Identification of novel imidazole flavonoids as potent and selective inhibitors of protein tyrosine phosphatase

Article abstract of DOI:10.1016/j.bioorg.2019.03.074

A series of imidazole flavonoids as new type of protein tyrosine phosphatase inhibitors were synthesized and characterized. Most of them gave potent protein phosphatase 1B (PTP1B) inhibitory activities. Especially, compound 11a could effectively inhibit P

Full text of DOI:10.1016/j.bioorg.2019.03.074

Accepted Manuscript
Identification of novel imidazole flavonoids as potent and selective inhibitors
of protein tyrosine phosphatase
Ling Zhang, Yu Ge, Qing Ming Wang, Cheng-He Zhou
PII:
S0045-2068(18)31472-X
https://doi.org/10.1016/j.bioorg.2019.03.074
YBIOO 2900
DOI:
Reference:
Bioorganic Chemistry
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Revised Date:
Accepted Date:
14 December 2018
18 March 2019
30 March 2019
Please cite this article as: L. Zhang, Y. Ge, Q. Ming Wang, C-H. Zhou, Identification of novel imidazole flavonoids
as potent and selective inhibitors of protein tyrosine phosphatase, Bioorganic Chemistry (2019), doi: https://doi.org/
10.1016/j.bioorg.2019.03.074
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Title page
Title:
Identification of novel imidazole flavonoids as potent and selective inhibitors of protein tyrosine
phosphatase
Author names and affiliations:
Ling Zhang1,*, Yu Ge1, Qing Ming Wang1,* and Cheng-He Zhou2
1,* School of Pharmacy, Yancheng Teachers’ University, Yancheng, Jiangsu 224051, People’s Republic of
China
2
Laboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing, 400715, P.R. China
Tel.: 0515-88258905
E-mail: zling891613@163.com (Ling Zhang), wangqm@yctu.edu.cn (Qing Ming Wang)
Abstract:
A series of imidazole flavonoids as new type of protein tyrosine phosphatase inhibitors were synthesized
and characterized. Most of them gave potent protein phosphatase 1B (PTP1B) inhibitory activities.
Especially, compound 11a could effectively inhibit PTP1B with an IC50 value of 0.63 μM accompanied
with high selectivity ratio (9.5-fold) over T-cell protein tyrosine phosphatase (TCPTP). This compound is
cell permeable with relatively low cytotoxicity. The high binding affinity and selectivity was disclosed by
molecular modeling and dynamics studies. The structural features essential for activity were confirmed by
quantum chemical studies.
Keywords:
Flavonoid; Imidazole; Protein tyrosine phosphatase; Selectivity; Cell viability
1

1. Introduction
Protein tyrosine phosphatases (PTPs) exert an significant effect on catalysis protein tyrosine
dephosphorylation and modulation several cellular signal transduction pathways [1]. Dysregulation of PTPs
activities causes aberrant tyrosine phosporylation, which lead to the pathogenesis of many human diseases
such as cancers, autoimmune disorders, obesity and diabetes [2]. Among the PTPs, PTP1B is a key
negative regulator of insulin signaling and acts by directly inactivating insulin receptor (IR) through
dephosphorylation tyrosine residues in the regulatory domain [3]. A number of synthetic PTP1B inhibitors
have been discovered [4-6]. Compound 1 designed on the basis of catalytic pocket characteristics, was a
classic PTP1B inhibitor (IC50 = 32 nM) with modest caco-2 permeability, but without selectivity (Figure 1).
Compound 2 (IC50 = 620 nM) was found to interact with the PTP1B catalytic site Cys215 through
establishment of covalent bond, however, the selectivity or membrane permeability was not further reported
[7]. PTP inhibitors especially that can inhibit the particular PTP with good permeability are therefore highly
desirable [8].
Fig. 1 Some reported PTP1B inhibitors
Chemical modification of biological active compounds of natural origin is one of the most efficient
approaches in drug development. Flavonoids with typical benzopyrone framework are a class of plant
phenolic compounds that are widely found in fruits, vegetables, seeds and herbs (Figure 2). A large number
of studies show that flavonoids exert beneficial effects in the prevention of many diseases, including cancer,
cardiovascular disease and neurodegenerative disorders. Specially, some natural flavones extracted from
plants and traditional Chinese medicine manifested to be good PTP1B inhibitors due to their low toxicity
and high hypoglycemic effects [9]. Especially, they are potentially powerful bioactive agents since it has
disclosed that they could selectively inhibit PTP1B activity in a non-competitive way different to the
2

traditional drugs [10,11], and improve insulin sensitivity in insulin-resistant HepG2 cells via the
IRS-1/PI3K/AKT pathway [12]. Recently, more and more flavonoids received much attention due to their
unique properties in the inhibition of PTP1B (Figure 3).
Fig. 2 General structure of flavonoids.
Fig. 3 Some reported flavonoid derivatives as PTP1B inhibitors
Imidazole derivatives has shown large potentiality in medicinal chemistry [13]. The unique structure of
imidazole endows its derivatives to readily bind with a variety of enzymes and receptors in biological
system via weak interactions such as coordination bonds, hydrogen bonds, ion-dipole, cation-π, π-π
stacking, hydrophobic effect, van der Waals force and so on. Literature reported that presence of imidazole
ring played an important role to improve the PTP1B inhibitory activity [14,15]. Imidazole derivatives were
shown to activate glucose uptake in cell cultures through inhibition of the PTP1B and also demonstrated
the inhibition of D-dimer formation, suggesting they could potentially relieve a hypercoagulative state in
diabetic patients [16] (Figure 4). This encourages us with special interest to investigate these imidazole
compounds as a novel type of PTP1B inhibitors with improved activity.
Fig. 4 Some reported imidazole derivatives as PTP1B inhibitors
In recent years, the actual trend in the field of chemistry of flavonoids has been modification by
3

purposeful introduction into the molecule of nitrogen heterocyclic substituent [17-20]. Such studies are of
great interest for the theory of organic synthesis and purposeful synthesis of new biologically active
compounds based on flavonoid system. However, much less work has been taken on the synthesis of
flavonoids containing nitrogen heterocyclic moiety at C-2 position.
In view of this situation and as an extension of previous work [21,22], it is meaningful for us to combine
flavonoids through their C-2 position with different imidazole carbaldehydes to generate a new structural
type of potentially PTP1B inhibitors and investigate their effect on the inhibition of PTP1B (Scheme 1).
Since substituents exert big influence on the bioactivities [23-25], various aliphatic chains with different
lengths and substituted phenyl moieties containing fluoro, chloro and nitro groups were further modified.
All the synthesized imidazole flavonoids (Scheme 1 and Scheme 2) were characterized and their PTP1B
inhibitory activity was also evaluated. The structural features essential for activity were also by
investigation of molecular modelling, molecular dynamics, energies and plots of HOMO and LUMO, and
plots of MEP.
2 Results and discussion
2.1. Chemistry
The synthetic route of target imidazole flavonoids was outlined in Scheme 1 and Scheme 2. Initially,
reactions of compounds 1a–c with imidazole-4-carbaldehyde afforded the corresponding azoles 2a–c and
3a–c in 30.1–53.2% yields (Scheme 1). Possible reactions of imidazole-4-carbaldehyde in the presence of
potassium carbonate are shown in Figure 5. In basic conditions, 4-carbaldehyde orientation easily occurred
during the N-alkylations of imidazole-4-carbaldehyde with alkyl halides. Conversely, the acidic conditions
favored the 5-carbaldehyde orientation. Considered the yields were poor under acidic conditions, potassium
carbonate was chosen to synthesize the target compounds. Four resonance forms of
imidazole-4-carbaldehyde (A–D) exist in basic conditions (Figure 5). Amongst, patterns A and C are more
stable than other patterns, so the N-1 and N-3 alkylated products could be obtained by N-alkylation of
imidazole-4-carbaldehyde. The N-1 alkylated one is predominant due to the relative low acidity of –NH–
proton compared to imidazole-5-carbaldehyde. In the preparations of imidazole-4-carbaldehydes 2a–c,
5a–e, imidazole-5-carbaldehyde derivatives 3a–c, 6a–e were obtained as by-products.
Condensation of 1,3-benzenediol with chloro-acetonitrile in the presence of ZnCl2 in ether was followed
by hydrolysis in water and produced ketone 7 in 86% yield [26]. The resulting 7 was reacted with
corresponding imidazole carbaldehydes in ethanol with 10% NaOH, was followed by acidification with
4

aqueous HCl to afford target compounds 8, 9a–c, 10a–c, 11a–e, and 12a–e in satisfactory yields.
The alkylation of imidazole-2-carbaldehyde with alkyl halides 1a–c afforded the corresponding azoles
13a–c (Scheme 2). N-Halobenzyl derivatives 14a–d were provided in quantitative yields by the reaction of
imidazole-2-carbaldehyde with a series of halobenzyl halides 4a–d. These prepared imidazole halides
13a–c and 14a–d respectively were further coupled with ketone 7 to smoothly produce the target
imidazole-flavonoid hybrids 15, 16a–c and 17a–d.
Scheme 1 Synthetic routes of flavonoid imidazoles (I). Reagents and conditions: (i) alkyl bromide, K2CO3, EtOH, reflux; (ii)
halobenzyl halide, K2CO3, EtOH, reflux; (iii) ClCH2CN, EtOEt, HCl (g), 0℃; (iv) 1 mol/L HCl, H2O, reflux; (v)
imidazole-4-carbaldehyde, 10%NaOH, rt, EtOH; (vi) compounds 2a-c, 10%NaOH, rt, EtOH; (vii) compounds 3a-c,
10%NaOH, rt, EtOH; (viii) compounds 5a-e, 10%NaOH, rt, EtOH; (ix) compounds 6a-e, 10%NaOH, rt, EtOH.
5

Scheme 2 Synthetic routes of flavonoid imidazoles (II). Reagents and conditions: (i) alkyl bromide, K2CO3, EtOH, reflux; (ii)
halobenzyl halide, K2CO3, EtOH, reflux; (iii) ClCH2CN, EtOEt, HCl (g), 0℃; (iv) 1 mol/L HCl, H2O, reflux; (v)
imidazole-2-carbaldehyde, 10%NaOH, rt, EtOH; (vi) compounds 13a-c, 10%NaOH, rt, EtOH; (vii) compounds 14a-d,
10%NaOH, rt, EtOH.
Fig. 5 Possible reactions of imidazole-4-carbaldehyde in the presence of potassium carbonate
2.2. Biological evaluation
2.2.1. Inhibition of phosphatases
The PTP1B inhibitory activity of all the synthesized target compounds 8, 9a–c, 10a–c, 11a–e, 12a–e, 15,
16a–c and 17a–e was evaluated. The results were summarized in Table 1. As illustrated in Table 1, most
compounds showed potential inhibitory activities for PTP1B. The results demonstrated that the obvious
6

effect of the substituents at the imidazoles on biological activity. Moderate PTP1B inhibitory activity was
found for most of N-alkyl derivatives 9a–c, 10a–c and 16a–c. Amongst, compound 9b (IC50 = 6.3 μmol/L)
and 16b (IC50 = 6.0 μmol/L) with pentyl group and 10a (IC50 = 5.0 μmol/L) with propyl group gave the
best bioactivity.
Most halobenzyl ones 11a–e, 12a–e and 17a–e exerted relatively better PTP1B inhibitory activities than
the alkyl derivatives 9a–c, 10a–c and 16a–c. Notably, in the series of imidazole-4-formyl derivatives,
3-chlorobenzyl hybrid 11a gave the best anti-PTP1B efficiency with IC50 value of 0.63 μmol/L. Besides,
compound 11e with p-methoxy group also displayed fairly good activities with the IC50 value of 1.0 μmol/L.
The replacement of chlorobenzyl moiety by fluorobenzyl group (compound 11d) resulted in unfavorable
potency at the concentrations of 5.0 μmol/L. The positional change of chlorine atom in compound 11a to
give derivatives 11b and 11c was not beneficial for the bioactivities.
To our surprise, generally all 5-position substituted imidazoles 10a–c, 12a–e and 2-position substituted
imidazoles 15, 16a–c and 17a–e displayed lower anti-PTP1B activities than that of 4-substituted ones 9a–c,
11a–e.
Considered the above discussion, the anti-PTP1B efficacies should be in relation to imidazole ring and
halobenzyl group to some extent. For this serial compounds, imidazole-formyl moieties contributed to the
anti-PTP1B activities in the order of imidazole-4-formyl derivatives > imidazole-2-formyl derivatives >
imidazole-5-formyl ones. The chlorophenyl group was more favorable for improving anti-PTP1B efficacy
compared with other benzyl ones.
7

Table 1 Inhibitory activities against PTP1B(μmol/L)
For compounds 8, 9a-c, 11a-e For compounds 10a-c, 12a-e
For compounds 15, 16a-c, 17a-e
Compounds
8: R = H
IC50
Compounds
11c:
IC50
Compounds
IC50
10.0+1.7
3.1+0.3
16a:
16b:
9.8+0.1
10.0+2.3
6.3+0.9
7.9+0.4
5.0+0.9
6.0+0.2
8.2+0.4
1.1+0.7
9a:
9b:
11d:
11e:
1.0+0.04 16c:
5.0+0.9
9c:
12a:
17a:
5.0+0.3
15.0+1.4
12.5+1.1
0.63+0.04
3.9+0.3
5.0+0.6
4.1+0.3
5.0+0.9
5.7+0.5
1.2+0.3
4.7± 0.2
10a:
10b:
12b:
12c:
17b:
5.0+0.5
17c:
5.0+0.5
10c:
12d:
17d:
3.1+0.4
12e:
11a:
11b:
17e:
15: R = H
11.2+0.4
Oleanolic Acid
Further, the selectivity of the 11a was determined by measuring their inhibitory activity against a panel
of several phosphatases including TCPTP, PTP-MEG2 and SHP-2. The IC50 values of inhibitor 11a against
the phosphatases, and the selectivity ratios were shown in Table 2. Compound 11a showed no activity
against PTP-MEG2, and only exhibited moderate activity for SHP-2. Obviously, 9.5-fold selectivity for
PTP1B over TCPTP was found for compound 11a.
Table 2 Inhibition of phosphatases by inhibitor 11a
IC50 (M)
Compd
PTP1B
0.63
TCPTP
5.99
PTP-MEG2
NA
SHP-2
16.87
Selective
9.5
11a
a NA: no activity
b Selective: IC50(TCPTP)/IC50(PTP1B)
Abbreviations: PTP1B, protein tyrosine phosphatase 1B; TCPTP, T-cell protein tyrosine phosphatase; PTP-MEG2,
megakaryocyte protein tyrosine phosphatase; SHP-2, src homology phosphatase 2.
c
2.2.2. Kinetic analysis of PTP1B inhibition
8

A kinetic analysis of inhibitor 11a was then performed using p-NPP as the substrate. The steady state
kinetics assays were conducted under five different concentrations of compound 11a (0, 1, 2, 4, 8 M). A
competitive inhibition mode versus p-NPP was identified since the lines converged at an intersection on the
y-axis above the x-axis (Figure 6).
0.5
Inhibitor 11a
8 μM
4 μM
0.4
2 μM
1 μM
0 μM
0.3
0.2
0.1
-1
0
1
2
3
4
5
6
1/[pNPP]
Fig. 6 Compound 11a is a classical competitive inhibitor
2.3. The influence of 11a on cell viability
Cell Counting Kit-8 (CCK8) method was used to investigate the effect of 11a on cell viability of
HEK293 (human embryonic kidney 293) cells. At high concentration, compound 11a still gave low toxicity
to normal human embryonic kidney cells (Figure 7). The IC50 value (324 g/mL) manifested 11a has lower
cytotoxicity.
120
Compound 11a
100
80
60
40
20
0
Control
5
10
20
40
80
160 320
Concentration (g/mL)
Fig. 7 Relative cell viabilities of compound 11a in HEK293 cells.
9

2.3. Molecular modeling
To disclose the observed high binding affinity and selectivity of the target flavonoids, the lowest-energy
conformations were calculated by using active site-docking simulations (Figure 8, Supplementary
Information: Table S3). The crystal structure data (protein tyrosine phosphatases 1B) were provided by the
protein data bank (PDB code: 1T4J). The calculated binding modes of represent compounds in the active
site of PTP1B support the bioactivity difference (Table 1) and were illustrated in Figure 8.
According to the docking evaluation, the most active hybrid 11a (E = -8.78 kJ/mol) with PTP1B might
rationalize the possible inhibitory mechanism. The hydroxyl group of this molecule could form hydrogen
bonds with Lys197, Glu200 of PTP1B with length of 1.8 Å. Meanwhile, the nitrogen atom of the imidazole
moiety and oxygen atom of this molecule could also form hydrogen bonds with the residue Asn193 with
length of 2.7 Å and 2.2 Å respectively. These cooperative binding might be beneficial to stabilize the
compound-PTP1B enzyme complex, which might be responsible for the good inhibitory efficacy of
compound 11a against PTP1B.
(A) Compound 8 (E = -6.94 kJ/mol)
(B) Compound 9a (E = -6.74 kJ/mol)
(C) Compound 10a (E = -7.33 kJ/mol)
(D) Compound 11a (E = -8.78 kJ/mol)
10

(E) Compound 12e (E = -7.77 kJ/mol)
(F) Compound 15 (E = -6.34 kJ/mol)
(G) Compound 16b (E = -7.48 kJ/mol)
(H) Compound 17b (E = -7.47 kJ/mol)
Fig. 8 Binding modes of all compounds in the active site of PTP1B.
The binding mode of compound 11a with TCPTP (PDB code: 1L8K) was used to preliminary explain the
selectivity of this inhibitor. The main interactions between inhibitor 11a and the TCPTP was shown in
Figure 9. This compound formed hydrogen bonding with amino acid residues Arg-7 with length of 1.7 Å
through the oxygen atom. This pattern was different with the binding of 11a with PTP1B.
11

Fig. 9 Three-dimensional conformation of compound 11a docked onto the active site of TCPTP.
2.4. Analysis of the Dynamics Studies
The interaction of the protein with ligands is a dynamic process. This results in a more stable complex
with lower binding energy, and could be displayed by molecular dynamics (MD) simulation.
To analyze the stability of the PTP1B-compound 11a complex, the root-mean-square deviation (RMSD)
values of atoms in PTP1B and PTP1B-compound 11a complexes were investigated (Figure 10,
Supplementary Information: Fig. S1-Fig. S3). The backbone RMSD value of PTP1B was lower than that of
TCPTP, which suggested that the PTP1B/11a was more stable than TCPTP/11a in 50 ns MD simulation
(Figure 10, Supplementary Information: Fig. S1-Fig. S3). That may be account for selectivity of PTP1B
over TCPTP.
0.45
TCPTP-Compound 11a
PTP1B-Compound 11a
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0
10
20
30
40
50
t (ns)
Fig. 10 Time dependence of root-mean-square deviations (RMSD’s) for 11a bound with TCPTP (1L8K, in black) and
PTP1B (1T4J, in red)
2.5. Molecular orbital calculation
Electronic effects were shown to be related with biological activity of drugs [27]. At the molecular level,
12

the frontier molecular orbitals (FMO) controlled the reactivity of a molecule, namely the highest occupied
molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) and they exerted
important effect in intermolecular interactions [28]. The extents of these stabilizing interactions in inversely
correlation with the energy gap between the interacting orbitals. Higher HOMO energy and lower LUMO
energy lead to larger stabilizing interactions, favoring for binding with the receptor. The orbital energies of
both HOMO and LUMO and their gaps, were calculated for all the compounds and are shown in Table 3. It
is obvious that compounds 9b, 10a, 11a, 11b and 12e having the lower energy gap (ΔE) of 1.78, 1.82, 1.99,
1.83 and 1.74 eV, respectively, exhibit the higher bioactivity.
Table 3 Energies of both HOMO and LUMO and their gaps (in eV) calculated for target compounds
Compounds
8
EHOMO
-3.210
-2.557
-2.767
-3.156
-2.557
-3.181
-3.178
-3.319
-3.129
-3.292
-3.211
-2.966
-3.401
-3.346
-3.347
-3.293
-2.476
-3.374
-3.327
-3.262
ELUMO
-1.232
-0.544
-0.985
-1.197
-0.734
-1.116
-1.116
-1.325
-1.306
-1.306
-1.279
-1.034
-1.252
-1.306
-1.279
-1.251
-0.734
-0.152
-0.160
-1.308
ΔE
1.98
2.01
1.78
1.96
1.82
2.07
2.06
1.99
1.83
1.99
1.93
1.93
2.15
2.04
2.07
2.04
1.74
3.22
3.17
1.95
9a
9b
9c
10a
10b
10c
11a
11b
11c
11d
11e
12a
12b
12c
12d
12e
15
16a
17a
Plot of the HOMO and LUMO of the compounds was helpful to determine which atoms were located at
the possible sites of electronic transfer between the compound and biological target [29]. The plots of the
HOMO and LUMO of all compounds obtained from DFT calculations were obtained (Supplementary
Information: Table S1). Some represent compounds are displayed in Figure 11. The results illustrate that
HOMO molecular orbital of 8 is mainly located in imidazole ring, indicating the existence of a possible
13

reactive sites. Therefore, electrophilic attacks might take place on these sites. On the other hand, the
LUMO of 8 is primarily concentrated on imidazole and flavonoid rings in which the negatively charged
polar residues of the receptor are favorable. Comparing with 8, the introduction of various substitutions to
the imidazole ring produced different characteristic. HOMO of N-alkyl derivative 9a presents similar
characteristic, while the LUMO changes significantly. In this case, the LUMO is primarily located in
imidazole ring. In contrast, HOMO and LUMO of halobenzyl derivative 11a presents similar characteristic
with compound 8.
Compounds
HOMO
LUMO
8
9a
11a
Fig. 11 Plots of the HOMO and LUMO of represent compounds
2.6. Molecular electrostatic potentials
In an attempt to further understand the different bioactivities, molecular electrostatic potentials (MEPs)
have been carried out for the lowest energy conformers (Figure 12, Supplementary Information: Table S2).
The results show that the nitrogen atom in 1-position of imidazole is more electronically available with the
lone pair in unsubstituted imidazole (compound 8, 15 vs 9a, 16b). Specially, compound 11a possess
increased positive charge regions on the oxygen atoms of OH group. The 5-position substituted imidazoles
(10a, 12a, 12b) possess an increased positive charge regions (in blue) located on the nitrogen atoms of
imidazole ring than 4-substituted ones (9a, 11a), which might had unfavorable effects on biological
activities.
14

Compounds
Molecular electrostatic potentials
8
9a
10a
12a
11a
12b
15
16b
Fig. 12 Molecular electrostatic potentials (MEPs) of represent compounds showing the most positive potential (deepest blue
color), the most negative potential (deepest red color), and the intermediate potential (intermediate shades) regions.
3 Conclusion
In conclusion, a series of flavonoid imidazoles were successfully synthesized by a convenient and
1
efficient procedure. Their structures were confirmed by H NMR, 13C NMR, MS, IR and HRMS spectra.
The in vitro protein tyrosine phosphatase inhibition evaluation revealed that most of the synthesized
compounds exhibited potent PTP1B inhibitory activities at the micromolar range. The most active
15

compound 11a with IC50 values of 0.63 μM displayed 9.5-fold selectivity over TCPTP. Molecular modeling
studies indicated that the imidazole ring played an important role in the interaction of inhibitor with PTP1B.
The MD studies revealed that the PTP1B/11a complex was more stable than TCPTP/11a, which was the
potent proof for observed 9.5-fold selectivity of 11a for PTP1B over TCPTP. These results provided
evidence that flavonoid imidazoles can be potent inhibitors of PTP1B. Further studies on these compounds
in cell permeability, selectivity and cellular activity to provide PTP1B inhibitors suitable for in vivo proof
of animal studies in diabetes are now in progress. All these will be discussed in the future paper.
4 Experimental protocols
4.1 General methods
Melting points were recorded on X-6 melting point apparatus and uncorrected. TLC analysis was done
using pre-coated silica gel plates. FT-IR spectra were carried out on Bruker RFS100/S spectrophotometer
(Bio-Rad, Cambridge, MA, USA) using KBr pellets in the 400–4000 cm-1 range. NMR spectra were
recorded on a Bruker AV 300 and 600 spectrometer using TMS as an internal standard. The chemical shifts
were reported in parts per million (ppm), the coupling constants (J) were expressed in hertz (Hz) and
signals were described as singlet (s), doublet (d), triplet (t), as well as multiplet (m). The mass spectra were
recorded on LCMS-2010A and the high-resolution mass spectra (HRMS) were recorded on an IonSpec
FT-ICR mass spectrometer with ESI resource. All other chemicals and solvents were commercially
available, and were used without further purification.
4.2 Synthesis of flavonoid imidazoles
4.2.1. Synthesis of 1-propyl-1H-imidazole-4-carbaldehyde (2a)
A mixture of imidazole-4-carbaldehyde (0.96 g, 0.01 mol) and potassium carbonate (1.38 g, 0.01 mol) in
acetonitrile (5 mL) was stirred at 60 ℃ for 1 h. After the mixture was cooled to room temperature,
compound 1a (2.44 g, 0.02 mol) was added and refluxed for 10 h (monitored by TLC, eluent, ethyl
acetate/petroleum, 1:1, v/v). After the solvent was evaporated under reduced pressure, and the resulting
residue was extracted with ethyl acetate (3×20 mL), the organic layers were combined, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography eluting with ethyl acetate/petroleum (1:2, v/v) to afford the target
1
compound 2a (0.61 g) as white solid. Yield: 44.1%; mp: 107–108 ℃. H NMR (400 MHz, DMSO-d6) δ:
9.69 (s, 1H, CHO), 7.76 (s, 1H, imidazole-2-H), 7.52 (s, 1H, imidazole-5-H), 3.99 (t, J = 7.0 Hz, 2H,
16

imidazole-CH2), 1.45 (dd, J = 14.1, 7.0 Hz, 2H, CH2), 0.75 (t, J = 7.2 Hz, 3H, CH3) ppm.
4.2.2. Synthesis of 1-pentyl-1H-imidazole-4-carbaldehyde (2b)
Compound 2b was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 1b
(3.02 g, 0.02 mol). The target compound 2b (0.88 g) was obtained as white solid. Yield: 53.2%; mp:
1
109–110 ℃. H NMR (400 MHz, CDCl3) δ: 9.77 (s, 1H, CHO), 7.44 (s, 1H, imidazole-2-H), 7.27 (s, 1H,
imidazole-4-H), 3.60 (t, J = 7.2 Hz, 2H, CH2), 1.81 (d, 2H, CH2), 1.30 (d, 4H, CH2CH2), 0.89 (t, J = 7.0 Hz,
3H, CH3) ppm.
4.2.3. Synthesis of 1-heptyl-1H-imidazole-4-carbaldehyde (2c)
Compound 2c was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 1c
(3.56 g, 0.02 mol). The target compound 2c (0.97 g) was obtained as white solid. Yield: 50.1%; mp:
109–110 ℃. 1H NMR (600 MHz, DMSO-d6) δ: 9.75 (s, 1H, CHO), 7.72 (s, 1H, imidazole-2-H), 7.57 (s, 1H,
imidazole-5-H), 4.01 (t, J = 7.0 Hz, 2H, imidazole-CH2), 1.68–1.60 (m, 2H, CH2), 1.20–1.18 (m, 8H, CH2),
0.81 (t, J = 7.1 Hz, 3H, CH3) ppm.
4.2.4. Synthesis of 1-propyl-1H-imidazole-5-carbaldehyde (3a)
Compound 3a was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 1a
(2.44 g, 0.02 mol). The target compound 3a (0.43 g) was obtained as white solid. Yield: 31.2%; mp:
109–110 ℃. 1H NMR (400 MHz, DMSO-d6) δ: 9.73 (s, 1H, CHO), 7.70 (s, 1H, imidazole-2-H), 7.63 (d, J =
1.0 Hz, 1H, imidazole-4-H), 3.85 (dd, J = 9.3, 4.4 Hz, 2H, imidazole-CH2), 1.80 (dt, J = 14.1, 7.2 Hz, 2H,
CH2), 0.91–0.89 (m, 3H, CH3) ppm.
4.2.5. Synthesis of 1-pentyl-1H-imidazole-5-carbaldehyde (3b)
Compound 3b was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 1b
(3.02 g, 0.02 mol). The target compound 3b (0.53 g) was obtained as white solid. Yield: 32.3%; mp:
1
106–108 ℃. H NMR (400 MHz, CDCl3) δ: 9.87 (s, 1H, CHO), 7.64 (s, 1H, imidazole-2-H), 7.57 (s, 1H,
imidazole-4-H), 4.00 (t, J = 7.2 Hz, 2H, CH2), 1.84 (dd, J = 14.8, 7.4 Hz, 2H, CH2), 1.32 (ddd, J = 15.3,
17

13.0, 6.2 Hz, 4H, CH2CH2), 0.91 (t, J = 7.1 Hz, 3H, CH3) ppm.
4.2.6. Synthesis of 1-heptyl-1H-imidazole-5-carbaldehyde (3c)
Compound 3c was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 1c
(3.56 g, 0.02 mol). The target compound 3c (0.58 g) was obtained as white solid. Yield: 30.1%; mp:
112–113 ℃. 1H NMR (600 MHz, DMSO-d6) δ: 9.45 (s, 1H, CHO), 7.71 (s, 1H, imidazole-2-H), 7.48 (s, 1H,
imidazole-4-H), 3.83 (t, J = 7.4 Hz, 2H, imidazole-CH2), 1.63 (dt, J = 12.1, 7.5 Hz, 2H, CH2), 1.27 (m, 8H,
CH2), 0.83 (t, J = 7.6 Hz, 3H, CH3) ppm.
4.2.7. Synthesis of 1-(3-chlorobenzyl)-1H-imidazole-4-carbaldehyde (5a)
Compound 5a was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 4a
(4.10 g, 0.02 mol). The target compound 5a (0.74 g) was obtained as white solid. Yield: 33.6%; mp:
121–122 ℃. 1H NMR (600 MHz, DMSO-d6) δ: 9.28 (s, 1H, CHO), 7.88 (s, 1H, imidazole-2-H), 7.65 (s, 1H,
imidazole-4-H), 7.08 (dd, J = 17.0, 5.9 Hz, 2H, Ph-H), 6.95 (s, 1H, Ph-2-H), 6.70 (d, J = 5.3 Hz, 1H, Ph-H),
5.35 (s, 2H, CH2) ppm.
4.2.8. Synthesis of 1-(2,4-dichlorobenzyl)-1H-imidazole-4-carbaldehyde (5b)
Compound 5b was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 4b
(4.79 g, 0.02 mol). The target compound 5b (0.87 g) was obtained as yellow solid. Yield: 34.2%; mp:
131–132 ℃. 1H NMR (600 MHz, DMSO-d6) δ: 9.82 (s, 1H, CHO), 7.75 (s, 1H, imidazole-2-H), 7.62 (s, 1H,
imidazole-4-H), 7.21 (d, J = 6.4 Hz, 1H, Ph-3-H), 6.56 (d, J = 52.3 Hz, 2H, Ph-5,6-2H), 5.35 (s, 2H, CH2)
ppm.
4.2.9. Synthesis of 1-(4-chlorobenzyl)-1H-imidazole-4-carbaldehyde (5c)
Compound 5c was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 4c
(4.10 g, 0.02 mol). The target compound 5c (0.91 g) was obtained as yellow solid. Yield: 41.2%; mp:
134–135 ℃. 1H NMR (600 MHz, DMSO-d6) δ: 9.71 (s, 1H, CHO), 7.78 (s, 1H, imidazole-2-H), 7.67 (s, 1H,
imidazole-4-H), 7.17 (d, J = 8.4 Hz, 2H, Ph-2,6-2H), 7.12 (d, J = 8.4 Hz, 2H, Ph-3,5-2H), 5.50 (s, 2H, CH2)
18

ppm.
4.2.10. Synthesis of 1-(4-fluorobenzyl)-1H-imidazole-4-carbaldehyde (5d)
Compound 5d was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 4d
(4.10 g, 0.02 mol). The target compound 5d (0.65 g) was obtained as yellow solid. Yield: 32.0%; mp:
1
134–135 ℃. H NMR (400 MHz, CDCl3) δ: 9.75 (s, 1H, CHO), 7.56 (s, 1H, imidazole-3-H), 7.54 (s, 1H,
imidazole-5-H), 7.13 (dd, J = 8.4, 5.2 Hz, 2H, Ph-2,6-2H), 6.99 (dd, J = 9.4, 7.7 Hz, 2H, Ph-3,5-2H), 5.09
(s, 2H, CH2) ppm.
4.2.11. Synthesis of 1-(4-methoxybenzyl)-1H-imidazole-4-carbaldehyde (5e)
Compound 5e was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 4e
(4.02 g, 0.02 mol). The target compound 5e (0.59 g) was obtained as yellow solid. Yield: 27.2%; mp:
1
134–135 ℃. H NMR (400 MHz, CDCl3) δ: 9.75 (s, 1H, CHO), 7.56 (s, 1H, imidazole-3-H), 7.54 (s, 1H,
imidazole-5-H), 7.13 (dd, J = 8.4, 5.2 Hz, 2H, Ph-2,6-2H), 6.99 (dd, J = 9.4, 7.7 Hz, 2H, Ph-3,5-2H), 5.09
(s, 2H, CH2) ppm.
4.2.12. Synthesis of 1-(3-chlorobenzyl)-1H-imidazole-5-carbaldehyde (6a)
Compound 6a was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 4a
(4.10 g, 0.02 mol). The target compound 6a (0.82 g) was obtained as white solid. Yield: 37.1%; mp:
1
123–124 ℃. H NMR (600 MHz, DMSO-d6) δ: 9.81 (s, 1H, CHO), 7.83 (s, 1H, imidazole-2-H), 7.75 (s, 1H,
imidazole-4-H), 7.00 (dd, J = 16.1, 7.5 Hz, 2H, Ph-H), 6.91 (s, 1H, Ph-2-H), 6.80 (d, J = 7.5 Hz, 1H, Ph-H), 5.31
(s, 2H, CH2) ppm.
4.2.13. Synthesis of 1-(2,4-dichlorobenzyl)-1H-imidazole-5-carbaldehyde (6b)
Compound 6b was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 4b
(4.79 g, 0.02 mol). The target compound 6b (0.91 g) was obtained as yellow solid. Yield: 35.5%; mp:
1
134–135 ℃. H NMR (600 MHz, DMSO-d6) δ: 9.74 (s, 1H, CHO), 7.86–7.72 (m, 2H, imidazole-2-H,
imidazole-4-H), 7.18 (d, J = 7.3 Hz, 1H, Ph-3-H), 6.78 (dd, J = 8.5, 2.3 Hz, 1H, Ph-5-H), 6.70 (d, J = 8.5 Hz, 1H,
19

Ph-6-H), 5.30 (s, 2H, CH2) ppm.
4.2.14. Synthesis of 1-(4-chlorobenzyl)-1H-imidazole-5-carbaldehyde (6c)
Compound 6c was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 4c
(4.10 g, 0.02 mol). The target compound 6c (0.86 g) was obtained as yellow solid. Yield: 39.2%; mp:
131–132 ℃. 1H NMR (600 MHz, DMSO-d6) δ: 9.76 (s, 1H, CHO), 7.83 (d, J = 7.2 Hz, 2H, imidazole-2-H,
imidazole-4-H), 7.46 (d, J = 8.1 Hz, 2H, Ph-2,6-2H), 7.16 (d, J = 8.1 Hz, 2H, Ph-3,5-2H), 5.13 (s, 2H, CH2)
ppm.
4.2.15. Synthesis of 1-(4-fluorobenzyl)-1H-imidazole-5-carbaldehyde (6d)\
Compound 6d was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 4d
(4.10 g, 0.02 mol). The target compound 6d (0.66 g) was obtained as yellow solid. Yield: 32.4%; mp:
1
134–135 ℃. H NMR (400 MHz, CDCl3) δ: 9.76 (s, 1H, CHO), 7.84 (s, 1H, imidazole-2-H), 7.73 (s, 1H,
imidazole-4-H), 7.28–7.19 (m, 2H, Ph-2,6-2H), 7.04 (t, J = 8.4 Hz, 2H, Ph-3,5-2H), 5.49 (s, 2H, CH2) ppm.
4.2.16. Synthesis of 1-(4-methoxybenzyl)-1H-imidazole-5-carbaldehyde (6e)
Compound 6e was prepared according to the procedure described for compound 2a starting from
imidazole-4-carbaldehyde (0.96 g, 0.01 mol), potassium carbonate (1.38 g, 0.01 mol) and compound 4e
(4.02 g, 0.02 mol). The target compound 6e (0.74 g) was obtained as yellow solid. Yield: 34.2%; mp:
137–138 ℃. 1H NMR (600 MHz, DMSO-d6) δ: 9.82 (s, 1H, CHO), 7.74 (d, J = 15.2 Hz, 2H, imidazole-2-H,
imidazole-5-H), 7.13 (d, J = 8.3 Hz, 2H, Ph-2,6-2H), 6.75 (d, J = 8.3 Hz, 2H, Ph-3,5-2H), 5.34 (s, 2H, CH2),
3.54 (s, 3H, CH3) ppm.
4.2.17. Synthesis of 7-hydroxy-2-(1H-imidazol-4-yl)-4H-chromen-4-one (8)
To a mixture of acetophenone 7 (0.56 g, 3.0 mmol) and imidazole-4-carbaldehyde (0.29 g, 3.0 mmol) in
ethanol (25 mL) was added 10% sodium hydrate aqueous (5 mL), the mixture was stirred for 24 h at room
temperature[17]. The solution was acidified with 1N HCl and filtered, and the filter cake was recrystallized
from ethanol got 8 as white power (0.60 g). Yield: 87.4%; mp: 185–186 ℃; IR (KBr, cm-1) ν: 3443 (OH),
1
3063 (Ar–H), 1719 (C=O), 1617, 1571 (aromatic frame); H NMR (400 MHz, DMSO-d6) δ: 11.44 (s, 1H,
OH), 7.91 (s, 1H, imidazole-2-H), 7.79 (s, 1H, imidazole-5-H), 7.59 (d, J = 8.4 Hz, 1H, flavone-5-H), 6.85
20

(d, J = 1.8 Hz, 1H, flavone-3-H), 6.77–6.72 (m, 2H, flavone-6-H, flavone-8-H) ppm; 13C NMR (101 MHz,
DMSO-d6) δ: 181.2, 167.7, 166.9, 146.0, 138.0, 130.6, 126.0, 113.9, 113.3, 104.1, 99.0 ppm; MS (m/z):
229 [M+H]+; HRMS (TOF) calcd for C12H8N2O3: [M+H]+, 229.0613; found, 229.0617.
4.2.18. Synthesis of 7-hydroxy-2-(1-propyl-1H-imidazol-4-yl)-4H-chromen-4-one (9a)
Compound 9a was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and compound 2a (0.41 g, 3.0 mmol). The target compound 9a (0.52 g)
was obtained as white solid. Yield: 64.0%; mp: 201–202 ℃; IR (KBr, cm-1) ν: 3464 (OH), 3050 (Ar–H),
1
1723 (C=O), 1619, 1543, 1481 (aromatic frame); H NMR (400 MHz, DMSO-d6) δ: 7.96 (s, 1H,
imidazole-2-H), 7.75 (s, 1H, imidazole-5-H), 7.54 (d, J = 8.5 Hz, 1H, flavone-5-H), 6.81 (d, J = 1.9 Hz,
1H, flavone-3-H), 6.71 (d, J = 2.0 Hz, 1H, flavone-6-H), 6.69 (s, 1H, flavone-8-H), 4.10 (t, J = 7.1 Hz, 2H,
imidazole-CH2), 1.64 (dd, J = 14.4, 7.3 Hz, 2H, CH2), 0.78 (t, J = 7.4 Hz, 3H, CH3) ppm; 13C NMR (101
MHz, DMSO-d6) δ: 180.9, 167.7, 167.1, 146.8, 140.9, 135.0, 126.1, 125.1, 113.6, 99.2, 97.6, 46.2, 24.3,
11.2 ppm; MS (m/z): 271 [M+H]+; HRMS (TOF) calcd for C15H14N2O3: [M+H]+, 271.1083; found,
271.1082.
4.2.19. Synthesis of 7-hydroxy-2-(1-pentyl-1H-imidazol-4-yl)-4H-chromen-4-one (9b)
Compound 9b was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and compound 2b (0.50 g, 3.0 mmol). The target compound 9b (0.53 g)
was obtained as white solid. Yield: 60.4%; mp: 191192 ℃; IR (KBr, cm-1) ν: 3458 (OH), 3060 (Ar–H), ,
1
1717 (C=O), 1624, 1536, 1473 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ: 11.44 (s, 1H, OH),
7.93 (s, 1H, imidazole-2-H), 7.77 (s, 1H, imidazole-5-H), 7.60 (d, J = 8.5 Hz, 1H, flavone-5-H), 6.87 (s, 1H,
flavone-3-H), 6.77 (dd, J = 8.5, 1.6 Hz, 1H, flavone-6-H), 6.74 (s, 1H, flavone-8-H), 4.18 (t, J = 7.1 Hz, 2H,
imidazole-CH2), 1.68 (dt, J = 14.7, 7.3 Hz, 2H, CH2), 1.29 (dt, J = 14.0, 6.9 Hz, 2H, CH2), 1.21 (dd, J =
15.1, 6.9 Hz, 2H, CH2), 0.85 (t, J = 7.3 Hz, 3H, CH3) ppm; 13C NMR (151 MHz, DMSO-d6) δ: 180.9, 167.8,
167.0, 141.2, 135.8, 126.0, 125.0, 113.5-113.4, 99.1, 97.7, 44.6, 31.6, 31.0, 28.5, 26.2, 22.4, 14.3 ppm; MS
(m/z): 299 [M+H]+; HRMS (TOF) calcd for C17H18N2O3: [M+H]+, 299.1396; found, 299.1400.
4.2.20. Synthesis of 2-(1-heptyl-1H-imidazol-4-yl)-7-hydroxy-4H-chromen-4-one (9c)
Compound 9c was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and compound 2c (0.58 g, 3.0 mmol). The target compound 9b (0.56 g)
was obtained as white solid. Yield: 57.4%; mp: 107108 ℃; IR (KBr, cm-1) ν: 3443 (OH), 3030 (Ar–H),
1
1714 (C=O), 1638, 1545, 1499, 1458 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ:11.33 (s, 1H,
21

OH), 7.92 (s, 1H, imidazole-2-H), 7.77 (s, 1H, imidazole-5-H), 7.60 (d, J = 8.4 Hz, 1H, flavone-5-H), 6.85
(d, J = 1.8 Hz, 1H, flavone-3-H), 6.76 (d, J = 1.9 Hz, 1H, flavone-6-H), 6.74 (s, 1H, flavone-8-H), 4.17 (t, J
= 7.1 Hz, 2H, imidazole-CH2), 1.71–1.63 (m, 2H, CH2), 1.27–1.21 (m, 8H, CH2), 0.84 (t, J = 7.0 Hz, 3H,
CH3) ppm; 13C NMR (151 MHz, DMSO-d6) δ: 180.6–180.5, 168.0–167.8, 147.0, 141.6, 135.7, 134.2,
133.7, 133.0–132.8, 129.6, 97.0–96.8 ppm; MS (m/z): 327 [M+H]+. HRMS (TOF) calcd for C19H22N2O3:
[M+H]+, 327.1709; found, 327.1714.
4.2.21. Synthesis of 7-hydroxy-2-(1-propyl-1H-imidazol-5-yl)-4H-chromen-4-one (10a)
Compound 10a was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and compound 3a (0.41 g, 3.0 mmol). The target compound 10a (0.52 g)
was obtained as white solid. Yield: 62.0%; mp: 203–205 ℃; IR (KBr, cm-1) ν: 3432 (OH), 3020 (Ar–H),
1
1716 (C=O), 1615, 1549, 1483 (aromatic frame); H NMR (400 MHz, DMSO-d6) δ: 11.18 (s, 1H, OH),
7.90 (s, 1H, imidazole-2-H), 7.83 (d, J = 1.0 Hz, 1H, imidazole-4-H), 7.59 (dd, J = 8.4, 2.9 Hz, 1H,
flavone-5-H), 6.78 (d, J = 1.9 Hz, 1H, flavone-3-H), 6.73–6.70 (m, 1H, flavone-6-H), 6.65 (s, 1H,
flavone-8-H), 4.03 (dd, J = 9.5, 4.6 Hz, 2H, imidazole-CH2), 1.80 (dt, J = 14.3, 7.3 Hz, 2H, CH2),
0.88–0.83 (m, 3H, CH3) ppm; 13C NMR (101 MHz, DMSO-d6) δ: 181.2, 167.7, 166.6, 146.0, 139.4, 134.1,
126.1, 125.0, 114.0, 113.2, 106.3, 98.9, 48.5, 24.3, 11.3 ppm; MS (m/z): 271 [M+H]+; HRMS (TOF) calcd
for C15H14N2O3: [M+H]+, 271.1083; found, 271.1088.
4.2.22. Synthesis of 7-hydroxy-2-(1-pentyl-1H-imidazol-5-yl)-4H-chromen-4-one (10b)
Compound 10b was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and compound 3b (0.50 g, 3.0 mmol). The target compound 10b (0.53 g)
was obtained as white solid. Yield: 60.0%; mp: 191192 ℃; IR (KBr, cm-1) ν: 3457 (OH), 3057 (Ar–H),
1
1718 (C=O), 1625, 1546, 1481 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ: 11.24 (s, 1H, OH),
7.89 (s, 1H, imidazole-2-H), 7.82 (s, 1H, imidazole-4-H), 7.58 (d, J = 8.4 Hz, 1H, flavone-5-H), 6.78 (d, J
= 1.9 Hz, 1H, flavone-3-H), 6.70 (dd, J = 8.4, 1.9 Hz, 1H, flavone-6-H), 6.64 (s, 1H, flavone-8-H), 4.05 (t,
J = 7.2 Hz, 2H, imidazole-CH2), 1.77 (dt, J = 14.8, 7.4 Hz, 2H, CH2), 1.31 (dt, J = 14.3, 7.2 Hz, 2H, CH2),
1.23 (td, J = 8.0, 4.0 Hz, 2H, CH2), 0.87 (t, J = 7.3 Hz, 3H, CH3) ppm; 13C NMR (151 MHz, DMSO-d6) δ:
181.2, 167.7, 166.9, 146.2, 139.7, 129.5, 128.4, 126.0, 113.8, 113.4, 105.7, 99.0, 47.7, 30.7, 28.8, 23.5, 13.9
ppm; MS (m/z): 299 [M+H]+; HRMS (TOF) calcd for C17H18N2O3: [M+H]+, 299.1396; found, 299.1399.
4.2.23. Synthesis of 2-(1-heptyl-1H-imidazol-5-yl)-7-hydroxy-4H-chromen-4-one (10c)
22

Compound 10c was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and compound 3c (0.58 g, 3.0 mmol). The target compound 10c (0.56 g)
was obtained as white solid. Yield: 57.1%; mp: 111113 ℃; IR (KBr, cm-1) ν: 3443 (OH), 3030 (Ar–H),
1
1721 (C=O), 1632, 1540, 1497, 1458 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ: 10.93 (s, 1H,
OH), 7.91 (s, 1H, imidazole-2-H), 7.68 (s, 1H, imidazole-4-H), 7.53 (d, J = 8.1 Hz, 1H, flavone-5-H), 6.76
(d, J = 1.7 Hz, 1H, flavone-3-H), 6.54 (dd, J = 7.3, 2.5 Hz, 1H, flavone-6-H), 6.44 (s, 1H, flavone-8-H),
4.03 (t, J = 7.1 Hz, 2H, imidazole-CH2), 1.84 (dt, J = 12.4, 8.1 Hz, 2H, CH2), 1.30 (m, 8H, CH2), 0.87 (t, J
= 7.3 Hz, 3H, CH3) ppm; 13C NMR (151 MHz, DMSO-d6) δ: 180.2, 168.7, 166.1, 149.9, 139.7, 129.5,
128.2, 126.0, 115.0, 114.2, 113.4, 101.7, 47.7, 31.8, 30.3, 29.3, 27.4, 22.4, 11.3 ppm; MS (m/z): 327
[M+H]+. HRMS (TOF) calcd for C19H22N2O3: [M+H]+, 327.1709; found, 327.1714.
4.2.24. Synthesis of 2-(1-(3-chlorobenzyl)-1H-imidazol-4-yl)-7-hydroxy-4H-chromen-4-one (11a)
Compound 11a was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and compound 5a (0.66 g, 3.0 mmol). The target compound 11a (0.54 g)
was obtained as white solid. Yield: 51.1%; mp: 167168 ℃; IR (KBr, cm-1) ν: 3443 (OH), 3030 (Ar–H),
1722 (C=O), 1626, 1541, 1493, 1458 (aromatic frame); 1H NMR (600 MHz, DMSO-d6) δ: 11.28 (s, 1H,
OH), 8.13 (s, 1H, imidazole-2-H), 7.85 (s, 1H, imidazole-4-H), 7.57 (d, J = 8.4 Hz, 1H, flavone-5-H), 7.38
(dd, J = 18.0, 7.7 Hz, 2H, Ph-2,4-2H), 7.25 (s, 1H, Ph-5-H), 7.10 (d, J = 7.5 Hz, 1H, Ph-6-H), 6.83 (d, J =
1.9 Hz, 1H, flavone-3-H), 6.72 (dd, J = 8.5, 1.9 Hz, 1H, flavone-6-H), 6.69 (s, 1H, flavone-8-H), 5.55 (s,
2H, CH2) ppm; 13C NMR (151 MHz, DMSO-d6) δ: 180.9, 167.2, 166.4, 146.7, 141.1, 140.2, 133.0, 131.6,
128.3, 127.5, 126.1, 125.9, 125.3, 113.3, 98.3, 96.1, 30.6, 30.5 ppm; MS (m/z): 353 [M+H]+. HRMS (TOF)
calcd for C19H13ClN2O3: [M+H]+, 353.0693; found, 353.0694.
4.2.25. Synthesis of 2-(1-(2,4-dichlorobenzyl)-1H-imidazol-4-yl)-7-hydroxy-4H-chromen-4-one (11b)
Compound 11b was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and compound 5b (1.27 g, 5.0 mmol). The target compound 11b (0.69 g)
was obtained as white solid. Yield: 35.7%; mp: 181182 ℃; IR (KBr, cm-1) ν: 3421 (OH), 3015 (Ar–H),
1
1715 (C=O), 1629, 1543, 1488, 1462 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ: 8.02 (s, 1H,
OH), 7.85 (s, 1H, imidazole-2-H), 7.72 (s, 1H, imidazole-4-H), 7.54 (d, J = 6.9 Hz, 1H, flavone-5-H), 7.41
(d, J = 6.2 Hz, 1H, Ph-3-H), 6.77 (d, J = 54.8 Hz, 4H, Ph-5,6-2H, flavone-3,6-2H), 6.59 (s, 1H,
flavone-8-H), 5.58 (s, 2H, CH2) ppm; 13C NMR (151 MHz, DMSO-d6) δ: 180.8, 167.7, 166.9, 146.8,
141.8–141.7, 140.1, 134.0, 131.2, 128.2, 127.0, 126.1, 125.7, 125.4, 113.6, 99.2, 97.5, 49.0, 47.2 ppm; MS
23

(m/z): 387 [M+H]+. HRMS (TOF) calcd for C19H12Cl2N2O3: [M+H]+, 387.0303; found, 387.0308.
4.2.26. Synthesis of 2-(1-(4-chlorobenzyl)-1H-imidazol-4-yl)-7-hydroxy-4H-chromen-4-one (11c)
Compound 11c was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and compound 5c (1.10 g, 5.0 mmol). The target compound 11c (0.61 g)
was obtained as white solid. Yield: 34.5%; mp: 171172 ℃; IR (KBr, cm-1) ν: 3450 (OH), 3028 (Ar–H),
1
1714 (C=O), 1635, 1540, 1477, 1458 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ: 11.62 (s, 1H,
OH), 9.08 (s, 1H, imidazole-2-H), 8.18 (s, 1H, imidazole-4-H), 7.60 (d, J = 8.5 Hz, 1H, flavone-5-H), 7.47
(d, J = 8.5 Hz, 2H, Ph-2,6-2H), 7.32 (d, J = 8.5 Hz, 2H, Ph-3,5-2H), 6.91 (d, J = 1.9 Hz, 1H, flavone-3-H),
6.77 (dd, J = 8.5, 1.9 Hz, 1H, flavone-6-H), 6.72 (s, 1H, flavone-8-H), 5.70 (s, 2H, CH2) ppm; 13C NMR
(151 MHz, DMSO-d6) δ: 180.6, 168.1, 167.7, 148.6, 139.0, 134.9, 133.4, 129.5, 126.4, 126.2, 113.9, 113.1,
99.4, 95.1, 48.5 ppm; MS (m/z): 353 [M+H]+. HRMS (TOF) calcd for C19H13ClN2O3: [M+H]+, 353.0693;
found, 353.0701.
4.2.27. Synthesis of 2-(1-(4-fluorobenzyl)-1H-imidazol-4-yl)-7-hydroxy-4H-chromen-4-one (11d)
Compound 11d was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and compound 5d (1.02 g, 5.0 mmol). The target compound 11d (0.65 g)
was obtained as white solid. Yield: 38.5%; mp: 171172 ℃; IR (KBr, cm-1) ν: 3443 (OH), 3030 (Ar–H),
1
1720 (C=O), 1630, 1542, 1497, 1455 (aromatic frame); H NMR (400 MHz, DMSO-d6) δ: 11.38 (s, 1H,
OH), 8.17 (s, 1H, imidazole-2-H), 7.96 (s, 1H, imidazole-5-H), 7.52 (d, J = 8.5 Hz, 1H, flavone-5-H),
7.41–7.36 (m, 2H, Ph-2,6-2H), 7.20–7.14 (m, 2H, Ph-3,5-2H), 6.77 (s, 1H, flavone-3-H), 6.67 (dd, J = 8.4,
1.9 Hz, 1H, flavone-6-H), 6.59 (s, 1H, flavone-8-H), 5.29 (s, 2H, CH2) ppm; 13C NMR (101 MHz,
DMSO-d6) δ: 181.1, 167.8, 167.0, 163.5, 161.1, 146.7, 139.0, 133.6, 133.0, 130.5, 126.2, 124.8, 116.2,
116.0, 113.6, 104.1, 99.0, 49.9 ppm; MS (m/z): 337 [M+H]+; HRMS (TOF) calcd for C19H13FN2O3:
[M+H]+, 337.0988; found, 337.0984.
4.2.28. Synthesis of 7-hydroxy-2-(1-(4-methoxybenzyl)-1H-imidazol-4-yl)-4H-chromen-4-one (11e)
Compound 11e was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and compound 5e (1.09 g, 5.0 mmol). The target compound 11e (0.41 g)
was obtained as white solid. Yield: 23.5%; mp: 184185 ℃; IR (KBr, cm-1) ν: 3440 (OH), 3025 (Ar–H),
1
2944 (CH3), 1715 (C=O), 1628, 1540, 1497, 1458 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ:
8.05 (s, 1H, imidazole-2-H), 7.77 (s, 1H, imidazole-5-H), 7.50 (d, J = 8.5 Hz, 1H, flavone-5-H), 7.13 (d, J
24

= 8.7 Hz, 2H, Ph-2,6-2H), 6.92 (d, J = 8.7 Hz, 2H, Ph-3,5-2H), 6.70 (s, 1H, flavone-3-H), 6.63 (d, J = 6.4
Hz, 2H, flavone-6-H, flavone-8-H), 5.40 (s, 2H, CH2), 3.71 (s, 3H, CH3) ppm; 13C NMR (151 MHz,
DMSO-d6) δ: 180.8, 168.2, 167.1, 164.5, 161.2, 146.1, 141.0, 132.3, 132.0, 131.0, 126.1, 125.9, 116.1,
115.5, 113.3, 104.4, 95.6, 55.4, 32.6 ppm; MS (m/z): 337 [M+H]+; HRMS (TOF) calcd for C20H16N2O4:
[M+H]+, 337.0988; found, 337.0984.
4.2.29. Synthesis of 2-(1-(3-chlorobenzyl)-1H-imidazol-5-yl)-7-hydroxy-4H-chromen-4-one (12a)
Compound 12a was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and compound 6a (1.10 g, 5.0 mmol). The target compound 12a (0.58 g)
was obtained as white solid. Yield: 33.1%; mp: 163164 ℃; IR (KBr, cm-1) ν: 3422 (OH), 3025 (Ar–H),
1
1720 (C=O), 1629, 1540, 1497, 1455 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ: 11.28 (s, 1H,
OH), 8.13 (s, 1H, imidazole-2-H), 7.85 (s, 1H, imidazole-4-H), 7.57 (d, J = 8.4 Hz, 1H, flavone-5-H), 7.38
(dd, J = 18.0, 7.7 Hz, 2H, Ph-H), 7.25 (s, 1H, Ph-2-H), 7.10 (d, J = 7.5 Hz, 1H, Ph-H), 6.83 (d, J = 1.9 Hz,
1H, flavone-3-H), 6.72 (dd, J = 8.5, 1.9 Hz, 1H, flavone-6-H), 6.69 (s, 1H, flavone-8-H), 5.55 (s, 2H, CH2)
ppm; 13C NMR (151 MHz, DMSO-d6) δ: 180.9, 167.7, 166.3, 145.6, 142.3, 140.5, 134.5, 131.3, 128.8,
126.9, 126.0, 125.8, 125.1, 114.4, 98.5, 96.1, 30.5, 30.1 ppm; MS (m/z): 353 [M+H]+; HRMS (TOF) calcd
for C19H13ClN2O3: [M+H]+, 353.0693; found, 353.0695.
4.2.30. Synthesis of 2-(1-(2,4-dichlorobenzyl)-1H-imidazol-5-yl)-7-hydroxy-4H-chromen-4-one (12b)
Compound 12b was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and compound 6b (1.27 g, 5.0 mmol). The target compound 12b (0.63 g)
was obtained as white solid. Yield: 32.7%; mp: 180181 ℃; IR (KBr, cm-1) ν: 3422 (OH), 3030 (Ar–H),
1
1721 (C=O), 1629, 1530, 1498, 1444 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ: 11.44 (s, 1H,
OH), 7.96–7.92 (m, 2H, imidazole-2-H, imidazole-4-H), 7.71 (d, J = 2.1 Hz, 1H, flavone-5-H), 7.58 (d, J =
8.4 Hz, 1H, Ph-3-H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H, Ph-5-H), 7.17 (d, J = 8.4 Hz, 1H, Ph-6-H), 6.82 (d, J =
1.9 Hz, 1H, flavone-3-H), 6.74 (dd, J = 8.5, 1.9 Hz, 1H, flavone-6-H), 6.65 (s, 1H, flavone-8-H), 5.44 (s,
2H, CH2) ppm. 13C NMR (151 MHz, DMSO-d6) δ: 181.2, 168.1, 166.8, 146.2–146.1, 139.3, 113.2,
106.2–106.1, 99.1–99.0, 46.9, 28.4, 14.3 ppm; MS (m/z): 387 [M+H]+; HRMS (TOF) calcd for
C19H12Cl2N2O3: [M+H]+, 387.0303; found, 387.0307.
4.2.31. Synthesis of 2-(1-(4-chlorobenzyl)-1H-imidazol-5-yl)-7-hydroxy-4H-chromen-4-one (12c)
Compound 12c was prepared according to the procedure described for compound 8 starting from
25

acetophenone 7 (0.93 g, 5.0 mmol) and compound 6c (1.10 g, 5.0 mmol). The target compound 12c (0.55 g)
was obtained as white solid. Yield: 31.3%; mp: 174175 ℃; IR (KBr, cm-1) ν: 3423 (OH), 3011 (Ar–H),
1
1723 (C=O), 1634, 1553, 1507, 1455 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ: 7.93 (d, J = 7.8
Hz, 2H, imidazole-2-H, imidazole-4-H), 7.53 (d, J = 8.5 Hz, 1H, flavone-5-H), 7.45 (d, J = 8.4 Hz, 2H,
Ph-2,6-2H), 7.36 (d, J = 8.4 Hz, 2H, Ph-3,5-2H), 6.69 (d, J = 1.6 Hz, 1H, flavone-3-H), 6.65 (dd, J = 8.5,
1.7 Hz, 1H, flavone-6-H), 6.59 (s, 1H, flavone-8-H), 5.33 (s, 2H, CH2) ppm. 13C NMR (151 MHz,
DMSO-d6) δ: 180.8, 168.7, 168.0, 146.5, 139.3, 136.8, 134.6, 133.0, 129.9, 129.2, 125.9, 124.6, 114.1,
112.8, 105.3, 98.8, 49.5 ppm; MS (m/z): 353 [M+H]+; HRMS (TOF) calcd for C19H12ClN2O3: [M+H]+,
353.0693; found, 353.0700.
4.2.32. Synthesis of 2-(1-(4-fluorobenzyl)-1H-imidazol-5-yl)-7-hydroxy-4H-chromen-4-one (12d)
Compound 12d was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and compound 6d (1.02 g, 5.0 mmol). The target compound 12d (0.59 g)
was obtained as white solid. Yield: 35.5%; mp: 170171 ℃; IR (KBr, cm-1) ν: 3440 (OH), 3030 (Ar–H),
1
1726 (C=O), 1629, 1556, 1499, 1458 (aromatic frame); H NMR (400 MHz, DMSO-d6) δ: 11.72 (s, 1H,
OH), 9.43 (s, 1H, imidazole-2-H), 8.29 (s, 1H, imidazole-4-H), 7.60 (d, J = 8.5 Hz, 1H, flavone-5-H),
7.46–7.40 (m, 2H, Ph-2,6-2H), 7.29–7.22 (m, 2H, Ph-3,5-2H), 6.93 (d, J = 1.9 Hz, 1H, flavone-3-H),
6.81–6.75 (m, 2H, flavone-6-H, flavone-8-H), 5.74 (s, 2H, CH2) ppm. 13C NMR (101 MHz, DMSO-d6) δ:
180.6, 168.2, 167.9, 163.6, 161.2, 149.2, 138.0, 131.5, 130.2, 126.6, 124.6, 116.5, 116.3, 114.1, 112.9, 99.5,
94.4, 49.0 ppm; MS (m/z): 337 [M+H]+; HRMS (TOF) calcd for C19H12FN2O3: [M+H]+, 337.0988; found,
337.0990.
4.2.33. Synthesis of 7-hydroxy-2-(1-(4-methoxybenzyl)-1H-imidazol-5-yl)-4H-chromen-4-one (12e)
Compound 12e was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and compound 6e (1.08 g, 5.0 mmol). The target compound 12e (0.40 g)
was obtained as white solid. Yield: 23.1%; mp: 172173 ℃; IR (KBr, cm-1) ν: 3426 (OH), 3035 (Ar–H),
1
2934 (CH3), 1726 (C=O), 1626, 1548, 1479, 1458 (aromatic frame); H NMR (600 MHz, DMSO-d6) δ:
11.47 (s, 1H, OH), 7.94 (d, J = 15.2 Hz, 2H, imidazole-2-H, imidazole-5-H), 7.57 (d, J = 8.4 Hz, 1H,
flavone-5-H), 7.33 (d, J = 8.7 Hz, 2H, Ph-2,6-2H), 6.95 (d, J = 8.7 Hz, 2H, Ph-3,5-2H), 6.87 (d, J = 1.9 Hz,
1H, flavone-3-H), 6.75 (dd, J = 8.4, 1.9 Hz, 1H, flavone-6-H), 6.64 (s, 1H, flavone-8-H), 5.25 (s, 2H, CH2),
3.74 (s, 3H, CH3) ppm; 13C NMR (101 MHz, DMSO-d6) δ: 181.2, 167.7, 166.9, 159.4, 146.2, 139.2, 134.2,
129.6, 126.0, 124.8, 114.6, 113.8, 113.4, 105.9, 98.9, 55.6, 49.9 ppm; MS (m/z): 349 [M+H]+; HRMS (TOF)
26

calcd for C20H16N2O4: [M+H]+, 349.1188; found, 349.1200.
4.2.34. Synthesis of 7-hydroxy-2-(1H-imidazol-2-yl)-4H-chromen-4-one (15)
Compound 15 was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and 1H-imidazole-2-carbaldehyde (0.29 g, 3.0 mmol). The target
compound 15 (0.50 g) was obtained as white solid. Yield: 73.4%; mp: 170171 ℃; IR (KBr, cm-1) ν: 3400
1
(OH), 3019 (Ar–H), 2955 (CH3), 1721 (C=O), 1628, 1550, 1483, 1452 (aromatic frame); H NMR (400
MHz, DMSO-d6) δ: 12.39 (s, 1H, OH), 7.61 (d, J = 8.4 Hz, 1H, flavone-5-H), 7.33 (m, 2H,
imidazole-4,5-2H), 6.79 (s, 1H, flavone-3-H), 6.71 (d, J = 8.4 Hz, 1H, flavone-6-H), 6.60 (s, 1H,
flavone-8-H) ppm; 13C NMR (101 MHz, DMSO-d6) δ: 181.4, 168.9, 167.1, 146.9, 140.2, 130.1, 126.4,
113.7, 113.3, 100.2, 99.1 ppm; MS (m/z): 229 [M+H]+; HRMS (TOF) calcd for C12H8N2O3: [M+H]+,
229.0613; found, 229.0616.
4.2.35. Synthesis of 7-hydroxy-2-(1-propyl-1H-imidazol-2-yl)-4H-chromen-4-one (16a)
Compound 16a was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and 13a (0.41 g, 3.0 mmol). The target compound 16a (0.59 g) was
obtained as white solid. Yield: 72.2%; mp: 167168 ℃; IR (KBr, cm-1) ν: 3422 (OH), 3032 (Ar–H), 2925
(CH3), 1722 (C=O), 1628, 1555, 1480, 1451 (aromatic frame); 1H NMR (400 MHz, DMSO-d6) δ: 7.61 (d, J
= 8.5 Hz, 1H, flavone-5-H), 7.43 (d, J = 0.9 Hz, 1H, imidazole-4-H), 7.22 (d, J = 0.7 Hz, 1H,
imidazole-5-H), 6.78–6.63 (m, 3H, flavone-3-H, flavone-6-H, flavone-8-H), 4.15 (t, J = 7.1 Hz, 2H,
imidazole-CH2), 1.72 (dd, J = 14.4, 7.3 Hz, 2H, CH2), 0.85 (t, J = 7.4 Hz, 3H, CH3) ppm; 13C NMR (101
MHz, DMSO-d6) δ: 181.8, 168.9, 168.0, 147.8, 139.8, 131.1, 126.3, 123.7, 113.8, 112.7, 99.0, 96.7, 47.5,
24.7, 11.3 ppm; MS (m/z): 271 [M+H]+; HRMS (TOF) calcd for C15H14N2O3: [M+H]+, 271.1083; found,
271.1078.
4.2.36. Synthesis of 7-hydroxy-2-(1-pentyl-1H-imidazol-2-yl)-4H-chromen-4-one (16b)
Compound 16b was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and 13b (0.50 g, 3.0 mmol). The target compound 16b (0.66 g) was
obtained as white solid. Yield: 73.2%; mp: 163163 ℃; IR (KBr, cm-1) ν: 3431 (OH), 3025 (Ar–H), 2921
(CH3), 1725 (C=O), 1627, 1600, 1466, 1452 (aromatic frame); 1H NMR (400 MHz, DMSO-d6) δ: 7.27 (d, J
= 1.1 Hz, 1H, flavone-5-H), 7.12 (d, J = 8.9 Hz, 1H, imidazole-4-H), 7.07 (d, J = 1.1 Hz, 1H,
imidazole-5-H), 6.18 (s, 1H, flavone-3-H), 5.94–5.90 (m, 1H, flavone-6-H), 5.73 (d, J = 1.8 Hz, 1H,
27

flavone-8-H), 4.07 (t, J = 7.1 Hz, 2H, imidazole-CH2), 1.68 (dt, J = 14.5, 7.2 Hz, 2H, CH2), 1.30 (dd, J =
15.1, 8.0 Hz, 2H, CH2), 1.24–1.19 (m, 2H, CH2), 0.85 (t, J = 7.1 Hz, 3H, CH3) ppm; 13C NMR (101 MHz,
DMSO-d6) δ: 182.3, 176.1–175.9, 151.3, 140.7, 129.9, 125.0, 122.1, 120.6, 103.2, 98.9, 91.0, 45.9, 31.0,
28.5, 22.0, 14.2 ppm; MS (m/z): 299 [M+H]+; HRMS (TOF) calcd for C17H18N2O3: [M+H]+, 299.1396;
found, 299.1401.
4.2.37. Synthesis of 2-(1-heptyl-1H-imidazol-2-yl)-7-hydroxy-4H-chromen-4-one (16c)
Compound 16c was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and 13c (0.58 g, 3.0 mmol). The target compound 16c (0.67 g) was
obtained as white solid. Yield: 68.2%; mp: 169170 ℃; IR (KBr, cm-1) ν: 3409 (OH), 3030 (Ar–H), 2935
(CH3), 1721 (C=O), 1628, 1549, 1465, 1455 (aromatic frame); 1H NMR (400 MHz, DMSO-d6) δ: 7.55 (d, J
= 8.5 Hz, 1H, flavone-5-H), 7.36 (d, J = 0.8 Hz, 1H, imidazole-4-H), 7.15 (d, J = 0.6 Hz, 1H,
imidazole-5-H), 6.71 (d, J = 1.8 Hz, 1H, flavone-3-H), 6.66 (dd, J = 8.5, 1.9 Hz, 1H, flavone-6-H), 6.58 (s,
1H, flavone-8-H), 4.11 (t, J = 7.1 Hz, 2H, imidazole-CH2), 1.62 (dd, J = 14.1, 7.1 Hz, 2H, CH2), 1.22–1.10
(m, 8H, CH2), 0.76 (t, J = 6.9 Hz, 3H, CH3) ppm; 13C NMR (101 MHz, DMSO-d6) δ: 181.8, 168.8, 167.8,
147.7, 139.8, 131.2, 126.3, 123.7, 113.7, 113.1–112.9, 99.0, 96.8, 46.0, 31.6, 31.4, 28.5, 26.3, 22.4, 14.4
ppm; MS (m/z): 327 [M+H]+. HRMS (TOF) calcd for C19H22N2O3: [M+H]+, 327.1709; found, 327.1709.
4.2.38. Synthesis of 2-(1-(3-chlorobenzyl)-1H-imidazol-2-yl)-7-hydroxy-4H-chromen-4-one (17a)
Compound 17a was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.56 g, 3.0 mmol) and 14a (0.66 g, 3.0 mmol). The target compound 17a (0.71 g) was
obtained as white solid. Yield: 66.6%; mp: 169170 ℃; IR (KBr, cm-1) ν: 3405 (OH), 3028 (Ar–H), 2931
(CH3), 1724 (C=O), 1625, 1549, 1475, 1451 (aromatic frame); 1H NMR (400 MHz, DMSO-d6) δ: 7.39 (d, J
= 1.1 Hz, 1H, flavone-5-H), 7.38–7.33 (m, 2H, Ph-2,4-2H), 7.16 (d, J = 1.0 Hz, 1H, imidazole-5-H), 7.09 –
7.02 (m, 2H, Ph-5,6-2H), 6.15 (s, 1H, imidazole-4-H), 5.88 (dd, J = 8.9, 1.8 Hz, 1H, flavone-3-H), 5.67 (d,
J = 1.8 Hz, 1H, flavone-6-H), 5.43 (s, 1H, flavone-8-H), 5.29 (s, 2H, CH2) ppm; 13C NMR (101 MHz,
DMSO-d6) δ: 182.8, 170.5, 169.6, 154.4, 151.9, 141.1, 133.7, 131.0, 130.2, 129.0, 126.2, 125.0, 120.7,
105.1, 103.2, 98.9, 97.7, 90.6, 49.2 ppm; MS (m/z): 353 [M+H]+. HRMS (TOF) calcd for C19H13ClN2O3:
[M+H]+, 353.0693; found, 353.0688.
4.2.39. Synthesis of 2-(1-(2,4-dichlorobenzyl)-1H-imidazol-2-yl)-7-hydroxy-4H-chromen-4-one (17b)
28

Compound 17b was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and 14b (1.27 g, 5.0 mmol). The target compound 17b (1.42 g) was
obtained as white solid. Yield: 73.2%; mp: 165166 ℃; IR (KBr, cm-1) ν: 3420 (OH), 3031 (Ar–H), 2931
(CH3), 1728 (C=O), 1629, 1555, 1471, 1455 (aromatic frame); 1H NMR (400 MHz, DMSO-d6) δ: 7.44 (d, J
= 1.8 Hz, 1H, flavone-5-H), 7.39 (d, J = 6.1 Hz, 1H, Ph-3-H), 7.15 (d, J = 1.2 Hz, 1H, imidazole-5-H), 6.77
(d, J = 54.8 Hz, 2H, Ph-5,6-2H), 6.13 (s, 1H, imidazole-4-H), 5.85 (dd, J = 8.6, 1.4 Hz, 1H, flavone-3-H),
5.62 (d, J = 1.4 Hz, 1H, flavone-6-H), 5.41 (s, 1H, flavone-8-H), 5.23 (s, 2H, CH2) ppm; 13C NMR (101
MHz, DMSO-d6) δ: 181.5, 170.4, 168.8, 155.3, 152.0, 142.2, 133.8, 131.5, 130.3, 128.1, 126.3, 125.2,
120.8, 105.2, 103.1, 98.9, 97.5, 90.5, 49.1 ppm; MS (m/z): 387 [M+H]+. HRMS (TOF) calcd for
C19H12Cl2N2O3: [M+H]+, 387.0303; found, 387.0308.
4.2.40. Synthesis of 2-(1-(4-chlorobenzyl)-1H-imidazol-2-yl)-7-hydroxy-4H-chromen-4-one (17c)
Compound 17c was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and 14c (1.10 g, 5.0 mmol). The target compound 17c (1.29 g) was
obtained as white solid. Yield: 73.1%; mp: 169170 ℃; IR (KBr, cm-1) ν: 3423 (OH), 3044 (Ar–H), 2944
(CH3), 1720 (C=O), 1630, 1571, 1473, 1452 (aromatic frame); 1H NMR (400 MHz, DMSO-d6) δ: 7.49 (d, J
= 1.4 Hz, 1H, flavone-5-H), 7.20 (d, J = 2.2 Hz, 2H, Ph-2,6-2H), 7.18 (s, 2H, Ph-3,5-2H), 7.12 (d, J = 1.3
Hz, 1H, imidazole-5-H), 7.07 (d, J = 8.4 Hz, 1H, imidazole-4-H), 6.20 (s, 1H, flavone-3-H), 5.86 (dd, J =
8.4, 2.2 Hz, 1H, flavone-6-H), 5.65 (d, J = 1.9 Hz, 1H, flavone-8-H), 5.29 (s, 2H, CH2) ppm; 13C NMR
(101 MHz, DMSO-d6) δ: 181.7, 176.4, 172.4, 152.9, 142.6, 135.3, 132.2, 128.8, 124.1, 121.4, 114.6, 104.3,
97.6, 96.5, 91.6, 49.5 ppm; MS (m/z): 353 [M+H]+. HRMS (TOF) calcd for C19H13ClN2O3: [M+H]+,
353.0693; found, 353.0701.
4.2.41. Synthesis of 2-(1-(4-fluorobenzyl)-1H-imidazol-2-yl)-7-hydroxy-4H-chromen-4-one (17d)
Compound 17d was prepared according to the procedure described for compound 8 starting from
acetophenone 7 (0.93 g, 5.0 mmol) and 14d (1.02 g, 5.0 mmol). The target compound 17d (1.16 g) was
obtained as white solid. Yield: 69.1%; mp: 164165 ℃; IR (KBr, cm-1) ν: 3325 (OH), 3031 (Ar–H), 2936
(CH3), 1724 (C=O), 1625, 1539, 1471, 1455 (aromatic frame); 1H NMR (400 MHz, DMSO-d6) δ: 7.35 (d, J
= 1.1 Hz, 1H, flavone-5-H), 7.19 (d, J = 2.8 Hz, 2H, Ph-2,6-2H), 7.17 (s, 2H, Ph-3,5-2H), 7.13 (d, J = 1.0
Hz, 1H, imidazole-5-H), 7.08 (d, J = 8.9 Hz, 1H, imidazole-4-H), 6.17 (s, 1H, flavone-3-H), 5.88 (dd, J =
29