Regioselectivity of aminomethylation in 3-acetyl-7-hydroxycoumarins: Mannich bases and Betti bases

Article abstract of DOI:10.1039/d1nj01584b

7-Hydroxycoumarin is a privileged structure for anti-inflammatory drug development. In this study, several new 3-acetyl-7-hydroxycoumarin derivatives were designed, synthesized and tested as anti-inflammatory agents. Interestingly, Mannich bases and Betti bases were separately obtained under acidic or neutral conditions. The regioselectivity of aminomethylation was studied based on the atomic electron density distribution by analysing the Voronoi deformation density (VDD) atomic charges, which reasonably explained the experimental outcome. Detection of nitric oxide (NO) and tumour necrosis factor alpha (TNF-α) release revealed that Mannich bases displayed stronger anti-inflammatory activity than the corresponding Betti bases.

Full text of DOI:10.1039/d1nj01584b

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Regioselectivity of aminomethylation in
3-acetyl-7-hydroxycoumarins: Mannich bases and
Betti bases†
Cite this: New J. Chem., 2021,
45, 9864
Fan Gao, Deng Tao, Cheng Ju, Bei-Bei Yang, Xiu-Qi Bao, Dan Zhang,
Tian-Tai Zhang and Li Li
*
7-Hydroxycoumarin is a privileged structure for anti-inflammatory drug development. In this study,
several new 3-acetyl-7-hydroxycoumarin derivatives were designed, synthesized and tested as anti-
inflammatory agents. Interestingly, Mannich bases and Betti bases were separately obtained under acidic
or neutral conditions. The regioselectivity of aminomethylation was studied based on the atomic
electron density distribution by analysing the Voronoi deformation density (VDD) atomic charges, which
reasonably explained the experimental outcome. Detection of nitric oxide (NO) and tumour necrosis
factor alpha (TNF-a) release revealed that Mannich bases displayed stronger anti-inflammatory activity
than the corresponding Betti bases.
Received 1st April 2021,
Accepted 7th May 2021
DOI: 10.1039/d1nj01584b
rsc.li/njc
and chemical stability of drugs.16,17 The ketonic Mannich
reaction has been applied for industrial fluoxetine and atropine
Introduction
Inflammation is a protective process that occurs in response to production.18,19
infection or injury. However, persistent inflammation can lead
Betti bases, namely, phenolic Mannich bases, represent a
to tissue damage and even severe host injury via release of special type of Mannich base. They were first synthesized and
inflammatory mediators.1,2 Chronic inflammation is a prominent reported by Mario Betti in the early 20th century.20 Betti bases
factor in the pathogenic mechanisms of a wide range of can be used as asymmetric catalyst ligands,21 fluorescent
inflammatory conditions and diseases, such as atherosclerosis, probes,22 and other tools. The ligand AF40431 of the neuronal
rheumatoid arthritis, cancers and Parkinson’s disease.3–6
receptor sortilin (1, Fig. 1) and calcein blue (2) are typical Betti
7-Hydroxycoumarin extracted from Justicia pectoralis has bases displaying biological activities.23,24 Moreover, Betti bases
been reported to possess anti-inflammatory potential.7 Compounds 3 and 4 are effective against inflammation.25,26
containing 7-hydroxycoumarin moieties are ubiquitous in natural
In our previous work, 3-acetyl-7-hydroxycoumarin Mannich
fruits and plants and have gained widespread attention due to their bases (5, Fig. 1) were demonstrated to strongly counteract
biological activities, such as antioxidant and anti-inflammatory monoamine oxidase B and neuroinflammation.17 Interestingly,
activities.8,9 Recently, 3-acetyl-7-hydroxycoumarin derivatives have
been reported to be macrophage migration inhibitory factor (MIF)
tautomerase inhibitors and MIF-CD47 antagonists.10,11
The Mannich aminoalkylation reaction is a three-component
condensation reaction that typically occurs among an amine or
ammonia, formaldehyde and an a-H atom adjacent to a carbonyl
group. This reaction has excellent potential for synthetic and
medicinal chemistry12–14 and has recently also received consid-
erable attention in pesticide chemistry.15 Mannich bases are very
useful for improving the bioavailability, hydrophilic properties
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation,
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union
Medical College, Beijing 100050, China. E-mail: annaleelin@imm.ac.cn
† Electronic supplementary information (ESI) available: 1H- and 13C-NMR, ESI-
Fig. 1 Representative Betti bases and Mannich bases.
HRMS spectra and Cartesian coordinates. See DOI: 10.1039/d1nj01584b
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during optimization of the reaction conditions, derivatization the 1H-NMR spectrum, indicating that aminomethylation took
occurred at the C8 position or the ketonic methyl group to place at the C8 position. Thus, hydrochloric acid is crucial to
induce the formation of Betti bases or ketonic Mannich bases, regioselectivity. Under the same conditions used for compound
respectively. Electron density distribution is thought to affect 19, compounds 20–29 were obtained in modest to high yields.
regioselectivity. Some density functional theory (DFT)
For either the Mannich reaction or the Betti reaction, the
approaches, including electrostatic potential (ESP),27 Voronoi first step is to mix PFA and a secondary amine in ethanol. The
deformation density (VDD)28 charges, average local ionization reactant ratio of the Mannich reaction is ten equivalents of PFA
energy (ALIE),29 the Fukui function30 and a dual descriptor and secondary amine relative to the coumarin intermediate.15
(FDD),31 could be adopted to predict this property and The optimized ratio for the secondary amine, PFA and the
determine regioselectivity.
coumarin intermediate in the Betti reaction was 10 : 5 : 1.
To develop anti-inflammatory coumarin aminoalkylation
derivatives, various ketonic Mannich bases and Betti bases
were prepared. The underlying factors determining the regios-
electivity were investigated by using DFT to calculate the atomic
charge distribution. The anti-inflammatory activities of these
compounds were assessed by evaluating the inhibitory activity
of the compounds against nitric oxide (NO) production and
tumour necrosis factor alpha (TNF-a) in mouse macrophages.
Theoretical interpretation of regioselectivity
The mechanism underlying the Mannich reaction has been
explored for decades, but the exact mechanism is still
uncertain.10,32–34 When additional acid is added, the first step
is generally thought to be the formation of an N-hydroxymethyl
amine intermediate, followed by the removal of water to yield
imine cations. Then, the enols (or enolates) serve as nucleo-
philes in the nucleophilic addition reaction to generate ketonic
Mannich bases (Scheme 2a).32 Without acid, the prototypical
nucleophile attacks the imine to yield the aminomethylation
derivative.35,36
Results and discussion
Synthesis
The synthetic routes to target compounds 8–29 are shown in
Scheme 1.
Intermediate 6 was selected for theoretical exploration of
regioselectivity using DFT. Atomic charges are the most intuitive
Intermediates 6 and 7 were obtained through the Knoevenagel and concise representations of charge distribution in chemical
reaction and Pechmann condensation, respectively. The Mannich systems.37 In principle, atoms with more negative (positive)
reaction took place at the a-H of the carbonyl group to yield atomic charges tend to be more favourable sites for attack by
compounds 8–18 in ethanol under acidic conditions (pH 2–3) nucleophiles (electrophiles).38 Among various approaches to
with reflux at 78 1C. Only mono-Mannich bases were obtained, express charge density, VDD charge and Hirshfeld charge
even if large excesses of paraformaldehyde (PFA) and secondary approaches can reliably determine regioselectivity and accurately
amine were added. However, when hydrochloric acid was not quantify nucleophilicity and electrophilicity.39 The VDD method
added to the reaction mixture of PFA, piperidine and intermediate was employed to analyse electron density distribution in this
6, an unexpected compound instead of target molecule 8 was study. The VDD charge QA is computed as the integral of the
detected by using thin-layer chromatography (TLC). The aromatic deformation density Dr(r) related to the formation of a molecule
proton signal (d = 6.8 ppm) corresponding to H8 was absent from from atoms within the volume of the so-called Voronoi cell of
Scheme 1 Synthetic routes to target compounds 8–29. Reagents and conditions: (a) piperidine, CH3COOH, ethanol, rt, 5 h; (b) C2H5ONa, ethanol,
reflux, 1.5 h; (c) PFA, secondary amines or heterocyclic amines, ethanol, concentrated hydrochloric acid, reflux, 12 h; (d) PFA, secondary amines or
heterocyclic amines, ethanol, reflux, 8 h.
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Scheme 2 Reported mechanism of the Mannich reaction catalysed by acids (a) and a plausible mechanism of the process used to obtain Betti base
derivatives (b).
atom A (eqn (1)).28,40 The Voronoi cell of atom A is designated as
the area defined by the bond midplanes on and vertical to all
bond axes between nucleus A and its adjacent nuclei.41
!
ð
X
QA
¼
rðrÞ ꢀ
rBðrÞ dr
(1)
Voronoi cell of A
B
To evaluate the applicability of VDD charges for coumarins,
the 1H-NMR spectrum of 7-hydroxycoumarin (30) was obtained
in methanol-d4. There is a linear correlation between charge
density and chemical shifts42,43 that reflects the magnetic
shielding effects of extranuclear electrons.44 The VDD charges
of the aromatic carbon atoms in 7-hydroxycoumarin were in
line with the corresponding chemical shifts (Fig. 2).
The atomic charges of intermediate 6 were analysed with the
VDD method (Fig. 3a). The results showed that C8 was more
negatively charged than C5 and C6, making C8 a better site for
nucleophilic attack. These data suggest that the Betti reaction
took place at C8 instead of at C6 without addition of hydro-
chloric acid. However, when the reaction solution was acidic
(pH 2–3), the 3-acetyl group in compound 6 likely promoted
keto–enol tautomerism to enable direct insertion of electrophilic
groups at a-C.45 The VDD charges on the a-C of the 3-acetyl
group were more negative than those on the C8 atom
(ꢀ0.118 a.u. vs. ꢀ0.096 a.u.).
Fig. 3 Calculated VDD charges (QA) of compounds 6 and 31–33. (a)
Compound 6; (b) compounds 31–33.
phenyl ring (more than ꢀ0.07 a.u.), which hindered its
reaction.48 C6 and C8 on compound 33 displayed similar
charge densities, leading to a mixture of products.48 Thus,
the VDD atomic charge results were all consistent with the
chemical experiment results, indicating that charge density
analysis is a valuable tool for prediction of the regioselectivity
and nucleophilicity of the Mannich reaction for these coumarin
analogues.
The VDD method was also adopted to analyse the reactivity
of three coumarin derivatives, 4-phenyl-7-hydroxycoumarin (31,
Fig. 3b), 4-methyl-6-hydroxycoumarin (32), and 4,7-dimethyl-5-
hydroxycoumarin (33). It has been reported that the amino-
methylation reaction of compound 31 takes place at the C8
position,46,47 which bore
a negative atomic charge of
Anti-inflammatory activity
ꢀ0.099 a.u. Compound 32 had a lower charge density on the
The anti-inflammatory effects of the target compounds were
evaluated by detecting NO release in LPS-induced RAW264.7
mouse macrophages.49 Curcumin,
a
well-known anti-
inflammatory natural product, is used as the positive
control.17,50a It is the main active ingredient in the spice
turmeric and displays various biological activities including
anti-inflammatory and anti-cancer activities.50
Compounds 13, 15 and 18 were shown to exhibit good anti-
inflammatory activity (Table 1), and the coumarin Mannich
bases displayed stronger anti-inflammatory activity than the
Fig. 2 Comparison of the chemical shifts and VDD charges of aromatic
carbon atoms of 30. (a) Chemical shifts of C5, C6 and C8; (b) QA values
(a.u.) of C5, C6 and C8.
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Table 1 NO release-inhibiting activity of the target compounds
Materials and methods
Chemistry
Compd
Inhibition ratioa (%)
Compd
Inhibition ratioa (%)
8
9
26.76
47.94
57.65
56.76
13.53
62.27
55.91
67.35
27.73
17.94
66.82
19
20
21
22
23
24
25
26
4.09
3.18
1.36
Commercially available reagents were purchased from Innochem
(Shanghai, China) and used without further purification. With
tetramethylsilane (TMS) as an internal standard, 1H-NMR and
13C-NMR spectra were recorded on a Jeol ECZ-400S, a Bruker
Avance-III or WNMR-I 500, and a Bruker Avance-600 NMR System
by using DMSO-d6, D2O, CDCl3, CD3OD and CF3COOD as deut-
erated solvents. For compounds 24 and 25, a small amount of
CF3COOD was added to D2O to improve solubility. ESI-HRMS data
were collected on an Agilent 6520 Accurate-Mass Q-TOF LC/MS
spectrometer. TLC was conducted with glass precoated with silica
gel GF254 (Qingdao Marine Chemical Inc., China) to monitor the
reactions. Melting points were measured with a Yanaco MP-J3
melting point apparatus.
10
11
12
13
14
15
16
17
18
7.73
ꢀ1.07
18.13
7.73
1.33
27
28
29
ꢀ1.07
2.13
10.93
87.11
Curcumin
a
Inhibition of NO production tested at 10 mM.
coumarin Betti bases. Structure–activity relationship assessment
showed that the N-methylpiperazine Mannich derivative 15
displayed the highest anti-inflammatory activity. When the
methyl group was replaced by phenyl groups (16, 17), the activity
decreased dramatically, possibly due to steric hindrance of
the phenyl groups. Substitution of 4-hydroxypiperidine as the
hydrogen donor also improved the activity. Comparison of the
anti-inflammatory activities of compounds 11 and 10 with those
of compounds 8 and 9 revealed that the presence of a 5-methyl
group on the coumarin ring may contribute to the inhibition of
NO production.
In addition, the inhibitory activities of some compounds
(8–11, 19–22) against TNF-a release were tested using lipopoly-
saccharide (LPS)-treated RAW246.7 cells. Compounds 10 and
21 showed moderate activity compared with the positive control
dexamethasone (Table 2), indicating that the diethylamino
group was beneficial to the anti-inflammatory activity. The
Mannich bases displayed obviously stronger anti-inflammatory
activity than the corresponding Betti bases in both models.
Compounds 6 and 7 were synthesized using the protocol
described in our previous report.17
The general procedure for the preparation of target com-
pounds 8–18 is described below.
A secondary alkyl amine (20.0 mmol, 10 equiv.) was added to
a stirred suspension of PFA (0.61 g, 20.0 mmol, 10 equiv.)
(Innochem, #A34195) in ethanol (25 mL), and the pH of the
solution was adjusted to 2–3 with concentrated hydrochloric
acid. After 2 h of reflux at 78 1C, coumarin intermediate 6 or 7
(2.0 mmol, 1 equiv.) was added, and the reaction mixture
was refluxed at 78 1C for 10–30 h and monitored with TLC.
Subsequently, the mixture was cooled to room temperature and
filtered to obtain a yellow solid. The residue was washed three
times with ethanol or methanol to obtain a pure product.
3-(3-Piperidyl propionyl)-7-hydroxycoumarin hydrochloride (8).
Yellow solid, yield: 80%, m.p.: 244–246 1C (decomposed). The
1H- and 13C-NMR data were identical to those in our previous
report.15 ESI-HRMS: m/z [M + H]+ calcd for C17H20NO4 302.1387,
found 302.1378.
3-(3-Diethylamino propionyl)-7-hydroxycoumarin hydrochloride
(9). Yellow solid, yield: 77.9%, m.p.: 194–197 1C (decomposed).
1H-NMR (400 MHz, DMSO-d6): d 11.41 (br, 1H, D2O exchangeable),
10.11 (br, 1H, D2O exchangeable), 8.70 (s, 1H), 7.84 (d, J = 8.6 Hz,
1H), 6.91 (dd, J = 8.6, 2.2 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 3.52 (t, J =
7.2 Hz, 2H), 3.35 (t, J = 7.2 Hz, 2H), 3.13 (q, J = 7.2 Hz, 4H), 1.23 (t,
J = 7.2 Hz, 6H). 13C-NMR (100 MHz, DMSO-d6): d 193.6, 164.8,
159.0, 157.3, 148.6, 132.9, 118.1, 114.5, 110.7, 101.8, 46.6, 46.1, 36.2,
8.5. ESI-HRMS: m/z [M + H]+ calcd for C16H20NO4 290.1387, found
290.1382.
Conclusions
In conclusion, twenty-two coumarin ketonic Mannich bases and
Betti bases were synthesized and tested as anti-inflammatory
agents. The regioselectivity on 3-acetyl-7-hydroxycoumarin was
studied by using DFT calculations of the atomic charge distribu-
tion, and the VDD method was adopted to determine the
possible reactive site. The Mannich bases exhibited much stron-
ger anti-inflammatory activity than the corresponding Betti
bases in both NO release and TNF-a production models.
3-(3-Diethylamino propionyl)-5-methyl-7-hydroxycoumarin
hydrochloride (10). Yellow solid, yield: 61.2%, m.p.: 201–203 1C
(decomposed). 1H-NMR (400 MHz, DMSO-d6): d 11.35 (br, 1H),
10.17 (br, 1H), 8.61 (s, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.68 (d, J =
2.1 Hz, 1H), 3.54 (t, J = 7.2 Hz, 2H), 3.35 (t, J = 7.2 Hz, 2H) 3.13 (q, J =
7.2 Hz, 4H), 2.50 (overlapped, 3H), 1.24 (t, J = 7.2 Hz, 6H). 13C-NMR
(100 MHz, DMSO-d6): d 193.6, 164.5, 158.9, 158.1, 145.2, 141.5,
117.1, 115.5, 109.8, 100.0, 46.6, 46.0, 36.1, 18.0, 8.5. ESI-HRMS: m/z
[M + H]+ calcd for C17H22NO4 304.1543, found 304.1548.
3-(3-Piperidyl propionyl)-5-methyl-7-hydroxycoumarin hydro-
chloride (11). Yellow solid, yield: 84%, m.p.: 227–230 1C
Table 2 Inhibitory activities of compounds 8–11 and 19–22 against
TNF-a release
Compd
Inhibition ratioa (%)
Compd
Inhibition ratioa (%)
8
9
10
11
1.35
31.03
59.34
10.51
19
20
21
22
1.78
5.37
49.13
ꢀ3.04
70.00
Dexamethasone
a
Inhibition of TNF-a production tested at 10 mM.
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(decomposed). The 1H- and 13C-NMR data are the same as those 2.75 (t, J = 7.1 Hz, 2H), 2.61 (br, 4H), 2.49 (s, 3H). 13C-NMR
in our previous report.15 ESI-HRMS: m/z [M + H]+ calcd for (100 MHz, DMSO-d6): d 196.2, 164.1, 159.0, 158.0, 156.1, 153.7,
C18H22NO4 316.1543, found 316.1541.
3-(3-Morpholinyl
propionyl)-5-methyl-7-hydroxycoumarin 115.4, 109.8, 99.9, 52.6, 49.9, 18.0. ESI-HRMS: m/z [M + H]+
hydrochloride (12). Yellow solid, yield: 86%, m.p.: 239–241 1C calcd for C23H24FN2O4 411.1715, found 411.1715.
(decomposed). The 1H- and 13C-NMR data are the same as those
3-(3-(4-(Tetrahydrofuran-3-carbonyl)piperazin-1-yl) propanoyl)-
144.5, 141.3, 139.7, 124.8, 122.3, 119.2, 118.0, 116.0, 115.8,
in our previous report.17 ESI-HRMS: m/z [M + H]+ calcd for 5-methyl-7-hydroxycoumarin hydrochloride (18). Yellow solid,
C
17H20NO5 318.1336, found 318.1331.
3-(3-(4-Hydroxypiperidin-1-yl)propionyl)-5-methyl-7-
yield: 45.5%, m.p.: 241–243 1C (decomposed). 1H-NMR
(400 MHz, D2O): d 8.67 (s, 1H), 6.70 (s, 1H), 6.54 (s, 1H), 3.99–
hydroxycoumarin hydrochloride (13). Yellow solid, yield: 3.94 (m, 6H), 3.62–3.50 (m, 8H), 2.45 (s, 3H), 2.40–2.31 (br, 1H),
82.1%, m.p.: 201–203 1C (decomposed). 1H-NMR (400 MHz, 1.97 (s, 4H). 13C-NMR (100 MHz, DMSO-d6): d 193.5, 169.5, 164.5,
DMSO-d6): d 11.32 (br, 1H), 10.12 (br, 1H), 8.61 (s, 1H), 6.77 (dd, 158.9, 158.2, 145.3, 141.6, 117.1, 115.5, 109.8, 100.0, 75.0, 68.3,
J = 2.2, 0.8 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 3.57–2.98 (m, 9H), 50.8, 41.7, 38.4, 36.2, 27.8, 25.2, 18.0. ESI-HRMS: m/z [M + H]+
2.50 (overlapped, 3H), 1.99–1.92 (m, 2H), 1.75–1.65 (m, 2H). calcd for C22H27N2O6 415.1864, found 415.1867.
13C-NMR (100 MHz, DMSO-d6): d 193.6, 164.5, 158.9, 158.1,
The general procedure for the preparation of target com-
145.2, 141.6, 117.1, 115.5, 109.8, 100.0, 64.1, 59.4, 47.3, 31.6, pounds 19–29 is described below.
29.4, 18.0. ESI-HRMS: m/z [M + H]+ calcd for C18H22NO5
332.1492, found 332.1489.
A secondary alkyl amine (20.0 mmol, 10 equiv.) was added to
a stirred suspension of PFA (0.61 g, 10.0 mmol, 5 equiv.) in
3-(3-(4-(Hydroxymethyl)piperidin-1-yl) propanoyl)-5-methyl- ethanol (25 mL). After 2 h of reflux at 78 1C, a coumarin
7-hydroxycoumarin hydrochloride (14). Yellow solid, yield: intermediate (2.0 mmol, 1 equiv.) was added, and the reaction
81.6%, m.p.: 210–211 1C (decomposed). 1H-NMR (400 MHz, mixture was refluxed at 78 1C for 4–8 h and monitored with
DMSO-d6): d 11.37 (br, 1H), 10.03 (br, 1H), 8.60 (s, 1H), 6.77 (d, TLC. Subsequently, the mixture was cooled to room temperature
J = 2.0 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 3.58 (t, J = 7.2 Hz, 2H), and filtered to obtain a yellow solid. The residue was washed
3.47 (d, J = 12.0 Hz, 2H), 3.46–3.34 (m, 2H), 3.25 (d, J = 6.0 Hz, with ethanol or methanol to obtain a pure product.
2H), 2.96–2.88 (m, 2H), 2.50 (overlapped, 3H), 1.82 (d, J =
3-Acetyl-8-(piperidyl methyl)-7-hydroxycoumarin (19). Yellow
12.0 Hz, 2H), 1.62 (br, 1H), 1.49–1.40 (m, 2H). 13C-NMR solid, yield: 48.2%, m.p.: 231–233 1C (decomposed). 1H-NMR
(100 MHz, DMSO-d6): d 194.1, 164.9, 159.4, 158.6, 145.7, (400 MHz, DMSO-d6): d 8.42 (s, 1H), 7.55 (d, J = 8.9 Hz, 1H), 6.50
142.0, 117.6, 116.0, 110.3, 100.5, 65.3, 52.5, 51.6, 36.8, 36.3, (d, J = 8.9 Hz, 1H), 4.08 (s, 2H), 2.89–2.87 (m, 4H), 2.50 (s, 3H),
26.4, 18.5. ESI-HRMS: m/z [M + H]+ calcd for C19H24NO5 1.67–1.62 (m, 4H), 1.52–1.48 (m, 2H). 13C-NMR (125 MHz,
346.1649, found 346.1651.
DMSO-d6): d 194.0, 173.1, 159.7, 156.7, 147.6, 132.1, 117.7,
112.8, 107.5, 104.6, 52.3, 51.9, 30.1, 23.8, 22.2. ESI-HRMS: m/z
3-(3-(4-Methylpiperazin-1-yl)propanoyl)-5-methyl-7-
hydroxycoumarin hydrochloride (15). Yellow solid, yield: [M + H]+ calcd for C17H20NO4 302.1387, found 302.1389.
31.4%, m.p.: 210–212 1C (decomposed). 1H-NMR (400 MHz,
3-Acetyl-8-(diethylamino methyl)-7-hydroxycoumarin (20).
CF3COOD): d 9.07 (s, 1H), 6.92 (s, 1H), 6.81 (s, 1H), 4.22 (d, J = Yellow solid, yield: 18.1%, m.p.: 221–223 1C (decomposed).
8.0 Hz, 2H), 4.12–3.90 (m, 10H), 3.16 (s, 3H), 2.61 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): d 8.39 (s, 1H), 7.50 (d, J = 8.9
13C-NMR (100 MHz, CF3COOD): d 197.0, 164.4, 158.8, 149.6, Hz, 1H), 6.41 (d, J = 8.9 Hz, 1H), 4.15 (s, 2H), 2.94 (q, J = 7.2 Hz,
144.2, 116.8, 116.3, 115.3, 115.2, 112.2, 101.0, 53.9, 51.1, 50.0, 4H), 2.48 (s, 3H), 1.20 (t, J = 7.2 Hz, 6H). 13C-NMR (125 MHz,
43.4, 16.5. ESI-HRMS: m/z [M + H]+ calcd for C18H23N2O4 DMSO-d6): d 193.9, 175.1, 159.9, 157.0, 147.4, 132.3, 118.4,
331.1652, found 331.1657.
3-(3-(4-Phenylpiperazin-1-yl)propanoyl)-5-methyl-7-
hydroxycoumarin hydrochloride (16). Yellow solid, yield:
111.5, 106.8, 104.4, 47.5, 46.4, 30.1, 9.5. ESI-HRMS: m/z [M +
H]+ calcd for C16H20NO4 290.1387, found 290.1385.
3-Acetyl-8-(3-diethylamino methyl)-5-methyl-7-hydroxycoumarin
21.1%, m.p.: 230–231 1C (decomposed). 1H-NMR (400 MHz), hydrochloride (21). Yellow solid, yield: 20.2%, m.p.: 225–227 1C
DMSO-d6): d 11.35 (br, D2O exchangeable, 1H), 10.69 (br, D2O (decomposed). 1H-NMR (400 MHz, DMSO-d6): d 8.37 (s, 1H), 6.28 (s,
exchangeable, 1H), 8.63 (s, 1H), 7.26 (t, J = 8.8 Hz, 2H), 7.00 (d, 1H), 4.12 (s, 2H), 2.96 (q, J = 7.2 Hz, 4H), 2.48 (s, 3H), 2.33 (s, 3H),
J = 8.8 Hz, 2H), 6.88–6.84 (m, 1H), 6.78–6.77 (m, 1H), 6.68–6.67 1.20 (t, J = 7.2 Hz, 6H). 13C-NMR (125 MHz, DMSO-d6): d 193.8,
(m, 1H), 3.81 (br, 2H), 3.64 (t, J = 7.2 Hz, 2H), 3.57 (br, 2H), 3.48 175.6, 159.9, 158.0, 143.7, 140.0, 119.7, 109.8, 106.3, 102.6, 47.3,
(t, J = 7.2 Hz, 2H), 3.16 (br, 4H), 2.51 (overlapped, 3H). 13C-NMR 46.4, 30.1, 17.9, 9.4. ESI-HRMS: m/z [M + H]+ calcd for C17H22NO4
(150 MHz, DMSO-d6): d 193.7, 164.6, 159.0, 158.3, 149.6, 145.3, 304.1543, found 304.1546.
141.7, 129.2, 120.1, 117.2, 116.0, 115.6, 109.9, 100.1, 51.2, 50.8,
45.6, 36.4, 18.1. ESI-HRMS: m/z [M + H]+ calcd for C23H25N2O4 hydrochloride (22). Yellow solid, yield: 75.5%, m.p.: 234–235 1C
393.1809, found 393.1803.
(decomposed). 1H-NMR (400 MHz, DMSO-d6): d 8.39 (s, 1H), 6.36
3-Acetyl-8-(3-piperidyl methyl)-5-methyl-7-hydroxycoumarin
3-(3-(4-(2-Fluorophenyl) piperazin-1-yl) propanoyl)-5-methyl- (s, 1H), 4.05 (s, 2H), 2.90 (t, J = 5.0 Hz, 4H), 2.49 (s, 3H), 2.35 (s,
7-hydroxycoumarin hydrochloride (17). Yellow solid, yield: 3H), 1.66–1.65 (m, 4H), 1.50–1.49 (m, 2H). 13C-NMR (125 MHz,
39.4%, m.p.: 233–235 1C (decomposed). 1H-NMR (400 MHz, DMSO-d6): d 193.9, 173.5, 159.8, 157.7, 143.9, 139.9, 118.9, 111.2,
DMSO-d6): d 8.54 (s, 1H), 6.92–7.14 (m, 4H), 6.72 (d, J = 2.0 Hz 106.9, 102.8, 52.2, 51.7, 30.1, 23.7, 22.1, 17.9. ESI-HRMS: m/z [M +
1H), 6.60 (d, J = 2.0 Hz, 1H), 3.24 (t, J = 7.1 Hz, 2H), 3.00 (br, 4H), H]+ calcd for C18H22NO4 316.1543, found 316.1537.
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3-Acetyl-8-(morpholinyl methyl)-5-methyl-7-hydroxycoumarin
NJC
3-Acetyl-8-(3-(4-(tetrahydrofuran-3-carbonyl)piperazin-1-yl)
hydrochloride (23). Yellow solid, yield: 71.1%, m.p.: 231–233 1C methyl)-5-methyl-7-hydroxycoumarin hydrochloride (29). Yellow
(decomposed). 1H-NMR (400 MHz, DMSO-d6): d 8.52 (s, 1H), 6.68 solid, yield: 41.4%, m.p.: 222–224 1C (decomposed). 1H-NMR
(s, 1H), 3.86 (s, 2H), 3.61 (t, J = 4.2 Hz, 4H), 2.59 (t, J = 4.2 Hz, 4H), (400 MHz, DMSO-d6): d 8.53 (s, 1H), 6.71 (s, 1H), 4.65–4.63 (m,
2.55 (s, 3H), 2.46 (s, 3H). 13C-NMR (125 MHz, DMSO-d6): d 194.6, 1H), 3.84 (s, 2H), 3.79–3.67 (m, 2H), 3.63–3.39 (m, 4H), 2.62–2.52
165.2, 158.9, 156.1, 144.7, 140.0, 116.9, 115.6, 109.3, 105.6, 65.8, (overlapped, 7H), 2.48 (s, 3H), 2.06–1.92 (m, 2H), 1.96–1.75 (m,
52.4, 51.3, 30.1, 17.9. ESI-HRMS: m/z [M + H]+ calcd for 2H). 13C-NMR (125 MHz, D2O): d 198.9, 173.3, 164.4, 160.2,
C17H20NO5 318.1336, found 318.1342.
156.8, 147.2, 144.6, 117.0, 115.4, 110.5, 100.4, 75.0. 69.5, 51.0.
3-Acetyl-8-(4-hydroxypiperidin-1-yl methyl)-5-methyl-7-hydroxy- 48.4, 41.7, 38.8, 29.4, 25.1, 17.7. ESI-HRMS: m/z [M + H]+ calcd.
coumarin hydrochloride (24). Yellow solid, yield: 51.2%, m.p.: for C22H27N2O6 415.1864, found 415.1865.
210–211 1C (decomposed). 1H-NMR (500 MHz, D2O and
Biology
CF3COOD) d 8.30 (s, 1H), 6.61 (s, 1H), 4.11 (d, J = 5.2 Hz, 2H),
3.92–3.68 (m, 1H), 3.38 (d, J = 12.2 Hz, 1H), 3.17 (s, 2H), 2.99–2.93
(m, 1H), 2.33 (s, 3H), 2.21 (s, 3H), 1.95 (d, J = 13.5 Hz, 1H), 1.76 (s,
2H), 1.56–1.47 (m, 1H). 13C-NMR (100 MHz, D2O and CF3COOD) d
199.3, 163.2, 159.6, 156.3, 146.6, 144.4, 117.2, 114.9, 110.3, 100.9,
64.4, 60.5, 51.0, 47.7, 30.5, 28.8, 28.6, 17.5. ESI-HRMS: m/z [M +
H]+ calcd for C18H22NO5 332.1492, found 332.1495.
NO inhibition assay. Murine RAW264.7 macrophages were
obtained from the Institute of Basic Medical Sciences, Chinese
Academy of Medical Sciences and Peking Union Medical
College. The experiment was carried out following the protocol
in a previous report.51 We cultured the RAW264.7 cells in
Dulbecco’s modified Eagle medium (DMEM; #12100-500, Solarbio,
Beijing, China) supplemented with 10% fetal bovine serum (FBS;
#11011-8611, Sijiqing, Hangzhou, China) in a 5% CO2 atmosphere
and 100% relative humidity at 37 1C. The cells were seeded into 96-
well plates for 24 h at a cell concentration of 1.5 ꢁ 104 cells (100 mL)
per well. Then, the screened compounds at 1.0 ꢁ 10ꢀ5 mol Lꢀ1 and
curcumin (1.0 ꢁ 10ꢀ5 mol Lꢀ1) as a positive control were dissolved
in dimethyl sulfoxide (DMSO; #0231, Amresco, USA) and added to
3-Acetyl-8-((4-(hydroxymethyl)piperidin-1-yl)methyl)-5-
methyl-7-hydroxycoumarin hydrochloride (25). Yellow solid,
yield: 55.3%, m.p.: 211–213 1C (decomposed). 1H-NMR (400 MHz,
DMSO-d6): d 8.41 (s, 1H), 6.37 (s, 1H), 4.08 (s, 2H), 3.27 (d, J =
6.2 Hz, 2H), 3.17 (d, J = 11.8 Hz, 2H), 2.67 (t, J = 11.2 Hz, 2H), 2.50
(overlapped, 3H), 2.37 (s, 3H), 1.76 (d, J = 12.0 Hz, 2H), 1.55 (br, 1H),
1.35–1.24 (m, 2H). 13C-NMR (125 MHz, D2O and CF3COOD): d
202.9, 164.7, 160.7, 160.4, 158.2, 150.5, 148.1, 119.1, 117.4, 113.2,
102.1, 71.8, 54.7, 51.3, 34.0, 27.0, 18.4. ESI-HRMS: m/z [M + H]+
calcd for C19H24NO5 346.1649, found 346.1653.
the plates. After 1 h, the cells were treated with LPS (500 ng mLꢀ1
,
#L4391, Sigma, USA), and incubation was continued for an
additional 24 h. The supernatant of the culture medium was
collected (100 mL), and the NO2ꢀ concentration was detected using
an equal volume of Griess reagent to determine the NO concen-
tration. The optical density (OD) values were measured at 540 nm
on a microplate reader (BioTek H1, Winooski, VT, USA). The
inhibition ratio of NO production was calculated according to
eqn (2).
3-Acetyl-8-((4-methylpiperazin-1-yl)methyl)-5-methyl-7-
hydroxycoumarin hydrochloride (26). Yellow solid, yield:
42.2%, m.p.: 220–223 1C (decomposed). 1H-NMR (400 MHz,
D2O): d 8.82 (s, 1H), 6.96 (s, 1H), 4.63 (s, 2H), 3.76–3.68 (br, 8H),
3.03 (s, 3H), 2.67 (s, 3H), 2.58 (s, 3H). 13C-NMR (125 MHz, D2O):
d 199.3, 163.4, 160.5, 156.9, 147.6, 145.1, 117.8, 115.1, 110.9,
50.4, 50.1, 48.8, 48.6, 42.9, 29.1, 17.9. ESI-HRMS: m/z [M + H]+
calcd for C18H23N2O4 331.1652, found 331.1658.
ODmodel ꢀ ODtest
% inhibition ¼
ꢁ 100%
(2)
ODmodel ꢀ ODcontrol
3-Acetyl-8-((4-phenylpiperazin-1-yl)methyl)-5-methyl-7-
where ODmodel is the OD value of the model group (LPS), ODtest is
the OD value of the test group (LPS and test compounds), and
ODcontrol is the OD value of the control group (untreated).
hydroxycoumarin hydrochloride (27). Yellow solid, yield:
56.4%, m.p.: 245–247 1C (decomposed). 1H-NMR (400 MHz,
DMSO-d6): d 8.53 (s, 1H), 7.21 (t, J = 8.3 Hz, 2H), 6.94 (d, J =
8.2 Hz, 2H), 6.79 (t, J = 7.2 Hz, 1H), 6.68 (s, 1H), 3.97 (s, 2H),
3.22–3.15 (br, 4H), 2.92–2.74 (br, 4H), 2.55 (s, 3H), 2.47 (s, 3H).
TNF-a inhibition assay
13C-NMR (100 MHz, DMSO-d6): d 194.5, 165.8, 159.0, 156.1, The level of TNF-a was measured using ELISA kits (#88732422,
150.6, 144.7, 140.1, 129.0, 119.2, 116.6, 115.8, 115.6, 109.2, Thermo Fisher, USA). The specific procedure followed the
105.5, 51.8, 51.0, 47.8, 30.1, 17.9. ESI-HRMS: m/z [M + H]+ calcd protocol in a previous report.52 RAW264.7 cells were obtained
for C23H25N2O4 393.1809, found 393.1806.
from the American Type Culture Collection (Rockville, MD,
USA) and grown in RPMI-1640 culture medium (#12633012,
3-Acetyl-8-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-5-
methyl-7-hydroxycoumarin hydrochloride (28). Yellow solid, Thermo Fisher, USA) supplemented with 10% FBS (#10099,
yield: 51.4%, m.p.: 251–253 1C (decomposed). 1H-NMR Thermo Fisher, USA) in a 5% CO2 atmosphere at 37 1C. When
(500 MHz, DMSO-d6): d 8.55 (s, 1H), 7.16–6.96 (m, 4H), 6.70 the confluence reached approximately 80%, the cells were
(s, 1H), 3.99 (s, 2H), 3.08 (s, 4H), 2.81 (s, 4H), 2.56 (s, 3H), 2.48 seeded into 96-well plates at a concentration of 2.0 ꢁ 104 cells
(s, 3H). 13C-NMR (100 MHz, CDCl3) d 195.9, 165.6, 159.9, 157.1, (100 mL) per well and incubated for 12–18 h under 5% CO2.
156.0, 154.6, 145.7, 140.4, 139.4, 139.4, 124.7, 124.7, 123.3, The supernatant was discarded, and the cells were cultured
123.2, 119.2, 119.2, 118.1, 116.5, 116.3, 116.3, 110.5, 104.9, with 2% FBS for 4 h. Then, 1.0 ꢁ 10ꢀ5 mol Lꢀ1 screened
53.8, 52.8, 50.3, 30.8, 18.6. ESI-HRMS: m/z [M + H]+ calcd for compounds and dexamethasone as a positive control dissolved
C
23H24FN2O4 411.1715, found 411.1707.
in DMSO (#67685, Sigma, USA) were added to the plates, and
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the cells were incubated for 1 h. LPS (1 mg mLꢀ1) was
supplemented for an additional 24 h. The supernatant of the
culture medium was collected to detect TNF-a release. The OD
values were measured at 450 nm and 570 nm on a microplate
reader. The TNF-a concentrations after treatment with the
screened compounds were obtained with a standard curve.
The inhibition ratio of TNF-a was calculated based on eqn (3).
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Acknowledgements
We gratefully acknowledge the CAMS Innovation Fund for
Medical Sciences (CIFMS, No. 2016-I2M-3-009) and the Drug
Innovation Major Project (2018ZX09711-001-005) for providing
financial support for this work.
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