Chromanones: selective and reversible monoamine oxidase B inhibitors with nanomolar potency

Article abstract of DOI:10.1039/c5md00124b

A new series of C7-substituted chromanones has been designed, synthesized and evaluated for hMAO-B inhibitory activity in vitro. Most of the studied compounds were remarkably potent and selective MAO-B inhibitors and showed weak or no inhibition of MAO-A. Especially, compound 4f (IC₅₀ = 8.62 nM) was the best MAO-B inhibitor and exhibited the highest selectivity for MAO-B (SI > 11 627.9-fold). In addition, the structure-activity relationships for MAO-B inhibition indicated that substitutions at the C7 of the chromanone moiety, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking studies have been performed to explore the interaction modes of C7-substituted chromanones with MAO-B. Furthermore, the representative compounds 4f and 5d showed low neurotoxicity in SH-SY5Y cells in vitro. So the C7-substituted chromanones could be used to develop promising drug candidates for the therapy of neurodegenerative diseases.

Full text of DOI:10.1039/c5md00124b

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Page 1 of 33
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Chromanones: selective and reversible Monoamine Oxidase B inhibitors with
nanomolar potency
JinꢀShuai Lan, SaiꢀSai Xie, Ming Huang, YaꢀJian Hu, LingꢀYi Kong * and
XiaoꢀBing Wang *
State Key Laboratory of Natural Medicines, Department of Natural Medicinal
Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009,
People’s Republic of China
*Corresponding Author
Tel/Fax: +86ꢀ25ꢀ8327ꢀ1405.
Eꢀmail: cpu_lykong@126.com; xbwang@cpu.edu.cn.
1

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Abstract
A new series of C7ꢀsubstituted chromanones has been designed, synthesized and
evaluated for hMAOꢀB inhibitory activity in vitro. Most of the studied compounds
were remarkably potent and selective MAOꢀB inhibitors, and showed weak or no
inhibition of MAOꢀA. Especially, compound 4f (IC50 = 8.62 nM) was the best
MAOꢀB inhibitor and exhibited the highest selectivity for MAOꢀB (SI >
11627.9ꢀfold). In addition, the structureꢀactivity relationships for MAOꢀB inhibition
indicated that substitutions at the C7 of the chromanone moiety, particularly with the
halogen substituted benzyloxy, were more favorable for MAOꢀB inhibition.
Molecular docking studies have been done to explore the interaction modes of
C7ꢀsubstituted chromanones with MAOꢀB. Furthermore, the representative
compounds 4f and 5d showed low neurotoxicity in SHꢀSY5Y cells in vitro. So the
C7ꢀsubstituted chromanones could be used to develop promising drug candidates for
the therapy of neurodegenerative diseases.
Keywords
Monoamine Oxidase; chromanones; neurodegenerative diseases; Molecular docking.
Abbreviations
MAO, Monoamine oxidase; CNS, central nervous system; 5ꢀHT, 5ꢀhydroxyꢀ
tryptamine; NE, norepinephrine; DA, dopamine; FAD, flavin adenine dinucleotide; SI,
selectivity index; BBB, bloodꢀbrain barrier; MTT, methyl thiazolyl tetrazolium.
2

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Introduction
Monoamine oxidases (MAOs) are flavoenzymes that can regulate and metabolize
amine neurotransmitters, such as serotonin, dopamine (DA) and epinephrine in the
peripheral tissues and central nervous system (CNS).1 In animals MAOs exist as two
isoforms, namely MAOꢀA and MAOꢀB, which were recognized on account of
differences in immunological properties, inhibitor specificity, amino acid sequences,
substrate preference and tissue distribution.2ꢀ6 Catecholaminergic neurons
predominantly contain MAOꢀA, while MAOꢀB is present in astrocytes and
serotonergic neurons.7 MAOꢀA is selectively inhibited by clorgyline and
preferentially metabolizes epinephrine, 5ꢀhydroxytryptamine (5ꢀHT) and
norepinephrine (NE). MAOꢀB specifically deaminates βꢀphenethylamine and
benzylamine and is selectively inhibited by selegiline and rasagiline. Both enzymes
can metabolize tryptamine, DA and tyramine.8ꢀ9
Recent Xꢀray crystal structures of the two MAO isoforms supply information about
the pharmacophoric requirements and the selective interactions, which are useful to
design potent and selective inhibitors.10ꢀ12 The active sites of hMAOs are thought to be
the main structural differences due to the different volume and shape of the
inhibitors/substrate binding pockets. hMAOꢀA has a single hydrophobic cavity, which
is nearly 550 Å3 volume. In contrast, the active site of hMAOꢀB consists of two
distinct cavities: one is the soꢀcalled “entrance cavity” of 290 Å3 volume, which is
located towards the outside of the protein and another larger cavity called “substrate
cavity” is connected to the flavine adenine dinucleotide cofactor (FAD), which is
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about 420 Å3 volume. There are narrow pockets in these cavities of both isoenzymes,
and the Tyr326 and Ile199 residues in hMAOꢀB act as a bottleneck and thus form a
gate, which separates the region as the two cavities.13
MAOs are important targets for discovering and developing drugs. Selective
inhibitors of MAOꢀA have been applied to treat depression and anxiety;14 while
selective MAOꢀB inhibitors have been applied alone or in combination to treat
Parkinson’s and Alzheimer’s diseases.15 Based on these aspects, novel MAO
inhibitors are needed.
To search for novel MAO inhibitors, the chromone scaffold [(4H)ꢀ1ꢀbenzopyranꢀ
4ꢀone] has been developed as a principally promising scaffold.16ꢀ21 The chromones
from both natural and synthetic origin are important bioactive molecules. Recently,
chromones and differently substituted chromones have been synthesized and
evaluated for their potential as MAO inhibitors, and display selective inhibition of
MAOꢀB from the micromolar to the nanomolar range (AꢀF, Fig. 1). Especially
chromone derivatives with the benzyloxy substituents at C7 are particularly potent
and selective MAOꢀB inhibitors.19 Because the structures of chromanone and
chromone are similar, we explore the probability that C7ꢀsubstituted chromanones
may have the potent MAO inhibitory properties. For this purpose, alkyloxy
substituents were selected for substitution at C7 of the chromanone ring, such as
benzyloxy, phenylethoxy and phenylpropoxy. To further examine the structure–
activity relationships (SARs) against MAO, different substitutions (F, Cl, Br, CN and
CH3) were introduced to the benzyloxy ring and C2 of the chromanone nucleus, and
4

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the effects on MAO inhibition were studied.
Results and discussion
Chemistry
The C7ꢀsubstituted chromanone derivatives (4 and 5) and C6ꢀsubstituted
benzofuranꢀ3(2H)ꢀone derivatives 7 were efficiently synthesized along with the
pathway shown in Scheme 1. The commercially available resorcinol was reacted with
3ꢀchloropropionic acid in the presence of trifluoromethanesulphonic acid to give the
chloride. Intramolecular cyclization of the chloride afforded the intermediate 2.22 On
the other hand, the intermediate 3 was obtained by reacting resorcinol with 3,
3ꢀdimethylacrylic acid in a ZnCl2/POCl3 mixture.23 Finally the intermediates 2, 3 and
6 reacted with the appropriate benzyl bromides in the presence of K2CO3 to give the
target molecules in good yields (75ꢀ93%).
Prediction of BBB penetration of compounds 4, 5 and 7
With the aim of developing the central nervous system (CNS) drugs, the ability of
compounds to cross the bloodꢀbrain barrier (BBB) is very important. So in the drug
discovery process, BBB permeability properties should be determined as early as
possible.24 To cross BBB, molecules should meet the limiting terms of Lipinski’s
rules25: molecular weight (MW) less than 500, the number of hydrogen bond acceptor
atoms (HBA) less than 10, the number of hydrogen bond donor atoms (HBD) less
than 5, the calculated logarithm of the octanolꢀwater partition coefficient (Clog P) less
than 5, and the small polar surface area less than 90 Å2. The log BB is calculated as
the following equation: logBB = ꢀ0.0148 × PSA + 0.152 ClogP + 0.139.25 Calculated
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log BB for potential applications in brains and defined by the restrictive terms of
Lipinski’s rules, as shown in Table 1, compounds 4, 5 and 7 satisfied possible brain
penetration and drugꢀlike standards.
Inhibition of hMAO activity
For target compounds 4, 5 and 7, the MAO inhibitory activities were explored by
measuring the effects on the production of hydrogen peroxide from pꢀtyramine,
according to the reported assay,26 with iproniazid and pargyline as references. The
corresponding IC50 values and MAOꢀB selectivity ratios were shown in Table 2.
Based on the screening data, it could be seen that most of the tested compounds were
selective inhibitors toward MAOꢀB and the IC50 values in the nanomolar range.
MAOꢀA inhibition was very weak and no apparent structureꢀactivity relationship
existed. Among the synthesized compounds, 4f was the most potent and selective
inhibitor against MAOꢀB (IC50 = 8.62 nM, SI > 11627.9), being more active than
iproniazid and pargyline.
Initially, to introduce groups with different sizes at C7 of chromanones, compounds
4a-c were synthesized. As shown in Table 2, the 7ꢀbenzyloxychromanone derivative
4a, exhibited an IC50 value of 57.37 nM for MAOꢀB. Extending the length of the C7
side chain of 4a with methylene and ethylene units to yield the phenylethoxy (4b,
IC50= 251.14 nM for MAOꢀB) and phenylpropoxy (4c, IC50= 21.45 ꢁM for MAOꢀB)
substituted homologues, resulted in an equal or a drastic loss of MAOꢀB inhibition
potency. From these results, it might be concluded that the length of the linker of 4a
was more suitable for volume of the substrate/inhibitors binding pockets than that of
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phenylethoxy and phenylpropoxy. Then we planned to introduce substituents with
varying electronic properties to benzyloxy substitution for studying possible effects on
MAOꢀB inhibition potency. Compared to 4a, 4d-k bearing electronꢀwithdrawing
groups exhibited an increase in MAOꢀB inhibition. However, 4l-m with an
electronꢀdonating group showed a slight decrease in MAOꢀB inhibition. For example,
4f (IC50 = 8.62 nM for MAOꢀB) possessing electronꢀwithdrawing substituent F was
about 7ꢀfold more active than 4a, while 4m (IC50 = 91.29 nM for MAOꢀB) substituted
with CH3, decrease the MAOꢀB inhibition potency of 4a by 2ꢀfold. Furthermore,
among 4d-k, compounds with para substitution of the benzyloxy phenyl ring were
more portent for MAOꢀB inhibition than ortho and meta substitution.
Moreover, to introduce substituents with different sizes to the 2ꢀposition of
chromanone ring for studying possible effects on MAO inhibition, compounds 5a-k
were synthesized. Compared to compounds 4a-m, an apparent decrease of MAOꢀB
inhibition was observed for 5a-k. For example, 4a (IC50 = 57.37 nM) possessing
small substituent H was almost twoꢀfold than 5a (IC50 = 97.47 nM) with the CH3
substituent. Like 4a-m, a similar trend against MAO inhibition was noted for 5a-k.
When the chromanone ring was substituted by the benzofuranone ring, compounds
7a-c were synthesized. Compound 7b (IC50 = 2.13 ꢁM) was the best MAOꢀB
inhibitory activity among them. And the size of substitution at C6 of benzofuranone
also affected the MAOꢀB inhibitory activity, but was not pivotal for MAOꢀA
inhibition. Compared to compounds 4 and 5, compounds 7a-c remarkably decreased
in MAOꢀB inhibitory activities. These results implied that the chromanone ring is
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important for MAOꢀB inhibitory activity.
Reversibility of MAO-B inhibition
As we know, MAOꢀB inhibitors could be classified as irreversible or reversible
because of the different interactions between the inhibitors and the enzyme. When
affecting the enzyme to give covalent complexes, the inhibitors are irreversible.
However, irreversible MAOꢀB inhibitors may display pharmacological side effects
and safety issues. For example the side effects of selegiline, which is induced by its
amphetamine metabolites, are the major drawbacks.27 Compared to irreversible
MAOꢀB inhibitors, the enzyme activity of reversible MAOꢀB inhibitors can be
regained when the inhibitors are metabolized. Moreover, when the substrate
concentration increases the enzyme activity will relieve. For these reasons,
discovering new reversible MAOꢀB inhibitors may be valuable.
To examine whether C7ꢀsubstituted chromanone derivatives were reversible or
irreversible MAOꢀB inhibitors, the time dependencies of inhibition were evaluated.28
Compound 4f was selected as a representative inhibitor since it displayed the most
potent MAOꢀB inhibitory activity. For a reversible inhibitor, the MAOꢀB activity
would almost be same, when the enzyme is preincubated with a reversible inhibitor
over different time periods. In contrast, when the enzyme is preincubated with an
irreversible inhibitor over different time periods, the MAOꢀB activity would show a
timeꢀdependent reduction. Compound 4f was preincubated with MAOꢀB over
different time periods (0ꢀ60 min) at a concentration of twofold IC50. As shown in Fig.
2, we could observe that MAOꢀB activities were 42.4% at 0 min, 44.5% at 15 min,
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45.5% at 30 min and 49.6% at 60 min, and these results demonstrated that 4f was not
a timeꢀdependent inhibitor of MAOꢀB at a concentration of IC50 and over the time
period (0ꢀ60 min). So these experiments clearly indicated that the chromones were
reversible MAOꢀB inhibitors.
Kinetic study of MAO-B inhibition
Compound 4f was also used to further investigate the mode of MAOꢀB inhibition.
The type of MAOꢀB inhibition was determined by MichaelisꢀMenten kinetic
experiments.29 The catalytic rates were measured at five different pꢀtyramine
concentrations (50ꢀ500 ꢁM), and each plot was constructed at four different
concentrations of 4f (0, 4.3, 8.6 and 17.2 nM). The overlaid reciprocal
LineweaverꢀBurk plots (Fig. 3) showed that the plots for different concentrations of 4f
were linear and intersected at the yꢀaxis. This pattern indicated that 4f was a
competitive MAOꢀB inhibitor, and these results further proved that the chromones
were reversible MAOꢀB inhibitors.
Molecular modeling studies
In order to explore the interaction modes of C7ꢀsubstituted chromanones with
MAOꢀB, we have carried out a structureꢀbased molecular modeling study using
hMAOs cocrystals deposited into the PDB. Crystallographic structure of MAOꢀB
(PDB code 2V61)30 was used to dock the derivatives under study. And molecular
docking study was performed using software package MOE 2008.10.31 According to
the inhibition results, compound 4f was selected as a typical ligand. The 3D and 2D
pictures of binding were illustrated in Fig. 4. As shown in Fig. 4A and 4B, compound
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4f located in the wellꢀknown binding pocket of MAOꢀB,32 with the chromanone
ring interacting with Tyr 398 and Tyr 60 at bottom of the substrate cavity. A
hydrogen bond formed between the carbonyl oxygen of the ligands and Tyr435ꢀOH.
Finally, the Fꢀsubstituted benzyl group occupied the entrance cavity, which was a
hydrophobic subpocket existing only in the MAOꢀB isoform and constituted by
Leu 171, Ile 199, Tyr 326, Ile 316, Phe 99, Pro 104 and Phe 168.
Cells toxicity
Based on the screening results above, compounds 4f and 5d as the most potent and
highly selective inhibitors against MAOꢀB were selected to further examine the
potential toxicity effect on the SHꢀSY5Y cells.33 After incubating the cells with
compound 4f and 5d for 48 h, the cell viability was determined by the
3ꢀ(4,5ꢀdimethylthiazolꢀ2ꢀyl)ꢀ2,5ꢀdiphenyltetrazolium (MTT) assay. As shown in the
Fig. 5, the result revealed that compounds 4f and 5d at 3ꢀ50 ꢁМ did not have
neurotoxicity. This suggested that compounds 4f and 5d might be used to develop
promising drug candidates for the therapy of neurodegenerative diseases.
Conclusions
In conclusion, a new series of C7ꢀsubstituted chromanones were designed,
synthesized and evaluated for hMAO inhibitory activity in vitro. It was observed that
most of the studied compounds were remarkably competitive and reversible MAOꢀB
inhibitors with nanomolar potency, and revealed weak or no inhibition of MAOꢀA. In
particular, compound 4f was the best MAOꢀB inhibitor with 892ꢀfold more active
than iproniazid. The MAO inhibition data indicated that substitutions at the C7
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position of the chromanone moiety, particularly with the benzyloxy substituent, were
more favorable for MAOꢀB inhibition. Moreover, halogen substituents on the
benzyloxy ring further increased MAOꢀB inhibition. Molecular docking studies of the
compound 4f suggested that the high MAOꢀB selectivity might be ascribed to the
hydrogen bond interaction and the larger set of residues interacting with MAOꢀB. Due
to low neurotoxicity in SHꢀSY5Y cells in vitro, these compounds could be used to
develop promising drug candidates for the therapy of neurodegenerative diseases.
Experimental
General
All common reagents and solvents were obtained from commercial suppliers and
used without further purification. Reaction progress was monitored using analytical
thin layer chromatography (TLC) on precoated silica gel GF254 plates (Qingdao
Haiyang Chemical Plant, Qingdao, China) plates and the spots were detected under
UV light (254 nm). Column chromatography was performed on silica gel (90ꢀ150 ꢁm;
Qingdao Marine Chemical Inc.) The purity of all compounds used for biological
evaluation was confirmed to be higher than 95% through analytical HPLC performed
with Agilent 1200 HPLC System. Melting point was measured on an XTꢀ4
1
micromelting point instrument and uncorrected. H NMR and 13C NMR spectra were
measured on a Bruker ACFꢀ500 spectrometer at 25 °C and referenced to TMS.
Chemical shifts are reported in ppm (δ) using the residual solvent line as internal
standard. Mass spectra were obtained on a MS Agilent 1100 Series LC/MSD Trap
mass spectrometer (ESIꢀMS) and a Mariner ESIꢀTOF spectrometer (HRESIꢀMS),
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respectively.
General procedure for the preparation of C7-substituted 4-Chromanone
derivatives (4 and 5).
7ꢀHydroxyꢀchromanꢀ4ꢀone (1.85 mmol) was suspended in acetonitrile (15 mL)
containing K2CO3 (3.70 mmol). The reaction was treated with an appropriately
substituted arylalkyl bromide (2.04 mmol) and heated under reflux for 8 h. The
reaction progress was monitored using silica gel TLC with hexanes/EtOAc as mobile
phase. Upon completion, the acetonitrile was evaporated in vacuo and the mixture
was then poured into water, which was extracted with 3 × 200 mL of EtOAc, washed
with brine, dried over anhydrous Na2SO4 and purified by chromatography (hexanes
/EtOAc) on silica gel.
7-(benzyloxy) chroman-4-one (4a).
1
Yield 87%, yellow solid; H NMR (500 MHz, DMSO) δ 7.69 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.44 (d, J = 7.2 Hz, 2H, ArꢀH), 7.40 (dd, J = 10.1, 4.7 Hz, 2H, ArꢀH), 7.37–
7.31 (m, 1H, ArꢀH), 6.70 (dd, J = 8.8, 2.4 Hz, 1H, ArꢀH), 6.62 (d, J = 2.4 Hz, 1H,
ArꢀH), 5.18 (s, 2H, ArꢀCH2), 4.50 (t, J = 6.4 Hz, 2H, OCH2), 2.70 (t, J = 6.4 Hz, 2H,
COCH2); 13C NMR (125 MHz, DMSO) δ 190.44, 164.93, 163.84, 136.80, 128.99,
128.99, 128.68, 128.53, 128.23, 128.23, 115.54, 110.69, 102.34, 70.22, 67.60, 37.38.
HRMS (ESI) m/z 531.1774 [2M+Na]+ (calcd for 531.1778, C32H28NaO6).
7-phenethoxychroman-4-one (4b).
Yield 81%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.66 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.35–7.26 (m, 4H, ArꢀH), 7.25–7.19 (m, 1H, ArꢀH), 6.61 (dd, J = 8.8, 2.4 Hz,
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1H, ArꢀH), 6.54 (d, J = 2.3 Hz, 1H, ArꢀH), 4.49 (t, J = 6.4 Hz, 2H, BnꢀCH2), 4.26 (t, J
= 6.8 Hz, 2H, OCH2), 3.03 (t, J = 6.8 Hz, 2H, ArꢀCH2), 2.69 (t, J = 6.4 Hz, 2H,
COCH2); 13C NMR (125 MHz, DMSO) δ 190.42, 165.07, 163.90, 138.54, 129.41,
129.41, 128.80, 128.80, 128.67, 126.82, 115.40, 110.41, 101.93, 69.13, 67.58, 37.38,
35.12. HRMS (ESI) m/z 559.2093 [2M+Na]+ (calcd for 559.2091, C34H32NaO6).
7-(3-phenylpropoxy) chroman-4-one (4c).
Yield 75%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.68 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.28 (t, J = 7.5 Hz, 2H, ArꢀH), 7.22 (d, J = 7.1 Hz, 2H, ArꢀH), 7.18 (t, J = 7.2
Hz, 1H, ArꢀH), 6.63 (dd, J = 8.8, 2.3 Hz, 1H, ArꢀH), 6.51 (d, J = 2.3 Hz, 1H, ArꢀH),
4.50 (t, J = 6.4 Hz, 2H, BnꢀCH2, alkyl chainsꢀH), 4.02 (dd, J = 6.7, 2.3 Hz, 2H,
OCH2), 2.76–2.64 (m, 4H, COCH2), 2.02 (dd, J = 14.8, 6.8 Hz, 2H, BnꢀCH2); 13C
NMR (125 MHz, DMSO) δ 190.42, 165.28, 163.90, 141.70, 128.83, 128.83, 128.81,
128.81, 128.68, 126.35, 115.36, 110.38, 101.83, 67.84, 67.58, 37.39, 31.83, 30.56.
HRMS (ESI) m/z 587.2399 [2M+Na]+ (calcd for 587.2404, C36H36NaO6).
7-((2-fluorobenzyl) oxy) chroman-4-one (4d).
1
Yield 88%, yellow solid; H NMR (500 MHz, DMSO) δ 7.72 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.58 (m, 1H, ArꢀH), 7.49–7.43 (m, 1H, ArꢀH), 7.32–7.24 (m, 2H, ArꢀH), 6.73
(dd, J = 8.8, 2.4 Hz, 1H, ArꢀH), 6.69 (d, J = 2.3 Hz, 1H, ArꢀH), 5.23 (s, 2H, ArꢀCH2),
4.54 (t, J = 6.4 Hz, 2H, OCH2), 2.74 (t, J = 6.4 Hz, 2H, COCH2);13C NMR (125 MHz,
DMSO) δ 190.45, 164.72, 163.86 (d, 1JCF = 245.1 Hz), 131.35, 131.16, 128.73, 124.98,
123.57, 116.03, 115.87, 115.69, 110.51, 102.25, 67.63, 64.42, 37.39. HRMS (ESI)
m/z 567.1588 [2M+Na]+ (calcd for 567.1590, C32H26NaO6F2).
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7-((3-fluorobenzyl) oxy) chroman-4-one (4e).
Yield 90%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.70 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.56 (m, 1H, ArꢀH), 7.50–7.40 (m, 1H, ArꢀH), 7.26 (dd, J = 15.8, 8.0 Hz, 2H,
ArꢀH), 6.71 (dd, J = 8.8, 2.4 Hz, 1H, ArꢀH), 6.67 (d, J = 2.3 Hz, 1H, ArꢀH), 5.21 (s,
2H, ArꢀCH2), 4.52 (t, J = 6.4 Hz, 2H, OCH2), 2.72 (t, J = 6.4 Hz, 2H, COCH2);13C
1
NMR (125 MHz, DMSO) δ 190.45, 164.72, 163.86 (d, JCF = 245.0 Hz), 131.35,
131.20, 128.73, 125.07, 123.63, 116.03, 115.87, 115.69, 110.51, 102.25, 67.63, 64.59,
37.39. HRMS (ESI) m/z 567.1589 [2M+Na]+ (calcd for 567.1590, C32H26NaO6F2).
7-((4-fluorobenzyl) oxy) chroman-4-one (4f).
Yield 91%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.69 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.50 (dd, J = 8.5, 5.6 Hz, 2H, ArꢀH), 7.23 (t, J = 8.8 Hz, 2H, ArꢀH), 6.70 (dd, J
= 8.8, 2.3 Hz, 1H, ArꢀH), 6.63 (d, J = 2.3 Hz, 1H, ArꢀH), 5.16 (s, 2H, ArꢀCH2), 4.51 (t,
J = 6.4 Hz, 2H, OCH2), 2.71 (t, J = 6.4 Hz, 2H, COCH2); 13C NMR (125 MHz,
DMSO) δ 189.86, 164.25, 163.27 (d, 1JCF = 242.6 Hz), 162.79, 132.47, 132.45, 130.01,
129.95, 128.12, 115.33, 115.16, 110.09, 101.78, 68.93, 67.04, 36.82. HRMS (ESI)
m/z 567.1586 [2M+Na]+ (calcd for 567.1590, C32H26NaO6F2).
7-((3-chlorobenzyl) oxy) chroman-4-one (4g).
Yield 85%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.70 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.52 (s, 1H, ArꢀH), 7.42 (t, J = 4.0 Hz, 3H, ArꢀH), 6.72 (dd, J = 8.8, 2.4 Hz,
1H, ArꢀH), 6.63 (d, J = 2.3 Hz, 1H, ArꢀH), 5.20 (s, 2H, ArꢀCH2), 4.51 (t, J = 6.4 Hz,
2H, OCH2), 2.71 (t, J = 6.4 Hz, 2H, COCH2); 13C NMR (125 MHz, DMSO) δ 190.43,
164.64, 163.82, 139.39, 133.67, 130.92, 128.73, 128.45, 127.86, 126.72, 115.68,
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110.62, 102.40, 69.23, 67.62, 37.38. HRMS (ESI) m/z 311.0443 [M+Na]+ (calcd for
311.0445, C16H13ClNaO3).
7-((4-chlorobenzyl) oxy) chroman-4-one (4h).
Yield 89%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.69 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.47 (s, 4H, ArꢀH), 6.70 (dd, J = 8.8, 2.4 Hz, 1H, ArꢀH), 6.62 (d, J = 2.4 Hz,
1H, ArꢀH), 5.18 (s, 2H, ArꢀCH2), 4.50 (t, J = 6.4 Hz, 2H, OCH2), 2.70 (t, J = 6.4 Hz,
2H, COCH2); 13C NMR (125 MHz, DMSO) δ 190.44, 164.71, 163.82, 135.86, 133.15,
130.05, 130.05, 129.01, 129.01, 128.71, 115.62, 110.66, 102.38, 69.33, 67.61, 37.37.
HRMS (ESI) m/z 311.0446 [M+Na]+ (calcd for 311.0445, C16H13ClNaO3).
7-((3-bromobenzyl) oxy) chroman-4-one (4i).
Yield 92%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.70 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.66 (s, 1H, ArꢀH), 7.54 (d, J = 7.9 Hz, 1H, ArꢀH), 7.45 (d, J = 7.6 Hz, 1H,
ArꢀH), 7.37 (t, J = 7.8 Hz, 1H, ArꢀH), 6.71 (dd, J = 8.8, 2.4 Hz, 1H, ArꢀH), 6.63 (d, J
= 2.3 Hz, 1H, ArꢀH), 5.19 (s, 2H, ArꢀCH2), 4.51 (t, J = 6.4 Hz, 2H, OCH2), 2.71 (t, J
= 6.4 Hz, 2H, COCH2); 13C NMR (125 MHz, DMSO) δ 190.45, 164.64, 163.82,
139.64, 131.36, 131.22, 130.75, 128.74, 127.12, 122.22, 115.68, 110.64, 102.39,
69.18, 67.62, 37.38. HRMS (ESI) m/z 354.9939 [M+Na]+ (calcd for 354.9440,
C16H13BrNaO3).
7-((4-bromobenzyl) oxy) chroman-4-one (4j).
Yield 91%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.69 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.60 (d, J = 8.4 Hz, 2H, ArꢀH), 7.41 (d, J = 8.4 Hz, 2H, ArꢀH), 6.70 (dd, J =
8.8, 2.4 Hz, 1H, ArꢀH), 6.61 (d, J = 2.4 Hz, 1H, ArꢀH), 5.17 (s, 2H, ArꢀCH2), 4.50 (t,
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J = 6.4 Hz, 2H, OCH2), 2.70 (t, J = 6.4 Hz, 2H, COCH2); 13C NMR (125 MHz,
DMSO) δ 190.44, 164.69, 163.82, 136.29, 131.94, 131.94, 130.34, 130.34, 128.71,
121.67, 115.63, 110.67, 102.39, 69.37, 67.61, 37.37. HRMS (ESI) m/z 354.9938
[M+Na]+ (calcd for 354.9440, C16H13BrNaO3).
4-(((4-oxochroman-7-yl) oxy) methyl) benzonitrile (4k).
Yield 79%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.88 (d, J = 8.2 Hz, 2H,
ArꢀH), 7.70 (d, J = 8.8 Hz, 1H, ArꢀH), 7.64 (d, J = 8.2 Hz, 2H, ArꢀH), 6.73 (dd, J =
8.8, 2.4 Hz, 1H, ArꢀH), 6.63 (d, J = 2.3 Hz, 1H, ArꢀH), 5.30 (s, 2H, ArꢀCH2), 4.51 (t,
J = 6.4 Hz, 2H, OCH2), 2.71 (t, J = 6.4 Hz, 2H, COCH2); 13C NMR (125 MHz,
DMSO) δ 190.44, 164.50, 163.81, 142.59, 132.96, 132.96, 128.78, 128.61, 128.61,
119.14, 115.77, 111.21, 110.59, 102.46, 69.19, 67.63, 37.37. HRMS (ESI) m/z
302.0787 [M+Na]+ (calcd for 302.0788, C17H13NNaO3).
7-((3-methylbenzyl) oxy) chroman-4-one (4l).
Yield 77%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.69 (dd, J = 8.8, 4.8 Hz,
1H, ArꢀH), 7.26 (dt, J = 17.5, 7.4 Hz, 3H, ArꢀH), 7.15 (d, J = 7.3 Hz, 1H, ArꢀH), 6.70
(dd, J = 8.8, 2.3 Hz, 1H, ArꢀH), 6.61 (d, J = 2.3 Hz, 1H, ArꢀH), 5.13 (s, 2H, ArꢀCH2),
4.50 (t, J = 6.4 Hz, 2H, OCH2), 2.70 (t, J = 6.4 Hz, 2H, COCH2), 2.32 (s, 3H,
ArꢀCH3); 13C NMR (125 MHz, DMSO) δ 190.43, 164.98, 163.83, 138.19, 136.70,
129.17, 128.89, 128.78, 128.67, 125.33, 115.51, 110.68, 102.30, 70.27, 67.60, 37.38,
21.44. HRMS (ESI) m/z 559.2089 [2M+Na]+ (calcd for 559.2091, C34H32NaO6).
7-((4-methylbenzyl) oxy) chroman-4-one (4m).
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Yield 80%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.68 (d, J = 8.8 Hz, 1H,
ArꢀH), 7.32 (d, J = 7.9 Hz, 2H, ArꢀH), 7.20 (d, J = 7.9 Hz, 2H, ArꢀH), 6.68 (dd, J =
8.8, 2.3 Hz, 1H, ArꢀH), 6.60 (d, J = 2.3 Hz, 1H, ArꢀH), 5.12 (s, 2H, ArꢀCH2), 4.49 (t,
13
J = 6.4 Hz, 2H, OCH2), 2.70 (t, J = 6.4 Hz, 2H, COCH2), 2.30 (s, 3H, ArꢀCH3); C
NMR (125 MHz, DMSO) δ 190.42, 164.97, 163.83, 137.84, 133.76, 129.54, 129.54,
128.64, 128.33, 128.33, 115.48, 110.72, 102.32, 70.14, 67.59, 37.38, 21.24. HRMS
(ESI) m/z 559.2094 [2M+Na]+ (calcd for 559.2091, C34H32NaO6).
7-(benzyloxy)-2, 2-dimethylchroman-4-one (5a).
Yield 86%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.66 (d, J = 8.7 Hz, 1H,
ArꢀH), 7.44 (d, J = 7.3 Hz, 2H, ArꢀH), 7.40 (t, J = 7.5 Hz, 2H, ArꢀH), 7.35 (dd, J =
8.3, 6.0 Hz, 1H, ArꢀH), 6.67 (dd, J = 8.8, 2.3 Hz, 1H, ArꢀH), 6.58 (d, J = 2.3 Hz, 1H,
ArꢀH), 5.17 (s, 2H, ArꢀCH2), 2.71 (s, 2H, COCH2), 1.39 (s, 6H, CH(CH3)2).13C NMR
(125 MHz, DMSO) δ 195.54, 170.06, 166.64, 141.61, 133.74, 133.28, 133.07, 133.02,
132.91, 132.80, 119.08, 114.91, 107.40, 84.91, 74.96, 64.97, 31.38, 31.38. HRMS
(ESI) m/z 587.2401 [2M+Na]+ (calcd for 587.2404, C36H36NaO6).
7-((2-fluorobenzyl) oxy)-2, 2-dimethylchroman-4-one (5b).
Yield 89%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.67 (d, J = 8.7 Hz, 1H,
ArꢀH), 7.56 (m, 1H, ArꢀH), 7.45 (m, 1H, ArꢀH), 7.26 (dd, J = 15.6, 8.0 Hz, 2H, ArꢀH),
6.67 (dd, J = 8.7, 2.4 Hz, 1H, ArꢀH), 6.62 (d, J = 2.3 Hz, 1H, ArꢀH), 5.20 (s, 2H,
ArꢀCH2), 2.72 (s, 2H, COCH2), 1.39 (s, 6H, CH(CH3)2). 13C NMR (125 MHz, DMSO)
δ 190.82, 165.09, 161.90 (d, 1JCF = 103.6 Hz), 131.42, 131.16, 128.15, 125.09, 123.67,
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116.03, 115.87, 114.48, 109.97, 102.57, 80.20, 64.58, 60.03, 26.62, 26.62. HRMS
(ESI) m/z 623.2211 [2M+Na]+ (calcd for 623.2216, C36H34F2NaO6).
7-((3-fluorobenzyl) oxy)-2, 2-dimethylchroman-4-one (5c).
1
Yield 87%, yellow solid; H NMR (500 MHz, DMSO) δ 7.67 (d, J = 8.7 Hz, 1H,
ArꢀH), 7.55 (m, 1H, ArꢀH), 7.44 (m, 1H, ArꢀH), 7.25 (dd, J = 15.7, 7.9 Hz, 2H, ArꢀH),
6.67 (dd, J = 8.7, 2.4 Hz, 1H, ArꢀH), 6.62 (d, J = 2.3 Hz, 1H, ArꢀH), 5.19 (s, 2H,
ArꢀCH2), 2.71 (s, 2H, COCH2), 1.39 (s, 6H, CH(CH3)2). 13C NMR (125 MHz, DMSO)
δ 195.59, 169.85, 166.66 (d, 1JCF = 152.4 Hz), 132.96, 132.86, 129.83, 129.80, 128.40,
128.31, 120.49, 119.22, 114.73, 107.30, 84.97, 69.36, 65.05, 31.38, 31.38. HRMS
(ESI) m/z 623.2213 [2M+Na]+ (calcd for 623.2216, C36H34F2NaO6).
7-((4-fluorobenzyl) oxy)-2, 2-dimethylchroman-4-one (5d).
1
Yield 87%, yellow solid; H NMR (500 MHz, DMSO) δ 7.66 (d, J = 8.7 Hz, 1H,
ArꢀH), 7.50 (dd, J = 8.5, 5.6 Hz, 2H, ArꢀH), 7.23 (t, J = 8.8 Hz, 2H, ArꢀH), 6.66 (dd, J
= 8.8, 2.3 Hz, 1H, ArꢀH), 6.58 (d, J = 2.3 Hz, 1H, ArꢀH), 5.15 (s, 2H, ArꢀCH2), 2.71
(s, 2H, COCH2), 1.39 (s, 6H, CH(CH3)2). 13C NMR (125 MHz, DMSO) δ 190.78,
1
165.18, 163.48 (d, JCF = 57.9 Hz), 161.88, 133.09, 130.61, 130.54, 128.10, 115.89,
115.72, 114.29, 110.12, 102.65, 80.16, 69.47, 48.26, 26.62, 26.62. HRMS (ESI) m/z
623.2210 [2M+Na]+ (calcd for 623.2216, C36H34F2NaO6).
7-((3-chlorobenzyl) oxy)-2, 2-dimethylchroman-4-one (5e).
Yield 83%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.67 (d, J = 8.7 Hz, 1H,
ArꢀH), 7.51 (s, 1H, ArꢀH), 7.44–7.40 (m, 3H, ArꢀH), 6.68 (dd, J = 8.8, 2.4 Hz, 1H,
ArꢀH), 6.58 (d, J = 2.3 Hz, 1H, ArꢀH), 5.19 (s, 2H, ArꢀCH2), 2.71 (s, 2H, COCH2),
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13
1.39 (s, 6H, CH(CH3)2). C NMR (125 MHz, DMSO) δ 190.77, 165.00, 161.84,
139.42, 133.65, 130.91, 128.43, 128.13, 127.88, 126.73, 114.46, 110.10, 102.69,
80.19, 69.21, 48.24, 26.62, 26.62. HRMS (ESI) m/z 655.1623 [2M+Na]+ (calcd for
655.1625, C36H34Cl2NaO6).
7-((4-chlorobenzyl) oxy)-2, 2-dimethylchroman-4-one (5f).
Yield 85%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.66 (d, J = 8.7 Hz, 1H,
ArꢀH), 7.46 (s, 4H, ArꢀH), 6.66 (dd, J = 8.7, 2.3 Hz, 1H, ArꢀH), 6.57 (d, J = 2.3 Hz,
1H, ArꢀH), 5.17 (s, 2H, ArꢀCH2), 2.70 (s, 2H, COCH2), 1.38 (s, 6H, CH(CH3)2). 13C
NMR (125 MHz, DMSO) δ 190.79, 165.08, 161.86, 135.91, 133.14, 130.07, 130.07,
129.00, 129.00, 128.12, 114.40, 110.13, 102.67, 80.18, 69.31, 48.24, 26.62, 26.62.
HRMS (ESI) m/z 655.1621 [2M+Na]+ (calcd for 655.1625, C36H34Cl2NaO6).
7-((3-bromobenzyl) oxy)-2, 2-dimethylchroman-4-one (5g).
Yield 84%, yellow solid; 1H NMR (500 MHz, DMSO) δ 7.69–7.63 (m, 2H, ArꢀH),
7.55 (d, J = 8.0 Hz, 1H, ArꢀH), 7.45 (d, J = 7.7 Hz, 1H, ArꢀH), 7.37 (t, J = 7.8 Hz, 1H,
ArꢀH), 6.67 (dd, J = 8.8, 2.4 Hz, 1H, ArꢀH), 6.58 (d, J = 2.3 Hz, 1H, ArꢀH), 5.18 (s,
2H, ArꢀCH2), 2.71 (s, 2H, COCH2), 1.38 (s, 6H, CH(CH3)2). 13C NMR (125 MHz,
DMSO) δ 190.81, 165.01, 161.86, 139.68, 131.36, 131.22, 130.78, 128.15, 127.15,
122.20, 114.46, 110.12, 102.69, 80.20, 69.16, 48.24, 26.62, 26.62. HRMS (ESI) m/z
361.0435 [M+H]+ (calcd for 361.0436, C18H18BrO3).
7-((4-bromobenzyl) oxy)-2, 2-dimethylchroman-4-one (5h).
Yield 85%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.66 (d, J = 8.7 Hz, 1H,
ArꢀH), 7.60 (d, J = 8.4 Hz, 2H, ArꢀH), 7.40 (d, J = 8.4 Hz, 2H, ArꢀH), 6.66 (dd, J =
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8.8, 2.4 Hz, 1H, ArꢀH), 6.56 (d, J = 2.3 Hz, 1H, ArꢀH), 5.15 (s, 2H, ArꢀCH2), 2.70 (s,
2H, COCH2), 1.38 (s, 6H, CH(CH3)2). 13C NMR (125 MHz, DMSO) δ 190.77, 165.06,
161.86, 136.35, 131.93, 131.93, 130.35, 130.35, 128.12, 121.66, 114.42, 110.13,
102.70, 80.18, 69.35, 48.25, 26.62, 26.62. HRMS (ESI) m/z 361.0430 [M+H]+ (calcd
for 361.0436, C18H18BrO3).
4-(((2, 2-dimethyl-4-oxochroman-7-yl) oxy) methyl) benzonitrile (5i).
1
Yield 84%, yellow oil; H NMR (500 MHz, DMSO) δ 7.88 (d, J = 8.2 Hz, 2H,
ArꢀH), 7.79 (d, J = 8.2 Hz, 1H, ArꢀH), 7.67 (d, J = 8.7 Hz, 1H, ArꢀH), 7.64 (d, J = 8.2
Hz, 2H, ArꢀH), 7.51 (d, J = 8.1 Hz, 1H, ArꢀH), 6.69 (dd, J = 8.8, 2.4 Hz, 1H, ArꢀH),
6.59 (d, J = 2.3 Hz, 1H, ArꢀH), 5.29 (s, 2H, ArꢀCH2), 2.71 (s, 2H, COCH2), 1.38 (s,
6H, CH(CH3)2). 13C NMR (125 MHz, DMSO) δ 195.57, 169.63, 166.62, 147.40,
137.80, 137.33, 133.34, 132.90, 132.02, 123.91, 115.96, 114.84, 107.52, 84.99, 73.93,
67.47, 53.00, 31.37, 31.37. HRMS (ESI) m/z 330.1099 [M+Na]+ (calcd for 330.1101,
C19H17NNaO3).
2, 2-dimethyl-7-((3-methylbenzyl) oxy) chroman-4-one (5j).
Yield 79%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.66 (d, J = 8.7 Hz, 1H,
ArꢀH), 7.26 (m, 3H, ArꢀH), 7.16 (d, J = 7.4 Hz, 1H, ArꢀH), 6.66 (dd, J = 8.8, 2.3 Hz,
1H, ArꢀH), 6.57 (d, J = 2.3 Hz, 1H, ArꢀH), 5.12 (s, 2H, ArꢀCH2), 2.70 (s, 2H,
COCH2), 2.32 (s, 3H, ArꢀCH3), 1.39 (s, 6H, CH(CH3)2). 13C NMR (125 MHz, DMSO)
δ 190.78, 165.34, 161.88, 138.17, 136.74, 129.16, 128.88, 128.81, 128.09, 125.35,
114.30, 110.14, 102.60, 80.15, 70.25, 48.26, 26.63, 26.63, 21.38. HRMS (ESI) m/z
615.2715 [2M+Na]+ (calcd for 615.2717, C38H40NaO6).
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2, 2-dimethyl-7-((4-methylbenzyl) oxy) chroman-4-one (5k).
Yield 77%, colorless solid; 1H NMR (500 MHz, DMSO) δ 7.65 (d, J = 8.7 Hz, 1H,
ArꢀH), 7.32 (d, J = 7.9 Hz, 2H, ArꢀH), 7.20 (d, J = 7.8 Hz, 2H, ArꢀH), 6.64 (dd, J =
8.8, 2.4 Hz, 1H, ArꢀH), 6.56 (d, J = 2.3 Hz, 1H, ArꢀH), 5.11 (s, 2H, ArꢀCH2), 2.70 (s,
2H, COCH2), 2.31 (s, 3H, ArꢀCH3), 1.38 (s, 6H, CH(CH3)2). 13C NMR (125 MHz,
DMSO) δ 190.20, 164.77, 161.29, 137.25, 133.23, 128.96, 128.96, 127.78, 127.78,
127.49, 113.69, 109.59, 102.05, 79.56, 69.54, 47.69, 26.06, 26.06, 20.67. HRMS (ESI)
m/z 615.2713 [2M+Na]+ (calcd for 615.2717, C38H40NaO6).
General procedure for the preparation of C6-substituted benzofuranone
derivatives (7).
6ꢀhydroxybenzofuranꢀ3(2H)ꢀone (1.85 mmol) was suspended in acetonitrile (15
mL) containing K2CO3 (3.70 mmol). The reaction was treated with an appropriately
substituted arylalkyl bromide (2.04 mmol) and heated under reflux for 8 h. The
reaction progress was monitored using silica gel TLC with hexanes/EtOAc as mobile
phase. Upon completion, the acetonitrile was evaporated in vacuo and the mixture
was then poured into water, which was extracted with 3 × 200 mL of EtOAc, washed
with brine, dried over anhydrous Na2SO4 and purified by chromatography (hexanes
/EtOAc) on silica gel.
6-(benzyloxy) benzofuran-3(2H)-one (7a).
1
Yield 86%, yellow solid; H NMR (500 MHz, DMSO) δ 7.54 (d, J = 8.6 Hz, 1H,
ArꢀH), 7.47 (d, J = 7.2 Hz, 2H, ArꢀH), 7.41 (dd, J = 10.1, 4.7 Hz, 2H, ArꢀH), 7.38–
7.33 (m, 1H, ArꢀH), 6.90 (d, J = 2.0 Hz, 1H, ArꢀH), 6.78 (dd, J = 8.6, 2.1 Hz, 1H,
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ArꢀH), 5.23 (s, 2H, COCH2), 4.76 (s, 2H, ArꢀCH2). 13C NMR (125 MHz, DMSO) δ
197.58, 176.14, 167.15, 136.55, 129.02, 129.02, 128.63, 128.36, 128.36, 125.16,
114.68, 112.41, 98.22, 75.98, 70.60. HRMS (ESI) m/z 263.0680 [M+Na]+ (calcd for
263.0679, C15H12NaO3).
6-phenethoxybenzofuran-3(2H)-one (7b).
1
Yield 87%, yellow solid; H NMR (500 MHz, DMSO) δ 7.51 (d, J = 8.6 Hz, 1H,
ArꢀH), 7.39–7.27 (m, 4H, ArꢀH), 7.23 (m, 1H, ArꢀH), 6.83 (d, J = 2.0 Hz, 1H, ArꢀH),
6.72–6.64 (m, 1H, ArꢀH), 4.75 (s, 2H, COCH2), 4.32 (t, J = 6.8 Hz, 2H, OCH2), 3.07
(t, J = 6.8 Hz, 2H, ArꢀCH2). 13C NMR (125 MHz, DMSO) δ 197.55, 176.24, 167.32,
138.44, 129.44, 129.44, 128.82, 128.82, 126.86, 125.10, 114.51, 112.21, 97.80, 75.93,
69.52, 35.07. HRMS (ESI) m/z 531.1775 [2M+Na]+ (calcd for 531.1778,
C32H28NaO6).
6-(3-phenylpropoxy) benzofuran-3(2H)-one (7c).
1
Yield 77%, yellow solid; H NMR (500 MHz, DMSO) δ 7.54 (d, J = 8.6 Hz, 1H
,
ArꢀH), 7.31 (t, J = 7.5 Hz, 2H
,
ArꢀH), 7.25 (d, J = 7.2 Hz, 2H
,
ArꢀH), 7.21 (t, J = 7.2
Hz, 1H ArꢀH), 6.81 (d, J = 1.8 Hz, 1H
,
,
ArꢀH), 6.73 (dd, J = 8.6, 2.0 Hz, 1H
,
ArꢀH),
H2),
4.78 (s, 2H, COCH2), 4.11 (t, J = 6.3 Hz, 2H, OCH2), 2.80–2.70 (m, 2H, Arꢀ
C
2.14–1.97 (m, 2H, alkyl chainsꢀH). 13C NMR (125 MHz, DMSO) δ 197.55, 176.24,
167.52, 141.67, 128.84, 128.84, 128.83, 128.83, 126.37, 125.11, 114.47, 112.18,
97.68, 75.94, 68.27, 31.82, 30.51. HRMS (ESI) m/z 559.2090 [2M+Na]+ (calcd for
559.2091, C34H32NaO6).
Acknowledgments
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We acknowledge the financial supports from the Program for Changjiang Scholars
and Innovative Research Team in University (IRT1193), A Project Founded by the
Priority Academic Program Development of Jiangsu Higher Education Institutions
(PAPD).
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S.ꢀW.; Seeburg, P. H.; Shih, J. C. Proc. Natl. Acad. Sci. U S A. 1988, 85, 4934ꢀ4938.
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DOI: 10.1039/C5MD00124B
Scheme 1. Synthesis of C7ꢀsubstituted 4ꢀChromanone derivatives 4, 5 and 7.
Reagents and conditions: (a) CF3SO3H, 80 °C, 1h; (b) NaOH, rt, 2h; (c) ZnCl2/POCl3,
50 °C, 2h; (d) K2CO3, CH3CN, reflux, 8h.
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DOI: 10.1039/C5MD00124B
Table 1
Physicochemical properties of compounds 4, 5 and 7.
Compounds
4a
MW a
254.09
268.11
282.13
272.08
272.08
272.08
288.06
288.06
322.00
322.00
279.09
268.11
268.11
282.13
300.12
300.12
300.12
316.09
316.09
360.04
360.04
307.12
296.14
296.14
240.08
254.09
268.11
≤450
Clog P a
3.512
3.841
4.220
3.655
3.655
3.655
4.225
4.225
4.375
4.375
2.945
4.011
4.011
4.550
4.693
4.693
4.693
5.263
5.263
5.413
5.413
3.983
5.049
5.049
3.153
3.482
3.861
≤5.0
HBA a
HBD a
PAS a
35.53
35.53
35.53
35.53
35.53
35.53
35.53
35.53
35.53
35.53
59.32
35.53
35.53
35.53
35.53
35.53
35.53
35.53
35.53
35.53
35.53
59.32
35.53
35.53
35.53
35.53
35.53
≤90
Log BB a
0.147
0.225
0.283
0.197
0.197
0.197
0.284
0.284
0.307
0.307
ꢀ0.244
0.251
0.251
0.333
0.355
0.355
0.355
0.442
0.442
0.464
0.464
ꢀ0.086
0.409
0.409
0.121
0.171
0.228
≥ꢀ0.3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
≤5
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
7a
7b
7c
3
3
≤10
Rules
a MW: molecular weight; C log P: calculated logarithm of the octanolꢀwater partition
coefficient; HBA: hydrogenꢀbond acceptor atoms; HBD: hydrogenꢀbond donor atoms;
PSA: polar surface area; log BB = ꢀ0.0148 × PSA + 0.152 ClogP + 0.139.
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DOI: 10.1039/C5MD00124B
Table 2.
hMAO inhibitory activities of the synthesized compounds.
Compounds
R
MAOꢀA inhibition
MAOꢀB
IC50 (nM)b
Selectivity
Indexc
0.9
(%)a
2
Hꢀ
71380 ± 2560b
78860 ± 3690
57.37 ± 2.35
251.14 ± 3.62
21450 ± 260
58.82 ± 1.84
52.65 ± 3.16
8.62 ± 0.96
35.26 ± 1.56
33.45 ± 1.29
30.27 ± 2.35
21.56 ± 3.61
47.28 ± 4.86
51.37 ± 3.27
91.29 ± 2.98
97.47 ± 1.56
68.78 ± 2.25
65.48 ± 1.79
10.26 ± 0.98
55.37 ± 2.59
44.18 ± 1.94
52.23 ± 1.67
45.36 ± 2.35
69.51 ± 1.67
98.32 ± 2.56
113.21 ± 3.12
15210 ± 510
2130 ± 120
20510 ± 490
198.5 ± 5.28
7690 ± 280
4a
C6H5ꢀCH2ꢀ
18
>1742
36.2
4b
C6H5ꢀ(CH2)2ꢀ
C6H5ꢀ(CH2)3ꢀ
2ꢀFC6H5ꢀCH2ꢀ
3ꢀFC6H5ꢀCH2ꢀ
4ꢀFC6H5ꢀCH2ꢀ
3ꢀClC6H5ꢀCH2ꢀ
4ꢀClC6H5ꢀCH2ꢀ
3ꢀBrC6H5ꢀCH2ꢀ
4ꢀBrC6H5ꢀCH2ꢀ
4ꢀCNC6H5ꢀCH2ꢀ
3ꢀCH3C6H5ꢀCH2ꢀ
4ꢀCH3C6H5ꢀCH2ꢀ
C6H5ꢀCH2ꢀ
58
4c
65
3.9
4d
35
>1700
>1898
>11628
>2841
>2994
>3311
>4638
>2114
>1946
>1095
>1026
>1454
>1527
>9709
>1085
>2262
>1916
>2203
>1439
>1017
>883
4e
26
4f
43
4g
35
4h
37
4i
28
4j
19
4k
27
4l
19
4m
26
5a
25
5b
2ꢀFC6H5ꢀCH2ꢀ
3ꢀFC6H5ꢀCH2ꢀ
4ꢀFC6H5ꢀCH2ꢀ
3ꢀClC6H5ꢀCH2ꢀ
4ꢀClC6H5ꢀCH2ꢀ
3ꢀBrC6H5ꢀCH2ꢀ
4ꢀBrC6H5ꢀCH2ꢀ
4ꢀCNC6H5ꢀCH2ꢀ
3ꢀCH3C6H5ꢀCH2ꢀ
4ꢀCH3C6H5ꢀCH2ꢀ
C6H5ꢀCH2ꢀ
28
5c
18
5d
25
5e
31
5f
28
5g
16
5h
21
23
5i
5j
18
5k
7a
25
38150 ± 1240b
46360 ± 1690b
39270 ± 2130b
nt.e
2.5
7b
C6H5ꢀ(CH2)2ꢀ
C6H5ꢀ(CH2)3ꢀ
ꢀ
21.8
7c
1.9
Pargyline
Iproniazid
ꢀ
ꢀ
6550 ± 240b
0.8
a) Test concentration is 100 ꢁM.
b) IC50: 50% inhibitory concentration (means ± SEM of three experiments).
c) Selectivity Index = IC50 (MAOꢀA)/IC50 (MAOꢀB).
e) nt. = not tested.
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Figure 1. Structures of known chromoneꢀbased MAO inhibitors.
29