ethyl acetoace- mixture of water and 1,4-dioxane, yielded compound 4 in
tate in H SO to yield 4-methylumbelliferone (1) [27].The 1M NaOH for 6 h.
2
4
successive hydrocarbylation performed under existence
of chloroethanol and anhydrous potassium carbonatein to furocoumarin 5. The desired derivatives 6a-6k were
Further oxidation of 4 with selenium dioxide led

Huijun Xie et al.: Synthesis and Activity of New Schiff Bases of Furocoumarinꢁ
ꢁ179
Figure 5ꢀStimulation of Schiff bases 6a-6k on melanin synthesis
Figure 6ꢀCellular protein concentration of Schiff bases 6a-6k
finally produced by refluxing 5 in 95% ethanol with corre- was 50 μM (Figure 4). After that, the synthesized Schiff
sponding aniline [28].
bases were evaluated for the ability to stimulate melanin
synthesis in B16 cells [29] (Figure 5). Meanwhile, we
measured protein concentration, in cells, to avoid errors.
In vitro melanin synthesis evaluation
The CCK-8 assay was first performed to study the cytoto-
xicity of 6a-6k to B16 cells, and none of the compounds thesized compounds (6a-6b,6e-6f, 6j-6k), of which
showed toxic effects to the cells when the concentration activation rates were 142%-237%, had superior relative
(Figure 6).
Compared to control group, more than half of syn-

ꢁ
Huijun Xie et al.: Synthesis and Activity of New Schiff Bases of Furocoumarin
1
80ꢁ
Table 1ꢂAnti-bacterial activity oftarget compounds 6a-6k
Compounds
Rꢁ
Concentration
Loading amount
(µL)
Inhibition zone
diameter (mm)
(
mM)
Candida
albicans
Escherichia
coli
Staphylococcus aureus
ꢂa
ꢂb
ꢂc
ꢃ-CHꢄ
ꢈ-CHꢄ
ꢈ-Cl
ꢅꢆ
ꢅꢆ
ꢅꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢇꢆ
ꢇꢆ
ꢇꢆ
NI
NI
NI
NI
9
ꢇꢇ
ꢂd
H
ꢈ-OCHꢄ
ꢄ,ꢈ-diCHꢄ
ꢈ-F
ꢄ,ꢈ-diF
ꢄ-Cl
ꢅꢆ
ꢅꢆ
ꢅꢆ
ꢅꢆ
ꢅꢆ
ꢅꢆ
ꢅꢆ
ꢅꢆ
ꢅꢆ
ꢅꢆ
ꢄ.ꢆ
ꢆ.ꢄ
ꢅ.ꢈ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
ꢃꢆ
9
NI
NI
NI
NI
NI
NI
NI
NI
NI
ꢉ
NI
ꢉ
ꢂe
ꢇꢆ
ꢇꢆ
ꢇꢃ
ꢇꢃ
ꢇꢇ
ꢇꢆ
ꢇꢆ
ꢋ
ꢂf
ꢉ
ꢂg
9
ꢂh
ꢇꢊ
NI
NI
9
ꢂi
ꢂj
ꢃ-OCHꢄ
ꢈ-OH
-
ꢂk
ꢃ
NI
ꢇꢃ
NI
ꢇ9
NI
ꢄ
-
-
ꢃꢄ
-
Ampicillin
Ampicillin
Amphotericin B
ꢇꢈ
NI
NI
-
ꢇꢅ
“NI”: not inhibit growth of bacteria (inhibition zone diameters ≤ꢋ mm).
melanin synthesis (Figure 5). It was clear that EDG (elect- including Candida albicans (ATCC 10231, Fungi), Escheri-
ron-donating group) substituted benzene (6a-6b, 6e, 6j), chia coli (ATCC 11229, Gram negative bacteria) and Staphy-
were beneficial to the effect, which was consistent with lococcus aureus (ATCC 6538, Gram positive bacteria).
our previous findings [22]. Furthermore, an introduction
Table 1 showed that all the tested compounds could
of a second EDG could significantly enhanced the amount moderately inhibit the growth of C. albicans (Candida
of melanin (6f>6a, 6b). It was noticed that demethylation albicans). The introduction of an aldehyde on 5-position
may remarkably enhance the stimulation effect as shown may significantly improve the inhibitory effect on C. albi-
in 6k, which was regarded as the most promising lead cans (5>4). Besides, compound 5, which showed higher
candidate. On the contrary, the activity of compounds value than positive control (Amphotericin B) against C.
substituted by -F (6g, 6h) and -Cl (6c, 6i) dropped dra- albicans, possessed a broad spectrum of activity not only
matically irrelevantly to type, position and numbers of against E. coli (Escherichia coli) but also S. aureus (Staphy-
the halogens. In general, an EDG and hydroxy on benzene lococcus aureus) as well.
caused an increase in melanogenesis, and it was suspec-
Among 6a-6p, compounds with any substituents (-F,
ted that this maybe caused by electrostatic forces and -Cl, -CH , -OCH or -OH) at para-position of benzene may
3
3
hydrophilicity.
generally inhibit the growth of the S. aureus(6b-6c, 6e-6h,
6
6
k). And the halogen, including both -F and -Cl (6c, 6g,
h), were more favorable to the activity than EDGs. Com-
In vitro anti-bacterial activity evaluation
pound 6h had comparable activity to the positive control
on C. albicans and S. aureus which suggested that a second
After that, all the Schiff bases were evaluated for their introduction of halogen to the benzene ring may strongly
anti-bacterial efficiency against three species of bacteria, increase the inhibitory effect against S.aureus.

Huijun Xie et al.: Synthesis and Activity of New Schiff Bases of Furocoumarinꢁ
ꢁ181
Conclusion
(30 mL), the mixture was heated to reflux for 6 h after
which potassium carbonate (0.7 g, 5.0 mmol) was added.
In this research, eleven novel 5-Schiff base substituted The solvent was evaporated and the residue was purified
furocoumarin derivatives 6a-6k have been synthesized using flash column chromatography on silica gel to afford
1
based on our previous research. The melanin synthesis compound 2. Yield 93%, white solid, m.p. 107–109°C; H
assay in B16 cells demonstrated that six compounds were NMR (400 MHz, CDCl ) δ 7.51 (d, J =9.0 Hz, 1H), 6.91–6.83
3
better than control group. Furthermore, derivative 6k (m, 2H),6.15 (d, J =1.1 Hz, 1H), 4.15 (t, J =8.7 Hz, 2H), 4.01
(
237%), which was 1.7-fold stronger than 8-MOP (136%), (m, 2H), 2.40 (d, J =1.1 Hz, 3H).
is now being studied for its mechanism of action in vivo.
In addition, all the Schiff bases were proved to inhibit
the growth of C. albicans in vitro. Substitution at the para- Synthesis of7-(2-Oxoethoxy)-4-methyl-2H-chromen-2-
position of benzene led to an increase in inhibition against one (3)
S. aureus, and a halogen substituent seemed to be more
preferable. It was impressive that compound 5, which Oxalyl chloride (0.126 g, 1.0 mmol) was dissolved in
presented the strongest potency against C. albicans, had dichloromethane (5 mL) at-78 °C filled with Ar. After addi-
abroad-spectrum anti-bacterial activity against both E. tion of DMSO (0.078 g, 1.0 mmol), the mixture was stirred
coli and S. aureus. The proposed scaffolds of derivatives for 20 min until a dichloromethane solution of compound
offer the possibility of convenient further modifications 2 (0.11 g, 0,05 mmol) was added dropwise. Half an hour
that could give rise to structures with improved anti-bac- later, Et N (0.250 g, 2.5 mmol) was added and the tempe-
3
terial inhibitory activities.
rature was increased to 25 °C slowly. The solvent was then
evaporated to yield compound 3. Yield 95%, white solid,
1
m.p. 142–144°C; H NMR (400 MHz, CDCl ) δ 9.85 (s, 1H),
3
7
.53 (d, J = 8.8 Hz, 1H), 6.89 (dd, J = 8.8, 2.6 Hz, 1H), 6.78 (d,
Experimental section
J = 2.5 Hz, 1H), 6.15 (d, J = 1.0 Hz, 1H), 4.68 (s, 2H), 2.39 (d,
J = 0.9 Hz, 3H).
All reagents were commercial and untreated. NMR were
acquired with CDCl and tetramethylsilane, which were
3
solvent and internal standard, on Varian (400 and 600
MHz) spectrometers. Uncorrected melting points were
measured using a Buchi B-540. Mass spectra were obtained
using ABSciex QSTAR Elite quadrupole-time-of-flight mass
spectrometry. Thermo Fisher Scientific Nilolet 6700 FT-IR
infrared spectrometer was used to record infrared data.
Synthesis of5-Methyl-7H-furo[3,2-g]chromen-7-onecom-
pounds (4)
The compound 3 (0.22 g, 1.0 mmol), which dissolved in
a mixed solvent of H O and 1,4-dioxane, was added to an
2
aqueous solution of sodiumhydroxide, and then refluxed.
The reaction was cooled until the disappearance of raw
materials then extracted with AcOEt (3 x 50 mL) after neu-
tralization. The organic extracts were concentrated and
purified by silica-gel column chromatography to give 4 as
Synthesis of 4-Methylumbelliferone (1)
The conc. H SO (1.0 mL) was added slowly, to a stirring
2
4
1
a white solid. Yield 70%, m.p. 158–159 °C; H NMR (400
mixture of resorcinol (4.0 g, 36.4 mol) in dry 1,4-dioxaneun-
der ice bath, making it below 20 °C during the process.
The solution was heated to 60 °C for 12 hours after an
addition of ethyl acetoacetate (5.6 g, 42.0 mmol). When the
starting material was consumed, the mixture was poured
into water, a white solid 1 was obtained after filtrating and
washing with methanol, Yield 89%, m.p. 200–203 °C.
MHz, CDCl ) δ 7.81 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.47 (s,
3
1
3
1
H), 6.85 (d, J = 2.1 Hz, 1H), 6.27 (s, 1H), 2.50 (s, 3H). C NMR
(
101 MHz, CDCl ) δ 161.24, 156.43, 152.78, 151.75, 146.96,
3
1
1
24.77, 116.70, 113.62, 106.67, 100.00, 19.30;IR (KBr) v: 2921,
-1
723, 1630, 1385, 1137, 1031, 928 cm ; HRMS (ESI) calcd for
+
C H O [M+H] 201.0552, found 201.0540.
1
2
9
3
Synthesis of7-(2-Hydroxyethoxy)-4-methyl-2H-chromen- Synthesis of7-Oxo-7H-furo[3,2-g]chromene-5-carbalde-
-one (2) hyde (5)
2
4
-Methylumbelliferone (1) (0.44 g, 2.5 mmol) and chloro- A solution of compound 4 (4.0 g, 10 mmol) and selenium
ethanol (0.30 g, 3.8 mmol) were dissolved in dry acetone dioxide (1.67 g, 15 mmol) in anhydrous xylene (50 mL) was

ꢁ
Huijun Xie et al.: Synthesis and Activity of New Schiff Bases of Furocoumarin
1
82ꢁ
1
3
heated to 140 °C and stirred for 24 h. The Se was filtered (s, 1H). C NMR(151 MHz, CDCl ): δ 161.12, 157.54, 156.42,
3
and the resulting filtrate was evaporated. Compound 5 152.59, 150.82, 147.06, 146.10, 129.63,127.94, 125.18,124.55,
was acquired via column chromatography purification. 121.12, 119.56, 118.72, 113.31, 107.13, 100.21. IR (KBr) v:
1
-1
Yield 63%, yellow solid, m.p. 176–177°C; H NMR (400 1705,1633, 1449, 1154, 1132, 761 cm ; HRMS (ESI) calcd for
+
MHz, CDCl ) δ 10.14 (s, 1H), 8.90 (s, 1H), 7.72 (d, J = 2.1 Hz, C H NO [M+H] 290.0812, found 290.0798.
3
18 12
3
1H), 7.54 (s, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.86 (s, 1H).
(Z)-5-((4-Methoxyphenyl)imino)methyl-
7
H-furo[3,2-g]chromen-7-one (6e). Yield 34%, light
1
yellow solid, m.p. 188–190°C; H NMR (400 MHz, CDCl ):
3
General synthesis method of Schiff bases 6a–6k
δ 9.18 (s,1H), 8.69 (s, 1H), 7.70 (d, J= 2.2 Hz, 1H), 7.53 (s, 1H),
7
.39 (d, J= 8.9 Hz, 2H), 7.01(d, J= 8.9 Hz, 2H), 6.89 (d, J= 2.0
1
3
A mixture of Compound 5 (1.0 mmol) and corresponding Hz, 1H), 6.76 (s, 1H), 3.88 (s, 3H). C NMR(151 MHz, CDCl ):
3
aniline (3.0 mmol) in ethanol (20 ml) was refluxed. After δ 161.26, 160.05, 156.35, 154.52, 152.58, 146.98, 146.37,
2
4 h, the reaction was evaporated and purified by silica 143.46, 125.08,122.99, 119.55, 117.85, 116.80, 114.84, 113.50,
gel chromatography to furnish 6a–6k.
107.12, 100.14, 55.74. IR (KBr) v:2924, 2843, 1706, 1631, 1560,
-1
+
(
Z)-5-((2-methylphenyl)imino)methyl-7H-furo[3,2- 1446, 1153, 759 cm ; HRMS (ESI) calcd for C H NO [M+H]
1
9
14
4
g]chromen-7-one (6a). Yield 40%, light yellow solid, m.p. 320.0917, found 320.0940.
1
1
1
81–183°C; H NMR (400 MHz, CDCl ): δ 9.23 (s,1H), 8.59 (s,
(Z)-5-((3,4-Dimethylphenyl)imino)methyl-
3
H), 7.71 (d, J= 2.1 Hz, 1H), 7.55 (s, 1H), 7.34–7.26 (m, 3H), 7.03 7H-furo[3,2-g]chromen-7-one (6f). Yield 33%, light
1
(
(
d, J= 7.2 Hz, 1H), 6.87 (d, J= 1.9 Hz, 1H), 6.79 (s, 1H), 2.46 yellow solid, m.p. 165–167°C; H NMR (400 MHz, CDCl ):
3
13
s, 3H). C NMR (101MHz, CDCl ): δ 161.19, 156.77, 156.38, δ 9.17 (s,1H), 8.66 (s, 1H), 7.70 (d, J= 2.2 Hz, 1H), 7.52 (s,
3
1
1
52.62, 149.92, 147.06, 146.14, 133.02,130.91, 127.79, 127.19, 1H), 7.23 (d, J= 7.9 Hz, 1H), 7.16(s, 1H), 7.11 (dd, J= 7.9, 2.0
25.17, 119.59, 118.71, 117.10, 113.41, 107.12, 100.20, 18.35. Hz, 1H), 6.89 (d, J= 2.1Hz, 1H), 6.74 (s, 1H), 2.34 (s,3H),
1
3
IR (KBr) v: 2924, 2853, 1709, 1634, 1448, 1156, 1134, 1012, 2.32 (s, 3H). C NMR (101 MHz, CDCl ): δ 161.19, 156.33,
3
-1
+
7
60 cm ; HRMS (ESI) calcd for C H NO [M+H] 304.0968, 156.08,152.56,148.46, 146.97, 146.29, 137.97, 136.96,
19
14
3
found 304.0990.
130.70, 125.09, 122.64, 119.61, 118.45,118.20, 113.41,
(
Z ) - 5 - ( ( 4 - M e t h y l p h e n y l ) i m i n o ) m e t h y l - 107.13, 100.10, 20.02, 19.65. IR (KBr) v: 2923, 2855, 1704,
-1
7
H-furo[3,2-g]chromen-7-one (6b). Yield 38%, light 1637,1568, 1447, 1157, 1130, 762 cm ; HRMS (ESI) calcd for
1
+
yellow solid, m.p. 193–194°C; H NMR (400 MHz, CDCl ): C H NO [M+H] 318.1125, found 318.1145.
3
20 16
3
δ 9.18 (s,1H), 8.67 (s, 1H), 7.70 (d, J= 2.2 Hz, 1H), 7.54 (s,
1
2
(Z)-5-((4-Fluorophenyl)imino)methyl-7H-furo[3,2-
H), 7.05 (d, J= 8.1 Hz, 2H), 6.90–6.85 (m, 3H), 6.77 (s, 1H), g]chromen-7-one (6g). Yield 30%, light yellow solid,
.42 (s, 3H). 13C NMR (151 MHz, CDCl ): δ 161.19,156.35, m.p. 179–181°C; H NMR (400 MHz, CDCl ): δ 9.13 (s,1H),
1
3
3
1
1
2
52.60, 148.19, 147.01, 146.27, 138.29, 130.24, 125.14, 121.21, 8.65 (s, 1H), 7.71 (d, J= 2.2 Hz, 1H), 7.54 (s, 1H), 7.39–7.31 (m,
19.60,118.35, 116.04, 113.42, 107.14, 100.17, 21.31; IR (KBr) v: 2H), 7.22–7.12(m, 2H), 6.89 (d, J= 1.9 Hz, 1H), 6.77 (s, 1H).
-1
13
926, 2851, 1707, 1630,1445, 1150, 1135, 1011, 944, 759 cm ;
C NMR (101 MHz, CDCl ): δ 161.23,157.07, 152.77, 151.77,
3
+
HRMS (ESI) calcd for C H NO [M+H] 304.0968, found 147.39, 146.97, 145.95, 125.17, 122.97, 119.44, 118.71,116.69,
1
9
14
3
3
04.0948.
116.40, 113.64, 107.10, 106.68, 100.03. IR (KBr) v: 1720,
-1
(
Z)-5-((4-Chlorophenyl)imino)methyl-7H-furo[3,2- 1625, 1569, 1450,1228, 1082, 755 cm ; HRMS (ESI) calcd for
+
g]chromen-7-one (6c). Yield 31%, yellow solid, m.p. C H FNO [M+H] 308.0717, found 308.0693.
2
1
8
11
3
1
00–202°C; H NMR (600 MHz, CDCl ): δ 9.13 (s,1H),8.64 (s,
H), 7.71 (d, J= 2.0 Hz, 1H), 7.55 (s, 1H), 7.45 (d, J= 7.4 Hz, 2H), 7H-furo[3,2-g]chromen-7-one (6h). Yield 28%, light
(Z)-5-((3,4-Difluorophenyl)imino)methyl-
3
1
1
3
1
7
.28 (d, J= 8.2 Hz, 2H), 6.89 (d, J= 1.9 Hz, 1H), 6.78 (s, 1H). C yellow solid, m.p. 163–164°C; H NMR (400 MHz, CDCl ): δ
3
NMR (151 MHz, CDCl ): δ 160.84, 157.72, 147.23, 146.99, 9.09 (s, 1H), 8.62 (s, 1H), 7.69 (d, J= 2.2 Hz, 1H), 7.49 (s, 1H),
3
13
145.68, 138.10, 133.61, 129.65, 125.06, 124.42,122.36, 113.02, 6.91–6.89 (m, 2H),6.87–6.84 (m, 2H), 6.79 (s, 1H). C NMR (101
1
1
3
19.28, 118.88, 106.96, 100.14. IR (KBr) v: 1717, 1623, 1576, MHz, CDCl ): δ 161.26, 156.47,154.30, 152.79, 147.39, 146.98,
3
-
1
+
234,1076 cm ; HRMS (ESI) calcd for C H ClNO [M+H]
145.23, 132.69, 127.82, 124.57, 119.15, 116.70,113.66, 110.18,
108.74, 106.68, 100.32. IR (KBr) v: 1722, 1630, 1569, 1457, 1334,
Z)-5-(Phenylimino)methyl-7H-furo[3,2-g]chro- 1231,1100, 763 cm ; HRMS (ESI) calcd for C H F NO [M+H]
18
11
3
24.0422, found 324.0440.
-1
+
(
18
10
2
3
men-7-one (6d). Yield 36%, yellow solid, m.p. 210–211°C; 326.0623, found326.0651.
1
H NMR (600 MHz, CDCl ): δ 9.16 (s, 1H), 8.66 (s,1H), 7.71
( Z ) - 5 - ( ( 3 - C h l o r o p h e n y l ) i m i n o ) m e t h y l -
3
(
d, J= 2.1 Hz, 1H), 7.55 (s, 1H), 7.51–7.46 (m, 2H), 7.36 (t, J=7.4 7H-furo[3,2-g]chromen-7-one (6i). Yield 31%, yellow
1
Hz,1H), 7.33 (d, J= 7.4 Hz, 2H), 6.89 (d, J = 2.1 Hz, 1H), 6.78 solid, m.p. 192–193°C; H NMR (600 MHz, CDCl ): δ 9.12 (s,
3

Huijun Xie et al.: Synthesis and Activity of New Schiff Bases of Furocoumarinꢁ
ꢁ183
1
H),8.63 (s, 1H), 7.72 (d, J= 2.1 Hz, 1H), 7.56 (s, 1H), 7.45– Anti-bacterial activity assay
7
.38 (m, 1H), 7.36–7.31 (m,2H), 7.21 (d, J= 8.3, 1H), 6.90 (d,
1
3
J= 2.0 Hz, 1H), 6.79 (s, 1H). C NMR (101 MHz,CDCl ): δ The agar spread method was employed to determine the
3
1
1
1
1
3
61.31, 157.36, 154.20, 152.51, 150.13, 148.07, 147.41, 133.73, anti-bacterial activity of 6a-6k. Samples of the strain were
31.18,128.41, 126.87, 125.38, 120.92, 118.62, 117.79, 114.73, incubated at 37 °C for 18 h after inoculation with a suita-
08.66, 101.11. IR (KBr) v:1717, 1635, 1580, 1461, 1227, ble medium. After centrifugation the strains were kept in
-1
+
076, 756 cm ; HRMS (ESI) calcd for C H ClNO [M+H]
suspension in sterile water. The well was produced by the
mixture of bacteria (1 mL) and agar media (100 mL). After
1
8
11
3
24.0422, found 324.0439.
(
Z)-5-((2-Methox yphenyl)imino)methyl- addition of compounds, the wells were cultured at 37 °C
7
H-furo[3,2-g]chromen-7-one (6j). Yield 35%, light for 24 h. Inhibitory activity was evaluated, based on the
1
yellow solid, m.p. 169–170°C; H NMR (400 MHz, CDCl ): measurement of the diameter of inhibition zone. Averages
3
δ 9.13 (s,1H), 8.76 (s, 1H), 7.69 (d, J= 2.2 Hz, 1H), 7.53 (s, were obtained from three assays and the compound was
1
H), 7.33–7.28 (m, 1H), 7.15 (dd,J= 7.9, 1.4 Hz, 1H), 7.08–7.01 considered as inactive if the diameter ≤7 mm.
1
3
(
m, 2H), 6.87 (d, J= 2.1, 1H), 6.76 (s, 1H), 3.94 (s,3H). C
NMR (101 MHz, CDCl ): δ 161.26, 156.44, 152.79, 151.77, Acknowledgements: This research was financially
3
147.38,146.97, 124.78, 124.56, 121.24, 119.14, 116.70, 113.64, supported by the Xinjiang Key Laboratory of Xinjiang
1
1
07.11, 106.68, 100.30,100.04, 55.67. IR (KBr) v: 2925, 2850, Indigenous Medicinal Plants Resource Utilization (No.
-1
706, 1635, 1576, 1444, 1154, 1136, 758 cm ; HRMS (ESI) 2018D04020); Funds for the Youth Innovation on Promo-
+
calcd for C H NO [M+H] 320.0917, found 320.0933.
tion Association, Chinese Academy of Science (2019425);
19
14
4
(
Z)-5-((4-Hydrox yphenyl)imino)methyl- Tianshan Youth Program of Xinjiang Autonomous Region
7
H-furo[3,2-g]chromen-7-one (6k). Yield 30%, yellow in 2019 (2019Q028).
1
solid, m.p. 218–220°C; H NMR (400 MHz, CDCl ): δ 9.18
3
(
s,1H),8.68 (s, 1H), 7.71 (d, J= 2.2 Hz, 1H), 7.54 (s, 1H), 7.35 Conflict of interest: The authors state no conflict of
(
d, J= 8.6 Hz, 2H), 6.95 (d, J= 8.8 Hz, 2H), 6.89 (d, J= 2.0 Hz, interest.
13
1
1
1
1
H), 6.76 (s, 1H). C NMR (101 MHz,CDCl ): δ 163.43, 157.74,
3
55.91, 154.56, 148.87, 141.31, 138.07, 132.03, 124.53,122.85,
20.55, 116.92, 115.81, 111.55, 107.95, 100.97. IR (KBr) v: 3367,
-1
References
705, 1634,1448, 1152, 1133, 760 cm ; HRMS (ESI) calcd for
+
C H NO [M+H] 306.0761, found 306.0736.
18
12
4
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