Synthesis and anti-inflammatory activity of 2-oxo-2H-chromenyl and 2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates

Article abstract of DOI:10.1016/j.bmcl.2020.127341

Cycloaddition reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (3a-g) and 4-chloro-2H-chromene-3-carbaldehydes (7a-h) with activated alkynes (4a-b) provided the 2-oxo-2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates (5a-n) and 2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates (8a-p). All the prepared compounds were screened for anti-inflammatory activity. In vitro anti-inflammatory activity data demonstrated that the compounds 5g, 5i, 5k-l and 8f are effective among the tested compounds against TNF-α (1.108 ± 0.002, 0.423 ± 0.022, 0.047 ± 0.001, 0.070 ± 0.002 and 0.142 ± 0.001 μM) in comparison with standard compound Prednisolone (0.033 ± 0.002 μM). Based on in vitro results, three compounds (5i, 5k and 8f) have been selected for in vivo experiments and these compounds are identified as better compounds with respect to anti-inflammatory activity in LPS induced mice model. Compound 5i was identified as potent and showed significant reduction in TNF-α and IL-6.

Full text of DOI:10.1016/j.bmcl.2020.127341

Journal Pre-proofs
Synthesis and anti-inflammatory activity of 2-oxo-2H-chromenyl and 2H-
chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates
Siva Hariprasad Kurma, Shailaja Karri, Madhusudana Kuncha, Ramakrishna
Sistla, China Raju Bhimapaka
PII:
S0960-894X(20)30452-2
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127341
BMCL 127341
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
5 March 2020
4 June 2020
6 June 2020
Please cite this article as: Hariprasad Kurma, S., Karri, S., Kuncha, M., Sistla, R., Raju Bhimapaka, C., Synthesis
and anti-inflammatory activity of 2-oxo-2H-chromenyl and 2H-chromenyl-5-oxo-2,5-dihydrofuran-3-
carboxylates, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127341
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Bioorganic & Medicinal Chemistry Letters
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Synthesis and anti-inflammatory activity of 2-oxo-2H-chromenyl and 2H-
chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates
Siva Hariprasad Kurmaa,c, Shailaja Karrib, Madhusudana Kunchab, Ramakrishna Sistlab,*,
China Raju Bhimapakaa,c*
aDepartment of Organic Synthesis & Process Chemistry, bDepartment of Applied Biology,
CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India.
cAcSIR-Postal Staff College Area, Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201002.
ABSTRACT
ARTICLE INFO
Article history:
Received
Revised
Accepted
Available online
Cycloaddition reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (3a-g) and 4-chloro-
2H-chromene-3-carbaldehydes (7a-h) with activated alkynes (4a-b) provided the 2-oxo-2H-
chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates (5a-n) and 2H-chromenyl-5-oxo-2,5-
dihydrofuran-3-carboxylates (8a-p). All the prepared compounds were screened for anti-
inflammatory activity. In vitro anti-inflammatory activity data demonstrated that the compounds
5g, 5i, 5k-l and 8f are effective among the tested compounds against TNF-α (1.108±0.002,
0.423±0.022, 0.047±0.001, 0.070±0.002 and 0.142±0.001 µM) in comparison with standard
compound Prednisolone (0.033±0.002 µM). Based on in vitro results, three compounds (5i, 5k
and 8f) have been selected for in vivo experiments and these compounds are identified as better
compounds with respect to anti-inflammatory activity in LPS induced mice model. Compound
5i was identified as potent and showed significant reduction in TNF-α and IL-6.
Keywords:
2H-Chromenyl-5-oxo-2,5-dihydrofuran-3-
carboxylates ;
4-Chloro-2-oxo-2H-chromene-3-carbaldehydes;
4-Chloro-2H-chromene-3-carbaldehydes;
Activated alkynes;
Cycloaddition reaction.
2009 Elsevier Ltd. All rights reserved
O
Furanones (butenolides) are important heterocyclic compounds1-2
having unsaturated γ-lactone ring system found to be an essential
subunit in natural products (Fig.1). These compounds have been
displayed broad range of medicinal and pharmaceutical
properties such as anti-microbial, anti-cancer, anti-inflammatory,
anti-malarial, anti-viral, anti-oxidant, anti-convulsant, anti-
ulcerative, anti-psychotic and anti-tuberculosis. Geiparvarin,
Ascorbic acid, Inotilone, Rubrolide-O, Firocoxib and Rofecoxib
are important molecules having furanone moiety (Fig.1)
displayed anti-tumor, anti-oxidant and anti-inflammatory
activities1. Therefore, the furanone moiety had the immense
importance and the preparations of furanone containing novel
heterocyclic compounds are worth to carry out the research.
O
Cl
HO
HO
O
O
O
O
O
Br
O
Br
OH
O
HO
Geiparvarin
Br
Inotilone
O
O
Rubrolide O
S
HO
O
O
O
HO
SO2CH3
O
O
OH
HO
O
O
Rofecoxib
Ascorbic acid
Firocoxib
Figure 1. Important molecules with Furanone moiety.
prepared 4-chloro-2-oxo-2H-chromene-3-carbaldehydes based
compounds
such
as
Knoevenagel
derivatives,
2-oxo-2H-
identified 2H-
6H-
On the other hand, coumarins are important natural products3
and privileged heterocyclic compounds associated with various
biological activities namely anti-coagulant, anti-cancer, anti-
viral, anti-oxidant, anti-microbial and anti-inflammatory
properties4-9. Due to the importance of coumarins, our research
group focused work on coumarins and prepared various novel
coumarin heterocyclic compounds10-13. The author research group
chromenoquinolinones14
and
We
chromenylpyrazolecarboxylates10.
chromenylpyrazolecarboxylate compounds as potential anti-
cancer agents with better photophysical properties10. Author
research group also worked on 4-chloro-2H-chromene-3-
carbaldehydes and prepared useful heterocyclic compounds such
as 2H-chromenylphenyloxazolones15, 2H-chromenylmethylene
benzohydrazides16 and chromenyldihydropyridines17.
The furanone moieties coupled with the coumarins to obtain
novel heterocyclic compounds have not been explored and
moreover, biological profiles of these compounds are also had
not been studied. Therefore, the present research work has been
----------------------------------------------
*Corresponding author. E-mail address: chinaraju@iict.res.in

R
O
O
R
Cl
R
designed to prepare coumarin based furanone compounds by
cycloaddition reaction of 4-chloro-2-oxo-2H-chromene-3-
carbaldehydes10,18 and 4-chloro-2H-chromene-3-carbaldehydes15-
with activated alkynes. The target compounds were evaluated
for anti-inflammatory activity for the first time and the results
were discussed below.
R1
R2
R1
R2
CHO
R1
R2
c
a, b
O
OH
R3
R3
R3
7a-g
17
6a-g
1a-g
CO2R4
R = R1 = R2 = R3 = H
PPh3
DCM, rt
1a
1b
1c
1d
1e
1f
4a-b
R = R2 = R3 = H, R1 = CH3
R = R1 = CH3, R2 = R3 = H
R = R3 = H, R1 = R2 = CH3
R = R1 = H, R2 = R3 = CH3
R = R2 = R3 = H, R1 = Cl
R = R2 = R3 = H, R1 = Br
CO2R4
Scheme I describes the preparation of target compounds 2-
oxo-2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates 5a-n.
The required starting materials 4-chloro-2-oxo-2H-chromene-3-
carbaldehydes 3a-g were prepared starting from phenols 1a-g.
The acetylation of phenols 1a-g with acetyl chloride in the
presence of pyridine in dry DCM provided the phenyl acetates.
The Fries rearrangement of phenyl acetates in presence of AlCl3
at 120 °C and subsequent reaction with diethyl carbonate in the
presence of NaH in one-step provided the 4-hydroxycoumarins
2a-g. Vilsmeier-Haack reaction (VH) of 2a-g in the presence of
POCl3 and dry DMF provided 4-chloro-2-oxo-2H-chromene-3-
carbaldehydes 3a-g. [3+2] Cycloaddition reaction19-20 of 3a-g
with activated alkynes 4a-b in the presence of PPh3 in dry DCM
provided the series of target compounds 5a-n (Table 1, Scheme
I).21 All the prepared compounds are unknown and characterized
by spectral data (SI).
OR4
R4O2C
Cl
R
1g
R1
R2
O
O
Reaction conditions
a) Acrylonitrile, K2CO3, tBuOH, reflux, 24-36 h, 60-65%.
b) TFA, TfOH, 0 oC-rt, 19-24 h, 75-80%.
c) Oxalyl chloride, Dry DMF, 0 oC-80 oC, 3 h, 75-80%.
O
R3
8a-n
R = R1 = R2 = R3 = H, R4 = C2H5
R = R1 = R2 = R3 = H, R4 = CH3
8a
8b
8c R = R2 = R3 = H, R1 = CH3, R4 = C2H5
R = R2 = R3 = H, R1 = CH3, R4 = CH3
8d
8e
8f
8g
8h
8i
8j
8k
R = R1 = CH3, R2 = R3 = H, R4 = C2H5
R = R1 = CH3, R2 = R3 = H, R4 = CH3
R = R3 = H, R1 = R2 = CH3, R4 = C2H5
R = R3 = H, R1 = R2 = CH3, R4 = CH3
R = R1 = H, R2 = R3 = CH3, R4 = C2H5
R = R1 = H, R2 = R3 = CH3, R4 = CH3
R = R2 = R3 = H, R1 = Cl, R4 = C2H5
R = R2 = R3 = H, R1 = Cl, R4 = CH3
8l
8m
8n
R = R2 = R3 = H, R1 = Br, R4 = C2H5
R = R2 = R3 = H, R1 = Br, R4 = CH3
Scheme 2 Preparation of 2H-chromenyl-5-oxo-2,5-dihydrofuran-
3-carboxylates 8a-n.
OH
R
OH
R
Cl
R3
R2
R1
R2
R1
R2
CHO
O
d
a, b, c
R
O
O
O
Further, the naphthyl based target compounds 8o-p also
prepared as per the Scheme III under our optimized reaction
conditions starting from naphthalen-1-ol 1h (Table 2).22 All the
prepared compounds 8a-p are unknown and characterized by
spectral data (see SI).
R1
R3
R3
3a-g
2a-g
1a-g
CO2R4
4a-b
CO2R4
R = R1 = R2 = R3 = H,
1a
1b
1c
1d
1e
1f
PPh3
DCM, rt
R = R2 = R3 = H, R1 =CH3,
R = R3 = H, R1 = R2 = CH3,
R = R2 = H, R1 = R3 = CH3,
R = R2 = R3 = H, R1 = Cl,
R = R2 = R3 = H, R1 = Br,
R = R2 = R3 = H, R1 = Ph,
OR4
R4O2C
Cl
R
1g
O
Cl
R1
R2
O
O
CHO
OH
Reaction conditions
a) AcCl, Pyridine, DCM, 0 oC-rt, 5 h, 95-98%.
b) AlCl3, 0 oC-120 oC, 5 h, 90-95%.
O
O
a, b
c
R3
O
O
c) NaH, CO(OC2H5)2, 0 oC-110 oC, 4 h, 65-75%
d) Dry DMF, POCl3, 0 oC-60 oC, 4-5 h, 65-74%.
5a-n
R = R1 = R2 = R3 = H, R4 = C2H5
R = R1 = R2 = R3 = H, R4 = CH3
7h
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
1h
Reaction conditions
6h
CO2R4
R = R2 = R3 = H, R1 = CH3, R4 = C2H5
R = R2 = R3 = H, R1 = CH3, R4 = CH3
R = R3 = H, R1 = R2 = CH3, R4 = C2H5
R = R3 = H, R1 = R2 = CH3, R4 = CH3
R = R2 = H, R1 = R3 = CH3, R4 = C2H5
R = R2 = H, R1 = R3 = CH3, R4 = CH3
PPh3
DCM, rt
a) Acrylonitrile, K2CO3, tBuOH, reflux, 24-36 h, 58-60%.
b) TFA, TfOH, 0 oC-rt, 24 h, 70-74%.
4a-b
CO2R4
c) Oxalyl chloride, Dry DMF, 0 oC-80 oC, 4 h, 70-73%.
OR4
R = R2 = R3 = H, R1 = Cl, R4 = C2H5
R = R2 = R3 = H, R1 = Cl, R4 = CH3
R4O2C
Cl
8o
8p
R
R
4 = C2H5
4 = CH3
R = R2 = R3 = H, R1 = Br, R4 = C2H5
R = R2 = R3 = H, R1 = Br, R4 = CH3
O
O
R = R2 = R3 = H, R1 = Ph, R4 = C2H5
R = R2 = R3 = H, R1 = Ph, R4 = CH3
O
8o-p
Scheme
1
Preparation of 2-oxo-2H-chromenyl-5-oxo-2,5-
dihydrofuran-3-carboxylates 5a-n.
Scheme
3
Preparation of 2H-benzochromenyl-5-oxo-2,5-
dihydrofuran-3-carboxylates 8o-p.
Next, we have prepared another set of target compounds 2H-
chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates 8a-p and
depicted in scheme II (Table 2). The Michael addition of phenols
1a-g with acrylonitrile in the presence of K2CO3 in tert.butanol
under reflux conditions and subsequent reaction with
trifluoroacetic acid in presence of trifluoromethanesulfonic acid
at room temperature provided the corresponding chroman-4-ones
6a-g. Chroman-4-ones 6a-g under VH reaction conditions with
oxalyl chloride in dry DMF provided the corresponding 4-chloro-
Thus prepared target compounds 5a-n and 8a-p were
evaluated for anti-inflammatory activity based on inhibition of
TNF-α and IL-6 (enzyme-linked immunosorbent assay,
ELISA).23 From the in vitro anti-inflammatory activity profiles of
the target compounds, two compounds of 2-oxo-2H-chromenyl-
5-oxo-2,5-dihydrofuran-3-carboxylates 5i, 5k and one 2H-
chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylate 8f compound
have been chosen for in vivo animal experiments using LPS
induced mice model. The biological activity results were
discussed below.
In vitro anti-inflammatory activity results of 2-oxo-2H-
chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates 5a-n were
tabulated in Table 1 and were compared with the standard drug
prednisolone. The percent viability of the tested compounds 5a-n
were assessed at 20 µM on U937 cell line, which displayed
2H-chromene-3-carbaldehydes
7a-g.
Thus
obtained
carbaldehydes 7a-g were subjected to [3+2] cycloaddition
reaction with activated alkynes 4a-b and provided the target
compounds 8a-n (Scheme II, Table 2).

viability ranging from 75.9 to 96.8%. The % inhibitions of the
compounds 5a-n were measured at 20 μM on TNF-α and IL-6.
The compounds have shown inhibition of TNF-α in the range of
14.8-97.1% with respect to prednisolone (98.0%), whereas, we
could not observe the inhibition against IL-6. The IC50 values
were calculated for five compounds 5g and 5i-l based on %
inhibition and were found to be in the range of 0.047-6.243 µM
with respect to prednisolone (IC50 0.033 µM).
coumarin at 6th and 7th positions. Whereas, methyl groups present
on coumarin at 6th and 8th positions displayed the activity (5g,
IC50 1.108 µM). It is also observed that the ethoxy group present
on furanone 5g has shown the activity when compared to
methoxy group 5h. The chloro substitution on coumarin with
ethoxy group on furanone 5i (IC50 0.423 µM) has displayed better
activity when compared to methoxy compound 5j (IC50 6.243
µM). The bromo substituted coumarin compounds 5k (IC50 0.047
µM) and 5l (IC50 0.070 µM) have shown potent activity in
comparison with the standard prednisolone (IC50 0.033 µM). The
phenyl
The structure activity relationships of the target compounds
denoted that the compounds 5a-f could not show the activity
which may be due to the presence of methyl groups present on
Table 1 2-Oxo-2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates and anti-inflammatory activity profiles of 5a-n.
TNF-α
U937
Cellline
Yield
(%)
S.No. Compound
R
R1
R2
R3
R4
IC50 (μM)
%Viability
% Inhibition
at 20 μM
at 20 μM
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
H
H
H
H
H
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
68
64
65
64
69
71
63
66
46
49
48
41
62
64
75.9
78.3
79.8
84.3
79.0
75.9
96.8
86.1
90.7
93.1
83.0
85.3
83.1
82.3
40.7
27.1
32.3
14.8
26.8
34.9
80.2
44.9
97.1
75.0
91.0
76.9
20.0
44.2
---
---
---
---
---
---
H
H
H
CH3
CH3
CH3 CH3
CH3 CH3
CH3
CH3
Cl
Cl
Br
Br
Ph
H
H
H
H
H
H
H
H
1.108 ± 0.002
---
9
0.423 ± 0.022
6.243 ± 0.120
0.047 ± 0.001
0.070 ± 0.002
---
10
11
12
13
14
Ph
H
---
Prednisolone
(1μM)
98.0
0.033 ±0.0021
Table 2 2H-Chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates and anti-inflammatory activity profiles of 8a-p.
U937
TNF-α
Cellline
Yield
(%)
S.No. Compound
R
R1
R2
R3
R4
%Viability
% Inhibition
IC50 (μM)
at 20 μM
at 20 μM
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
H
H
H
H
CH3
CH3
H
H
H
H
H
H
H
H
---
---
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
H
H
H
H
---
---
H
H
H
H
H
H
H
H
CH3
CH3
H
H
H
H
---
---
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
76
74
79
75
76
73
81
78
82
79
67
65
67
63
78
76
88.9
88.1
81.6
88.5
85.2
92.1
93.4
90.7
89.9
93.8
79.4
84.6
87.2
94.3
83.6
80.2
50.6
95.5
6.40
35.6
29.7
70.4
96.1
49.7
23.3
45.7
75.9
19.4
73.3
80.2
4.10
29.1
98.0
---
18.67 ± 0.01
CH3
CH3
CH3
CH3
CH3
CH3
H
H
Cl
Cl
Br
---
---
---
0.142 ± 0.001
11.19 ± 1.26
---
---
9
10
11
12
13
14
15
16
---
10.612 ± 0.025
---
3.261 ± 0.23
13.026 ± 1.56
---
Br
---
---
---
Prednisolone
(1μM)
0.033 ±0.0021

substitution on coumarins 5m-n at 6th position could not show the
activity. Based on above observations, the electron withdrawing
groups present on coumarin 5i, 5k-l displayed potent anti-
inflammatory activity when compared to electron donating
groups 5g.
1000
800
600
400
200
0
###
**
***
***
***
In vitro anti-inflammatory activity results of 2H-chromenyl-
5-oxo-2,5-dihydrofuran-3-carboxylates 8a-p were tabulated in
Table 2 and were compared along with standard drug
prednisolone. The % viability of all the target compounds was
measured at 20 μM on U937 cell line which displayed the
viability ranging from 79.4 to 94.3%. The % inhibitions of the
compounds 8a-p were measured at 20 μM on TNF-α and IL-6.
The compounds have shown the anti-inflammatory activity for
TNF-α in the range of 4.1-95.5% with respect to prednisolone
(98.0%), whereas we could not observe the activity on IL-6. The
IC50 values were calculated for six compounds 8b, 8f-g, 8k and
8m-n based on % inhibition and were found to be in the range of
0.142-18.67 µM with respect to prednisolone (IC50 0.033 µM).
The structure activity relationships of the target compounds
denoted that the compound 8b (IC50 18.67 µM) has shown
moderate activity due to the presence of methoxy group present
on furanone moiety when compared to 8a. The methyl group
present on coumarins 8c-d at 6th position could not show the
activity. The methyl groups present on coumarin 8f at 5th and 6th
positions and methoxy group present on furanone (IC50 0.142
µM) have shown potent anti-inflammatory activity when
compared to its ethoxy group 8e. The methyl groups present on
coumarin at 6th and 7th positions 8g-h and the change of methyl
position at 7th and 8th 8i-j could not show the activity, however
compound 8g (IC50 11.19 µM) has shown moderate activity. The
chloro substitution on coumarin with ethoxy group present on
furanone 8k (IC50 10.612 µM) has shown moderate activity when
compared to methoxy group 8l. The bromo substituted coumarin
compound 8m (IC50 3.261 µM) having ethoxy group on furanone
has shown potent activity when compared to methoxy group 8n
(IC50 13.026 µM). The 2H-benzo[h]chromen-3-ylcompounds 8o
and 8p could not show the activity. The electron donating groups
present on coumarin 8f has shown the potent activity when
compared to electron withdrawing group 8m.
Figure 2. Effect of test compounds on LPS induced serum
inflammatory cytokine expression. Graph represents the serum
TNF-α level of different test groups in balb/c mice. All values are
expressed as mean ± S.E.M, n = 5.
### P<0.001compared to Vehicle control,
*** P<0.001compared to LPS Control,
** P<0.001compared to LPS Control.
The results indicated that the test compounds 5i and 8f have
displayed significant (P<0.001) inhibition in the TNF-α levels
and in IL-6 levels (P<0.001) when compared to those in LPS
control animals. Hence, based on in vivo experiments, compound
5i is considered as promising lead molecule to treat the
inflammatory disease in present series of the compounds.
1200
###
***
1000
800
600
400
200
0
***
***
***
Having achieved the in vitro results, next, we carried out the
In vivo anti-inflammatory activity on the identified compounds
employing LPS challenged mouse model. LPS has been
implicated as an important pathogenic factor for the induction of
sepsis, which is characterized by an inflammatory cytokine
storm.24-26 Hence, in vivo anti-inflammatory activity of
compounds 5i, 5k and 8f were evaluated against LPS induced
cytokine expression in Balb/c mice. The challenge with LPS in
mice showed significant (P<0.001) increase in TNF-α (Fig.2) and
IL-6 (Fig.3) levels in LPS alone group compared to the vehicle
control group of animals (P<0.001). In the treatment groups,
mice were pre-treated with the test compounds 5i, 5k and 8f at a
dose of 100 mg/kg for three consecutive days followed by LPS
challenge (10 mg/kg, IP).
Figure 3. Effect of test compounds on LPS induced serum
inflammatory cytokine IL-6. Graph represents the serum IL-6
level of different test groups in balb/c mice. All values are
expressed as mean ± S.E.M, n = 5.
### P<0.001compared to Vehicle control
*** P<0.001compared to LPS Control
Over all, among the present series of compounds, compounds
5g and 8f were having the methyl substitution and compounds 5i,
5k-l and 8m having chloro/bromo substitutions have shown the
anti-inflammatory activity (in vivo) and among these, 5i was
identified as the most potent compound. Four compounds in 5
series and 2 compounds in 8 series have shown the activity. It is
observed that the 2-oxo-2H-chromenyl-5-oxo-2,5-dihydrofuran-
3-carboxylates were identified as better compounds when
compared
to
2H-chromenyl-5-oxo-2,5-dihydrofuran-3-
carboxylates.
In conclusion, two series of compounds such as 2-oxo-2H-
chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates 5a-n and 2H-

20. Nozaki, K.; Sato, N.; Ikeda, K.; Takaya, H. J. Org. Chem. 1996, 61,
4516.
chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates 8a-p were
prepared by cycloaddition reaction. These compounds were not
reported earlier in the literature with synthetic methodology and
the assignment of the in vitro and in vivo anti-inflammatory
activity to all of the target compounds in this report is new
aspect. In vitro anti-inflammatory activity data demonstrated that
the compounds 5g, 5i, 5k-l and 8f are effective among the tested
compounds against TNF-α. Three compounds (5i, 5k and 8f) are
identified as better compounds with respect to anti-inflammatory
activity in LPS induced mice model. The compound 5i was
identified as the most effective in the LPS induced sepsis model
in mice which has demonstrated significant reduction in both
TNF-α and IL-6 levels. Therefore, we consider the coumarin
coupled with furanone moiety as a lead compound for anti-
inflammatory activity which can be explored further.
21. General procedure for the preparation of ethyl 2-(4-chloro-2-oxo-2H-
chromen-3-yl)-4-ethoxy-5-oxo-2,5-dihydrofuran-3-carboxylates (5a-n):
Diethyl but-2-ynedioate (4a, 1.5 equiv.) was added to a stirred solution
of the 4-chloro-2-oxo-2H-chromene-3-carbaldehyde (3a, 1 equiv.) in
DCM at room temperature and followed by Triphenylphosphine (1.5
equiv.). The contents were stirred at room temperature and the reaction
was monitored by TLC (2 h). After completion of the reaction, the
solvent was removed under reduced pressure. The residue was purified
by column chromatography using silica gel (60:120, ethyl acetate/hexane
5:95) afforded compound 5a in 68% as colourless solid. The remaining
2-oxo-2H-chromenyl-2,5-dihydrofuran-3-carboxylates
5b-n
were
prepared by the reaction of 4-chloro-2-oxo-2H-chromene-3-
carbaldehydes 3b-g with diethyl/methyl but-2-ynedioate 4a-b under our
optimized reaction conditions. The newly prepared compounds 5a-n
have been characterized by spectral data. Ethyl 2-(4-chloro-2-oxo-2H-
chromen-3-yl)-4-ethoxy-5-oxo-2,5- dihydrofuran-3-carboxylate (5a):
Yield: 68%; 2 h; colourless solid; mp 156-158 °C. IR (KBr): 3420, 2924,
2854, 1740, 1724, 1651, 1600, 1565, 1427, 1386, 1297, 1181, 1015 cm-1.
1H NMR (500 MHz, CDCl3): δ 7.96 (t, J = 8.8 Hz, 1H, aromatic), 7.65 (t,
J = 7.7 Hz, 1H, aromatic), 7.41 (t, J = 7.6 Hz, 1H, aromatic), 7.38-7.34
(m, 1H, aromatic), 6.59 (s, 1H, CH), 4.95-4.62 (m, 2H, OCH2), 4.18 (q, J
= 7.1 Hz, 2H, OCH2), 1.45 (t, J = 7.0 Hz, 3H, CH3), 1.20 (t, J = 7.1 Hz,
3H, CH3) ppm. 13C NMR (126 MHz, CDCl3): δ 166.60, 160.91, 156.97,
152.14, 150.06, 149.88, 133.72, 126.28, 125.06, 119.36, 118.99, 117.88,
116.83, 73.98, 69.06, 61.20, 15.52, 13.92 ppm. MS (ESI): (m/z) 379
[M+H]+. HRMS (ESI): (m/z)calcd for C18H16O7Cl [M+H]+ 379.0585,
Found: 379.0564.
Acknowledgments
We thank Director, CSIR-IICT (Communication No:
IICT/Pubs./2019/313) for providing all the required facilities to
carry out the research work. B. China Raju acknowledges
Science & Engineering Research Board (SERB), Department of
Science and Technology (DST), New Delhi for the financial
support (EEQ/2017/000314).
22. General procedure for the preparation of ethyl 2-(4-chloro-2H-
chromen-3-yl)-4-ethoxy-5-oxo-2,5-dihydrofuran-3-carboxylate (8a-p):
Diethyl but-2-ynedioate (4a, 1.5 equiv.) was added to a stirred solution of
4-chloro-2H-chromene-3-carbaldehyde (7a, 1 equiv.) in DCM at room
temperature followed by Triphenylphosphine (1.5 equiv.). The contents
were stirred at room temperature and the reaction was monitored by TLC
(2 h). After completion of the reaction, the solvent was removed under
reduced pressure. The residue was purified by column chromatography
using silica gel (60:120, ethyl acetate/hexane 5:95) afforded compound
8a in 76% as colourless solid. The remaining target4-chloro-2H-
chromenyl-2,5-dihydrofuran-3-carboxylates 8b-p were prepared by the
reaction of 4-chloro-chromene-3-arbaldehydes 7b-h with diethyl/methyl
but-2-ynedioate 4a-b under our optimized reaction conditions. The newly
prepared compounds 8a-p were characterized by spectral data. Ethyl 2-
(4-chloro-2H-chromen-3-yl)-4-ethoxy-5-oxo-2,5-dihydrofuran-3-
carboxylate (8a): Yield: 76%; 2 h; colourless solid; mp 170-172 °C. IR
(KBr): 2983, 2926, 1776, 1721, 1649, 1610, 1565, 1465, 1346, 1297,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at
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1214, 1116 cm-1. H NMR (500 MHz, CDCl3): δ 7.55 (dd, J = 7.8, 1.5
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Graphical Abstract
Synthesis and anti-inflammatory activity of
2-oxo-2H-chromenyl and 2H-chromenyl-5-oxo-2,5-
dihydrofuran-3-carboxylates
Leave this area blank for abstract info.
Siva Hariprasad Kurma, Shailaja Karri, Madhusudana Kuncha, Ramakrishna Sistla, China Raju Bhimapaka
OCH3
O
OC2H5
O
H3CO2C
CH3 Cl
C2H5O2C
Cl
H3C
Cl
O
O
O
O
O
8f,
IC50 0.142±0.001 µM
5i,
IC50 0.423±0.022 µM
Declaration of interests
☐ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐ The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.