2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors

Article abstract of DOI:10.2147/DDDT.S86225

Based on a previous report that substituted 2-acetylphenols may be promising leads for the design of novel monoamine oxidase (MAO) inhibitors, a series of C5-substituted 2-acetylphenol analogs (15) and related compounds (two) were synthesized and evaluate

Full text of DOI:10.2147/DDDT.S86225

Drug Design, Development and erapy
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O r i g i n a l r e s e a r c h
2-acetylphenol analogs as potent reversible
monoamine oxidase inhibitors
This article was published in the following Dove Press journal:
Drug Design, Development andTherapy
15 July 2015
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lesetja J legoabe1
anél Petzer1
Abstract: Based on a previous report that substituted 2-acetylphenols may be promising
leads for the design of novel monoamine oxidase (MAO) inhibitors, a series of C5-substituted
2-acetylphenol analogs (15) and related compounds (two) were synthesized and evaluated as
inhibitors of human MAO-A and MAO-B. Generally, the study compounds exhibited inhibitory
activities against both MAO-A and MAO-B, with selectivity for the B isoform. Among the
compounds evaluated, seven compounds exhibited IC50 values ,0.01 µM for MAO-B inhibition,
with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A
isoform. Analyses of the structure–activity relationships for MAO inhibition show that substitu-
tion on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition,
and the benzyloxy substituent is particularly favorable in this regard. This study concludes that
C5-substituted 2-acetylphenol analogs are potent and selective MAO-B inhibitors, appropriate
for the design of therapies for neurodegenerative disorders such as Parkinson’s disease.
Keywords: monoamine oxidase, MAO, inhibition, 2-acetylphenol, structure–activity
relationship
Jacobus P Petzer1,2
1centre of excellence for
Pharmaceutical sciences, 2Department
of Pharmaceutical chemistry, school
of Pharmacy, north-West University,
Potchefstroom, south africa
Introduction
Parkinson’s disease is a degenerative disorder of the central nervous system.1 One
of the main pathological characteristics of Parkinson’s disease is the destruction of
the dopamine-containing neurons of the nigrostriatal pathway, which results in the
deficiency of dopamine at the nerve terminals in the corpus striatum.1 The cornerstone
of Parkinson’s disease therapy is the replacement of the lost dopamine with its direct
metabolic precursor, l-3,4-dihydroxyphenylalanine (l-dopa).2 To enhance the thera-
peutic efficacy of l-dopa and to reduce the occurrence of l-dopa-associated side effects,
this drug is frequently administered in combination with inhibitors of the enzymes,
peripheral dopa decarboxylase, and catechol-O-methyl transferase.3,4 The inhibition
of these enzymes prevents the peripheral metabolism of l-dopa and allows for the
effective l-dopa dose to be reduced.5 A second strategy to increase the efficacy of
l-dopa is to inhibit the metabolism of dopamine with monoamine oxidase (MAO)
type B inhibitors.6 In the central nervous system, MAO-B is a major catabolic enzyme
of dopamine, and inhibition of this enzyme conserves the central dopamine supply.7
l-dopa is thus frequently also combined with MAO-B inhibitors with the aim of further
enhancing central dopamine levels.8–10 In early Parkinson’s disease, monotherapy with
MAO-B inhibitors may delay the necessity for l-dopa therapy.11
correspondence: lesetja J legoabe
centre of excellence for Pharmaceutical
sciences, north-West University,
Private Bag X6001, Potchefstroom 2520,
south africa
MAO consists of two distinct isoforms, MAO-A and MAO-B. Although both
isoforms metabolize dopamine in the central nervous system, only MAO-B inhibi-
tors are used in Parkinson’s disease, in part because MAO-B activity is higher than
that of MAO-A in the affected region, the basal ganglia.6 MAO-A inhibitors have
Tel +27 18 299 2182
Fax +27 18 299 4243
email lesetja.legoabe@nwu.ac.za
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License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
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legoabe et al
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been used in the clinic as antidepressants,12,13 but their use
is restricted by the occurrence of a potentially fatal hyper-
tensive response when taken with tyramine-containing
foods.14 This adverse effect is, however, mostly caused by
irreversible MAO-A inhibitors, and the newer generation
reversible inhibitors appear to be safe in this regard.15,16
Both reversible and irreversible MAO-B inhibitors, on
the other hand, have excellent safety profiles and are not
associated with a hypertensive response.17 Currently, two
irreversible MAO-B inhibitors, selegiline [(R)-deprenyl]
and rasagiline, are employed in the clinic for the treatment
of Parkinson’s disease. Based on the patent literature, many
research groups are actively developing MAO inhibitors,
and many of them intended for the treatment of Parkinson’s
disease.18
also selective for MAO-B over the MAO-A isoform, with
1e (selectivity index [SI] =3,950) possessing the highest
selectivity of the series. Based on these results, the current
study examines the MAO inhibitory properties of a series of
15 C5-substituted 2-acetylphenol analogs (2a–o) (Table 2).
In the present study, the 2-acetylphenol analogs were first
substituted on the C5 position with the benzyloxy, phe-
nylethoxy, and phenylpropoxy moieties to yield compounds
2a–c. The MAO inhibitory properties of the benzyloxy-
substituted 2-acetylphenol analog (2a) were further explored
by substitution on the benzyloxy phenyl ring with halogens
(F, Cl, I) and alkyl groups (CH3, CN, CF3) to yield 2d–m.
The selection of the benzyloxy-substituted homologues
for further investigation was based on the reports that the
benzyloxy moiety is particularly suited for MAO inhibition
by chromones19,20 and 3,4-dihydro-2(1H)-quinolinones.21
Literature also emphasizes the suitability of the benzyloxy
substituent for MAO inhibition by coumarin derivatives.22,23
Furthermore, for these classes of compounds, halogen
and alkyl substitution on the benzyloxy ring significantly
Since MAO-B inhibitors are considered useful agents
for the management of Parkinson’s disease, the goal of
this study was to discover novel MAO inhibitors. Such
compounds should possess selectivity for the MAO-B
isoform. In a recent study, we have shown that substituted
2-acetylphenols are promising leads for the design of MAO-B
inhibitors.19 In the reported study, a limited series of six
2-acetylphenol analogs (1a–f) were synthesized, and it was
found that substitution on the C5 position (eg, 1e and 1f)
was particularly favorable for high potency MAO-B inhi-
bition (Table 1). Compounds 1e and 1f thus represent
exceptionally potent MAO-B inhibitors with IC50 values of
0.004 µM and 0.011 µM, respectively. Substitution on C4
(1c, 1d) and C3 (1a, 1b), on the other hand, yielded lower
potency MAO-B inhibitors. The 2-acetylphenols were
Table 2 The ic50 values for the inhibition of recombinant human
MaO-a and MaO-B by 2-acetylphenol analogs 2a–o
2
5 ꢀ
Compound R
2+
SIb
IC50 (µM)a
MAO-A
MAO-B
2a
2b
2c
2d
2e
2f
c6h5ch2O–
1,194
30
8.36±0.442 0.007±0.002
4.70±0.716 0.157±0.041
10.7±2.30 0.060±0.013
50.7±4.45 0.0029±0.0003
3.70±0.335 0.003±0.0003
17.7±2.94 0.0013±0.0003
1.81±0.284 0.014±0.002
26.9±1.80 0.014±0.002
17.7±2.80 0.054±0.010
25.2±0.939 0.026±0.002
1.64±0.213 0.023±0.0003
2.72±0.352 0.004±0.001
13.6±0.238 0.010±0.003
8.65±1.04 0.103±0.015
60.4±8.00 0.156±0.050
c6h5(ch2)2O–
c6h5(ch2)3O–
178
Table 1 The ic50 values for the inhibition of recombinant human
MaO-a and MaO-B by previously reported 2-acetylphenol
analogs 1a–f19
(3-Fc6h4)ch2O–
(4-Fc6h4)ch2O–
(3-clc6h4)ch2O–
(4-clc6h4)ch2O–
(3-ic6h4)ch2O–
(3-ch3c6h4)ch2O–
(4-ch3c6h4)ch2O–
(3-cnc6h4)ch2O–
(4-cnc6h4)ch2O–
(4-cF3c6h4)ch2O–
ch3(ch2)3O–
17,482
1,233
13,615
129
2g
2h
2i
2
5
ꢀ
2
2
1,921
328
5
ꢀ
2+
ꢀ
5
2+
2j
969
2+
ꢀD±E
ꢀF±G
ꢀH±I
2k
2l
71
680
Compound
R
SIa
IC50 (µM)
2m
2n
2o
1,360
84
MAO-A
MAO-B
1a
1b
1c
1d
1e
1f
(3-Brc6h4)ch2O–
(4-Brc6h4)ch2O–
(3-Brc6h4)ch2O–
(4-Brc6h4)ch2O–
(3-Brc6h4)ch2O–
(4-Brc6h4)ch2O–
103
143
19.7
2.90
15.8
6.26
5.96
2.69
0.576
0.172
0.004
0.011
17
53
34
17
3,950
569
ch3(ch2)6O–
387
Methylene blue
lazabemide
0.07c
–
4.37c
0.016
–
0.091d
Notes: aall values are expressed as the mean ± sD of triplicate determinations.bThe
selectivity index is the selectivity for the MaO-B isoform and is given as the ratio
of ic50(MaO-a)/ic50(MaO-B). cValue obtained from harvey et al.29 dValue obtained
from Petzer et al.28
Abbreviations: MaO, monoamine oxidase; si, selectivity index; sD, standard
deviation.
Note: aThe selectivity index is the selectivity for the MaO-B isoform and is given as
the ratio of ic50(MaO-a)/ic50(MaO-B).
Abbreviations: MaO, monoamine oxidase; si, selectivity index.
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2-acetylphenols as MaO inhibitors
Table 3 The ic50 values for the inhibition of recombinant human
MaO-a and MaO-B by 2′,4′-dihydroxyacetophenone (4) and
2-acetylphenol derivatives 3a–b
Kynuramine.2HBr was obtained from Sigma-Aldrich, and
Slide-A-Lyzer dialysis cassettes with a molecular weight
cut-off of 10,000 and a sample volume capacity of 0.5–3 mL
were obtained from Thermo Fisher Scientific (Waltham,
MA, USA).
2
5ꢂ
5ꢀ
5ꢁ
chemistry
Compound R1
R2
R3
SIb
IC50 (µM)a
Procedure for the synthesis of c5-substituted
2-acetylphenol analogs (2a–o and 3a–b)
MAO-A MAO-B
4
hO–
hO– ch3–
1.2
47.7±3.12 39.7±5.03
19.5±2.47 0.027±0.003
38.2±3.13 0.004±0.001
To a mixture of 2′,4′-dihydroxyacetophenone (4; 1 mmol)
and anhydrous K2CO3 (2 mmol) in dry acetone (15 mL), the
appropriate alkyl or arylalkyl bromide (5; 1.1 mmol) was
added. The mixture was stirred under reflux for 24 hours,
cooled to room temperature, and filtered through a pad of
Celite. The solvent was removed under reduced pressure,
and the residues were recrystallized from ethanol. For the
3a
3b
c6h5ch2O– h–
ch3–
722
9,550
c6h5ch2O– hO– c2h5–
Notes: aall values are expressed as the mean ± sD of triplicate determinations.bThe
selectivity index is the selectivity for the MaO-B isoform and is given as the ratio of
ic50(MaO-a)/ic50(MaO-B).
Abbreviations: MaO, monoamine oxidase; si, selectivity index; sD, standard
deviation.
enhances MAO inhibitory potency. Lastly, 2-acetylphenol synthesis of 3a and 3b, 4′-hydroxyacetophenone (6) and
analogs with the nonaromatic n-butoxy (2n) and n-heptyloxy 2′,4′-dihydroxypropiophenone (7), respectively, were reacted
(2o) substituents were also included in this study. The effect with benzyl bromide under the same conditions as above.
on MAO inhibition of modification of the 2-acetylphenol Compounds 3a and 3b were purified by recrystallization
nucleus was investigated with acetophenone derivative 3a from ethanol.19
and 2-propanoylphenol derivative 3b (Table 3).
enzymology
ic50 value determination
Materials and methods
For the determination of IC50 values for MAO-A and MAO-B
inhibition, the recombinant human enzymes were employed.
Kynuramine, a nonselective MAO substrate, served as
enzyme substrate.24 The concentration of 4-hydroxyquinoline,
generated upon the oxidation of kynuramine by the MAOs,
was measured by fluorescence spectrophotometry (λex =310;
λem =400 nm). The protocol for these experiments has been
reported in detail in a recent publication.25 Employing vari-
ous inhibitor concentrations (spanning at least 3 orders of
magnitude), sigmoidal curves were constructed by graphing
residual enzyme activity versus the logarithm of inhibitor
concentration. The IC50 values were determined in triplicate
from these curves and are expressed as mean ± standard
deviation.
general
Unless otherwise specified, all starting materials and reagents
were obtained from Sigma-Aldrich (St Louis, MO, USA)
and were used without further purification. Proton (1H) and
carbon (13C) NMR spectra were recorded on a Bruker Avance
III 600 spectrometer (Karlsruhe, Germany) at frequencies
of 600 MHz and 151 MHz, respectively. CDCl3 served as a
NMR solvent, and chemical shifts are reported in parts per
million (δ). Spin multiplicities are given as singlet (s), doublet
(d), doublet of doublets (dd), triplet (t), quartet (q), pentet
(p), or multiplet (m). High-resolution mass spectra were
recorded on a Bruker micrOTOF-Q II mass spectrometer
in atmospheric-pressure chemical ionization mode. Melt-
ing points were determined with a Büchi M-545 (Büchi
Labortechnik, Flawil, Switzerland) melting point apparatus
and are uncorrected. Thin layer chromatography was car- recovery of enzyme activity after dialysis
ried out using silica gel 60 (EMD Millipore, Billerica, MA, The reversibility of MAO-B inhibition by 2e was investigated
USA) with UV254 fluorescent indicator. The mobile phase by measuring the recovery of MAO-B activity after mixtures
consisted of ethyl acetate (one part) and petroleum ether containing the enzyme and test inhibitor were dialyzed. The
(three parts). Fluorescence spectrophotometry was carried out protocol for these experiments has been reported in detail
with a Varian Cary Eclipse fluorescence spectrophotometer in recent publications.25,26 All reactions were carried out in
(Agilent Technologies, Santa Clara, CA, USA). Microsomes triplicate, and the residual enzyme catalytic rates (as percent-
from insect cells expressing recombinant human MAO-A age of the negative control value) were expressed as mean ±
and MAO-B (5 mg/mL) were obtained from Sigma-Aldrich. standard deviation.
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The construction of lineweaver–Burk plots and
Ki value calculations
the inhibition potencies were expressed as the correspond-
ing IC50 values.24 To measure the catalytic activities of the
MAO enzymes, the mixed MAO-A/B substrate, kynuramine,
was used. Kynuramine is oxidized by the MAOs to yield
4-hydroxyquinoline as final product. This metabolite
fluoresces in alkaline media and may thus be conveniently
quantified by fluorescence spectrophotometry.27 Using
the appropriate control reactions, it was determined that
none of the 2-acetylphenol analogs investigated here fluoresce
under the specific assay conditions and thus do not interfere
with the fluorescence measurement of 4-hydroxyquinoline.
IC50 values were estimated from sigmoidal plots of the
residual MAO activities recorded in the presence of the test
inhibitors versus the logarithm of inhibitor concentration.
The human MAO inhibitory properties of the C5-
substituted 2-acetylphenol analogs are shown in Tables 2
and 3. As evident from the SI values (SI .30), all of the
2-acetylphenol analogs (2a–o, 3a, b) are selective inhibitors
of MAO-B. Among these, seven compounds (of 17) exhib-
ited IC50 values ,0.01 µM for the inhibition of MAO-B.
These compounds (2a, 2d–f, 2l, m, 3b) may be viewed as
exceptionally potent MAO-B inhibitors and possess higher
potencies than the reference MAO-B inhibitor, lazabemide
(IC50 =0.091 µM).28 With IC50 values in the nanomolar range
(0.0013–0.157 µM), all of the 2-acetylphenol analogs may,
however, be viewed as potent MAO-B inhibitors. Among
the high potency inhibitors (IC50 ,0.01 µM), compounds
2d, 2f, and 3b may be highlighted. These compounds exhibit
SI values .9,550 and are thus the most selective MAO-B
inhibitors of the present study. The finding that C5-substituted
2-acetylphenol analogs are potent and selective MAO-B
inhibitors is in accordance to the previous study, which has
shown that substitution on the C5 position of 2-acetylphenol
(eg, 1e and 1f) yields selective MAO-B inhibitors. The IC50
values recorded for 1e and 1f are in the same range as those of
the most potent inhibitors of the present study (Table 1).19
The C5-substituted 2-acetylphenol analogs (2a–o, 3a, b)
also inhibited human MAO-A. With IC50 values in the
micromolar range (1.64–50.7 µM), these compounds are,
relative to their MAO-B inhibition potencies, weak MAO-A
inhibitors. Also, compared to the reference MAO-A inhibi-
tor, methylene blue (IC50 =0.07 µM), the 2-acetylphenol
analogs are at least 23-fold weaker as MAO-A inhibitors.29
The finding that C5-substituted 2-acetylphenol analogs are
relatively weak MAO-A inhibitors is in agreement to the
previous study, which has shown that 1e and 1f are weak
MAO-A inhibitors with IC50 values in the same range as
those of the C5-substituted 2-acetylphenol analogs of the
present study (Table 1).19
The mode of MAO-B inhibition by 2e was investigated by
constructing a set of six Lineweaver–Burk plots. The first plot
was constructed in the absence of inhibitor while the remaining
five plots were constructed in the presence of different con-
centrations of the test inhibitor. The inhibitor concentrations
that were selected were 1/4× IC50, 1/2× IC50, 3/4× IC50, 1× IC50,
and 11/4× IC50. Kynuramine was used at concentrations of
15–250 µM. The protocol for these experiments has been
reported in detail in recent publications.25,26 A Ki value for the
inhibition of MAO-B was estimated from a plot of the slopes
of the Lineweaver–Burk plots versus inhibitor concentration,
where the x-axis intercept equals −Ki. The Ki value may also
be estimated by global (shared) fitting of the inhibition data
directly to the Michaelis–Menten equation using the Prism 5
software package (GraphPad, San Diego, CA, USA).
Results and discussion
chemistry
The C5-substituted 2-acetylphenol analogs, 2a–o, were
synthesizedinlowtogoodyields(39%–93%)byreacting2′,4′-
dihydroxyacetophenone(4)withtheappropriatealkyloraryla-
lkylbromide(5)inthepresenceofK2CO3 inacetone(Figure1).
For the synthesis of 3a and 3b, 4′-hydroxyacetophenone
(6) and 2′,4′-dihydroxypropiophenone (7), respectively,
were reacted with benzyl bromide under the same condi-
tions as earlier. In each instance, the structures and purities
1
of the target compounds were verified by H NMR, 13C
NMR, and mass spectrometry as cited in the supplementary
materials.
Potencies of MaO inhibition
The 2-acetylphenol analogs were evaluated as inhibitors of
the recombinant human MAO-A and MAO-B enzymes, and
2
2
D
ꢁ
5
%U
5
+2
2+
2
2+
ꢁ
ꢀ
ꢂD R
2
2
5ꢅ
5ꢅ
%U
D
ꢁ
5ꢀ
5ꢀ
ꢃꢂ 5ꢀꢃ +ꢄ 5ꢅꢃ &+ꢅ
ꢅꢂ 5ꢀꢃ 2+ꢄ 5ꢅꢃ &ꢀ+ꢆ
+2
2
ꢄDꢂ 5ꢀꢃ +ꢄ 5ꢅꢃ &+ꢅ
ꢄEꢂ 5ꢀꢃ 2+ꢄ 5ꢅꢃ &ꢀ+ꢆ
Figure 1 synthetic route to the 2-acetylphenol analogs 2a–o and 3a–b.
Note: reagents and conditions: (a) acetone, K2cO3, reflux.
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2-acetylphenols as MaO inhibitors
structure–activity relationships for MaO
inhibition
MAO-B, 2′,4′-dihydroxyacetophenone (4) was evaluated as
an inhibitor of the human MAOs. The results document that
4 is a weak MAO-B inhibitor with an IC50 value of 39.7 µM.
Compound 4 is thus 250-fold weaker as a MAO-B inhibitor
than the weakest inhibitor of the present series, compound 2b
(IC50 =0.157 µM). This demonstrates that an appropriate C5
substituent is necessary for high potency MAO-B inhibition
by 2-acetylphenol analogs. Interestingly, 4 (IC50 =47.7 µM) is
a superior MAO-A inhibitor than some of the C5-substituted
2-acetylphenol analogs (eg, 2d and 2o).
From the inhibition data, some structure–activity relation-
ships (SARs) may be derived. The 2-acetylphenol analogs
with the nonaromatic n-butoxy and n-heptyloxy substituents,
compounds 2n (IC50 =0.103 µM) and 2o (IC50 =0.156 µM),
respectively, are among the three weakest MAO-B inhibitors
of the present study. This shows that these substituents may
be less suitable for MAO-B inhibition than, for example,
the benzyloxy-derived substituents (eg, 2a, 2d–m), which
yield compounds with IC50 values of 0.0013–0.054 µM. It
is noteworthy that substitution with the benzyloxy moiety
(2a) yields more potent MAO-B inhibition than substitu-
tion with the phenylethoxy (2b) and phenylpropoxy (2c)
moieties. This suggests that, among these three substituents,
the benzyloxy moiety is most suitable for MAO-B inhibition
by 2-acetylphenol analogs. Among the benzyloxy-derived
compounds (2a, 2d–m), no SARs for the inhibition of
MAO-B are apparent, and all compounds are potent MAO-B
inhibitors (IC50 ,0.054 µM). The effect of modification of
the 2-acetylphenol nucleus was investigated with aceto-
phenone derivative 3a and 2-propanoylphenol derivative
3b. Removal of the phenolic hydroxyl to yield 3a (IC50
=0.027 µM) resulted is a small loss of MAO-B inhibition
activity when compared to its 2-acetylphenol homologue 2a
(IC50 =0.007 µM), while the 2-propanoylphenol derivative
3b (IC50 =0.004 µM) was approximately equipotent to 2a.
It may thus be concluded that small structural modifications
to the 2-acetylphenol moiety are well tolerated and does not
necessarily abolish MAO-B inhibition activity. Interestingly,
3a and 3b are significantly weaker MAO-A inhibitors than
the corresponding 2-acetylphenol homologue 2a, which
suggests that removal of the phenolic hydroxyl (to yield 3a)
and replacing the acetyl group with propanoyl (to yield 3b)
may improve selectivity of inhibition for MAO-B. This is
exemplified by 3b, an equipotent MAO-B inhibitor to 2a,
but with improved selectivity. Lastly, it is interesting to note
that among the three most potent MAO-A inhibitors, two are
the nitrile-containing compounds 2k (IC50 =1.64 µM) and 2l
(IC50 =2.72 µM). This suggests that the nitrile group enhances
MAO-A inhibition, an observation for which the molecular
basis is not readily apparent.
reversibility of MaO-B inhibition
Employing dialysis, the present study also investigated the
reversibility of MAO-B inhibition by one representative
inhibitor, compound 2e (IC50 =0.003 µM). The reversibility
of inhibition was examined by measuring the recovery of
enzyme activity after dialysis of enzyme-inhibitor mixtures.26
Since none of the 2-acetylphenol analogs were potent MAO-A
inhibitors, only the reversibility of MAO-B inhibition was
further investigated. MAO-B and 2e, at an inhibitor concen-
tration of 4× IC50, was incubated for 15 minutes, dialyzed for
24 hours, and the residual enzyme activity was subsequently
measured. The results are given in Figure 2, which show that
the MAO-B inhibition by 2e is only partially reversed after
24 hours of dialysis, with the catalytic activity recovering to
52% of the negative control value (activity in the absence
of inhibitor). For reversible inhibition, the enzyme activity
is, however, expected to recover to 100% after dialysis. The
enzyme activity of undialyzed mixtures of MAO-B and 2e is
30% of the control value. As positive control, the irreversible
inhibitor, (R)-deprenyl, was similarly incubated with MAO-B
and dialyzed. As expected for irreversible inhibition, enzyme
ꢄꢀꢀ
ꢃꢂ
ꢂꢀ
ꢁꢂ
ꢀ
1,
ꢄH
'HSU
ꢄH
As mentioned earlier, a previous study has shown that
substitution on the C5 position of 2-acetylphenol (eg, 1e
and 1f) is particularly favorable for high potency MAO-B
inhibition and yields higher potency inhibitors than substitu-
tion on C4 (1c, 1d) and C3 (1a, 1b).19 To further evaluate
the importance of the C5 substituent for the inhibition of
'LDO\]HG
8QGLDO\]HG
Figure 2 reversibility of the inhibition of MaO-B by 2e.
Notes: MaO-B was preincubated in the absence of inhibitor (ni – dialyzed), in
the presence of 2e (2e – dialyzed) and in the presence of the irreversible inhibitor,
(R)-deprenyl (depr – dialyzed). These mixtures were subsequently dialyzed for
24 hours and the residual enzyme activity was measured. For comparison, the residual
activity of undialyzed mixtures of MaO-B with 2e is also shown (2e – undialyzed).
Abbreviations: MaO, monoamine oxidase; h, hour.
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activity is not recovered, with only 1.6% activity remaining. Conclusion
While the molecular basis for the observation that MAO-B In conclusion, this study shows that C5-substituted
inhibition is only partially reversed by dialysis, is not known, 2-acetylphenol analogs are highly potent MAO-B inhibi-
high potency MAO-B inhibitors such as 2e may act by tight tors with seven compounds (of 17) exhibiting IC50
binding. Potential tight binding of inhibitors to MAO-B values ,0.01 µM. The 2-acetylphenol analogs also are selec-
has been reported on a number of occasions,30–33 and partial tive for the MAO-B isoform as exemplified by compounds
recovery of MAO-B activity following dialysis of enzyme- 2d, 2f, and 3b, which possess SI values .9,550. With rela-
inhibitor mixtures has previously been reported.25 Further tively weak MAO-A inhibitory potencies (IC50 .17.7 µM),
investigation is necessary to clarify this point.
these three compounds may be suitable candidates for the
development of MAO-B selective inhibitors for Parkinson’s
disease. Such compounds are unlikely to provoke tyramine
competitive inhibition
To gain further insight into the mode of MAO-B inhibition induced adverse effects as a result of MAO-A inhibition.
by 2-acetylphenols, a set of Lineweaver–Burk graphs were Furthermore, the possibility that high potency 2-acetylphenol
constructed for the inhibition of MAO-B by the represen- analogs bind tightly to MAO-B is not of concern since
tative inhibitor, 2e. The set consisted of six graphs, each clinically used irreversible MAO-B inhibitors are reported to
constructed by measuring MAO-B catalytic rate at eight possess excellent safety profiles.17 Further examination of the
different kynuramine concentrations (15–250 µM). The first physicochemical, biochemical, and pharmacokinetic proper-
Lineweaver–Burk graph was constructed in the absence of ties is necessary to determine if promising 2-acetylphenols
inhibitor, while the remaining five graphs were constructed may be acceptable in vivo drugs.
in the presence of different concentrations of 2e. As shown
in Figure 3 the set of Lineweaver–Burk graphs is indica-
Acknowledgments
tive of competitive inhibition since the lines are linear and
intersect on the y axis. This suggests that 2e is a competitive
inhibitor of human MAO-B. From a replot of the slopes of
the Lineweaver–Burk plots versus the concentration of 2e,
a Ki value of 0.0038 µM is estimated for the inhibition of
MAO-B. Global (shared) fitting of the inhibition data directly
to the Michaelis–Menten equation yielded a similar Ki value
of 0.0039±0.00035 µM (r2=0.99).
The NMR and MS spectra were recorded by André Joubert
and Johan Jordaan of the SASOL Centre for Chemistry,
North-West University. This work is based on the research
supported in part by the Medical Research Council and
National Research Foundation of South Africa (Grant spe-
cific unique reference numbers 85642, 80647, and 80637).
The Grantholders acknowledge that opinions, findings and
conclusions, or recommendations expressed in any publica-
tion generated by the NRF supported research are that of the
authors and that the NRF accepts no liability whatsoever in
this regard.
ꢇꢈꢅꢀꢀ
ꢇꢈꢀꢀꢀ
ꢇꢀꢀ
ꢅꢀꢀ
Disclosure
The authors report no conflicts of interest in this work.
ꢆꢅ
íꢀꢁꢀꢀꢃ íꢀꢁꢀꢀꢂ ꢀꢁꢀꢀꢀ
ꢀꢁꢀꢀꢂ ꢀꢁꢀꢀꢃ
>,@ꢆꢂ—0
References
ꢅꢀ
ꢂꢅ
ꢀ
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Supplementary materials
2-acetyl-5-benzyloxyphenol (2a)
2-Acetyl-5-(4-fluorobenzyloxy)phenol (2e)
The title compound (clear crystals) was prepared in a yield
1
of 53%: mp 112.4°C–113.9°C (ethanol). H NMR (600
The title compound (clear crystals) was prepared in a yield of
93%: mp 103.1°C–103.4°C (ethanol), lit. mp 101°C–103°C.1
1H NMR (600 MHz, CDCl3) δ 12.71 (s, 1H), 7.62 (d,
J =8.7 Hz, 1H), 7.42–7.35 (m, 4H), 7.24 (s, 1H), 6.52–6.47
(m, 2H), 5.08 (s, 2H), 2.54 (s, 3H); 13C NMR (151 MHz,
CDCl3) δ 202.55, 165.13, 135.81, 132.31, 128.66, 128.27,
127.49, 114.03, 108.09, 101.82, 101.81, 70.16, 26.20;
APCI-HRMS m/z: calcd for C15H15O3 (MH+), 243.1016,
found 243.1001.
MHz, CDCl3) δ 12.72 (s, 1H), 7.62 (d, J =8.8 Hz, 1H), 7.37
(dd, J =8.4, 5.4 Hz, 2H), 7.06 (t, J =8.6 Hz, 2H), 6.51–6.45
(m, 2H), 5.03 (s, 2H), 2.54 (s, 3H); 13C NMR (151 MHz,
CDCl3) δ 202.60, 165.13, 164.92, 163.45, 161.81, 132.36,
131.60, 131.58, 129.45, 129.40, 115.70, 115.56, 114.12,
108.07, 101.78, 101.77, 69.49, 26.24; APCI-HRMS m/z:
calcd for C15H14FO3 (MH+), 261.0921, found 261.0932.
2-acetyl-5-(3-chlorobenzyloxy)phenol (2f)
The title compound (off-white crystals) was prepared in
a yield of 67%: mp 127.1°C–129.1°C (ethanol), lit. mp
127°C–128°C.3 1H NMR (600 MHz, CDCl3) δ 12.72
(s, 1H), 7.63 (d, J =8.9 Hz, 1H), 7.40 (s, 1H), 7.32–7.22
(m, 3H), 6.49 (dd, J =8.9 Hz, 1H), 6.45 (d, J =2.5 Hz, 1H),
5.04 (s, 2H), 2.54 (s, 3H); 13C NMR (151 MHz, CDCl3)
δ 202.63, 165.11, 164.74, 137.88, 134.61, 132.40, 129.96,
128.41, 127.41, 125.35, 114.22, 108.02, 101.82, 69.24, 26.25;
APCI-HRMS m/z: calcd for C15H14ClO3 (MH+), 277.0626,
found 277.0619.
2-acetyl-5-(2-phenylethoxy)phenol (2b)
The title compound (white crystals) was prepared in a yield
of 51%: mp 71.0°C–72.3°C (ethanol), lit. mp 69°C.2 1H
NMR (600 MHz, CDCl3) δ 12.71 (s, 1H), 7.60 (d, J =8.8 Hz,
1H), 7.31 (t, J =7.5 Hz, 2H), 7.28–7.22 (m, 3H), 6.44–6.38
(m, 2H), 4.19 (t, J =7.0 Hz, 2H), 3.09 (t, J =7.0 Hz, 2H),
2.53 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 202.50, 165.26,
165.15, 137.63, 132.27, 128.92, 128.53, 126.64, 107.85,
101.40, 101.39, 68.84, 35.40, 26.18; APCI-HRMS m/z: calcd
for C16H17O3 (MH+), 257.1172, found 257.1153.
2-acetyl-5-(4-chlorobenzyloxy)phenol (2g)
2-acetyl-5-(3-phenylpropoxy)phenol (2c)
The title compound (clear flakes) was prepared in a yield
of 61%: mp 76.4°C–78.1°C (ethanol), lit. mp 75°C–77°C.2
1H NMR (600 MHz, CDCl3) δ 12.73 (s, 1H), 7.61 (d, J =8.9
Hz, 1H), 7.31–7.25 (m, 2H), 7.19 (d, J =7.8 Hz, 3H), 6.43
(dd, J =8.9, 2.5 Hz, 1H), 6.37 (d, J =2.5 Hz, 1H), 3.97 (t,
J =6.3 Hz, 2H), 2.82–2.76 (m, 2H), 2.54 (s, 3H), 2.14–2.07
(m, 2H); 13C NMR (151 MHz, CDCl3) δ 202.49, 165.54,
165.18, 141.05, 132.25, 128.45, 126.03, 113.79, 107.92,
101.30, 101.29, 67.19, 31.97, 30.45, 26.18; APCI-
HRMS m/z: calcd for C17H19O3 (MH+), 271.1329, found
271.1326.
The title compound (off-white crystals) was prepared in
1
a yield of 62%: mp 102.2°C–102.5°C (ethanol). H NMR
(600 MHz, CDCl3) δ 12.71 (s, 1H), 7.62 (d, J =8.9 Hz, 1H),
7.37–7.30 (m, 4H), 6.50–6.43 (m, 2H), 5.03 (s, 2H), 2.54
(s, 3H); 13C NMR (151 MHz, CDCl3) δ 202.60, 165.10,
164.80, 134.32, 134.11, 132.37, 128.86, 128.79, 114.16,
108.01, 101.80, 69.34, 26.24; APCI-HRMS m/z: calcd for
C15H14ClO3 (MH+), 277.0626, found 277.0617.
2-acetyl-5-(3-iodobenzyloxy)phenol (2h)
The title compound (beige crystals) was prepared in a yield
of 58%: mp 143.7°C–144.6°C (ethanol).1H NMR (600 MHz,
2-Acetyl-5-(3-fluorobenzyloxy)phenol (2d) CDCl3) δ 12.72 (s, 1H), 7.76 (s, 1H), 7.64 (dd, J =16.8, 8.5 Hz,
The title compound (clear crystals) was prepared in a 2H), 7.35 (d, J =8.2 Hz, 1H), 7.11 (t, J =7.8 Hz, 1H),
yield of 52%: mp 108.5°C–112.3°C (ethanol), lit. mp 6.51–6.43 (m, 2H) 5.00 (s, 2H), 2.54 (s, 3H); 13C NMR
108°C–109°C.3 1H NMR (600 MHz, CDCl3) δ 12.72 (151 MHz, CDCl3) δ 202.62, 165.10, 164.73, 138.13, 137.30,
(s, 1H), 7.63 (d, J =8.9 Hz, 1H), 7.34 (q, J =7.7 Hz, 1H), 136.24, 132.40, 130.35, 126.53, 114.21, 108.01, 101.80,
7.14 (dd, J =26.5, 8.5 Hz, 2H), 7.01 (t, J =9.1 Hz, 1H), 94.49, 69.06, 26.25; APCI-HRMS m/z: calcd for C15H14IO3
6.52–6.44 (m, 2H), 5.07 (s, 2H), 2.54 (s, 3H);13C NMR (151 (MH+), 368.9982, found 368.9980.
MHz, CDCl3) δ 202.62, 165.10, 164.75, 163.75, 162.12,
138.41, 138.36, 132.39, 130.28, 130.23, 122.73, 122.71, 2-acetyl-5-(3-methylbenzyloxy)phenol (2i)
115.21, 115.07, 114.29, 114.19, 114.15, 108.02, 101.83, The title compound (clear needles) was prepared in a yield
1
101.81, 69.27, 69.25, 26.24; APCI-HRMS m/z: calcd for of 53%: mp 98.6°C–100.8°C (ethanol). H NMR (600
C15H14FO3 (MH+), 261.0921, found 261.0942.
MHz, CDCl3) δ 12.73 (s, 1H), 7.62 (d, J =8.8 Hz, 1H), 7.27
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2-acetylphenols as MaO inhibitors
(t, J =7.5 Hz, 1H), 7.23–7.17 (m, 2H), 7.14 (d, J =7.5 Hz, NMR (151 MHz, CDCl3) δ 202.65, 165.11, 164.63, 139.89,
1H), 6.53–6.47 (m, 2H), 5.03 (s, 2H), 2.54 (s, 3H), 2.36 132.45, 127.39, 125.64 (q), 114.30, 107.94, 101.87, 69.19,
(s, 3H); 13C NMR (151 MHz, CDCl3) δ 202.55, 165.20, 26.24; APCI-HRMS m/z: calcd for C16H14F3O3 (MH+),
165.12, 138.40, 135.69, 132.29, 129.05, 128.56, 128.24, 311.0890, found 311.0866.
124.61, 113.99, 108.11, 101.78, 70.25, 26.19, 21.37; APCI-
HRMS m/z: calcd for C16H17O3 (MH+), 257.1172, found 2-acetyl-5-butoxyphenol (2n)
257.1157.
The title compound (white powder) was prepared in a yield
of 47%: mp 42.7°C–43.1°C (ethanol), lit. mp 38°C–40°C.5
2-acetyl-5-(4-methylbenzyloxy)phenol (2j) 1H NMR (600 MHz, CDCl3) δ 12.72 (s, 1H), 7.59
The title compound (beige crystals) was prepared in a yield (d, J =8.9 Hz, 1H), 6.43–6.36 (m, 2H), 3.97 (t, J =6.5 Hz,
of 48%: mp 98.0°C–99.5°C (ethanol). 1H NMR (600 MHz, 2H), 2.53 (s, 3H), 1.79–1.72 (m, 2H), 1.46 (m, 2H), 0.95
CDCl3) δ 12.72 (s, 1H), 7.61 (d, J =9.2 Hz, 1H), 7.29 (d, (t, J =7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 202.45,
J =8.0 Hz, 2H), 7.19 (d, J =7.8 Hz, 2H), 6.51–6.45 (m, 165.71, 165.21, 132.21, 113.68, 107.98, 101.22, 68.05, 30.94,
2H), 5.03 (s, 2H), 2.53 (s, 3H), 2.35 (s, 3H); 13C NMR 26.16, 19.12, 13.75; APCI-HRMS m/z: calcd for C12H17O3
(151 MHz, CDCl3) δ 202.54, 165.23, 165.13, 138.16, 132.76, (MH+), 209.1172, found 209.1152.
132.28, 129.35, 127.67, 113.97, 108.15, 101.80, 70.15,
26.20, 21.19; APCI-HRMS m/z: calcd for C16H17O3 (MH+), 2-acetyl-5-heptyloxyphenol (2o)
257.1172, found 257.1159.
The title compound (white powder) was prepared in a yield
of 65%: mp 32.8°C–33.8°C (ethanol), lit. mp oil.6 1H NMR
2-acetyl-5-(3-cyanobenzyloxy)phenol (2k) (600 MHz, CDCl3) δ 12.73 (s, 1H), 7.60 (d, J =8.9 Hz,
The title compound (white powder) was prepared in a yield 1H), 6.44–6.36 (m, 2H), 3.96 (t, J =6.6 Hz, 2H), 2.53 (s,
of 65%: mp 125.0°C–125.8°C (ethanol). 1H NMR (600 MHz, 3H), 1.79–1.72 (m, 2H), 1.42 (p, J =7.1 Hz, 2H), 1.35–1.26
CDCl3) δ 12.71 (s, 1H), 7.71 (s, 1H), 7.67–7.59 (m, 3H), (m, 6H), 0.87 (t, J =6.9 Hz, 3H); 13C NMR (151 MHz, CDCl3)
7.50 (t, J =7.8 Hz, 1H), 6.50 (dd, J =8.9, 2.5 Hz, 1H), 6.44 δ 202.47, 165.73, 165.23, 132.22, 113.70, 108.02, 101.24,
(d, J =2.4 Hz, 1H), 5.10 (s, 2H), 2.55 (s, 3H); 13C NMR 68.40, 31.73, 28.97, 28.94, 26.19, 25.88, 22.58, 14.07;
(151 MHz, CDCl3) δ 202.67, 165.09, 164.35, 137.51, 132.50, APCI-HRMS m/z: calcd for C15H23O3 (MH+), 251.1642,
131.83, 131.43, 130.65, 129.50, 118.44, 114.39, 112.89, found 251.1659.
107.91, 101.78, 68.70, 26.27; APCI-HRMS m/z: calcd for
C16H14NO3 (MH+), 268.0968, found 268.0971.
4′-Benzyloxyacetophenone (3a)
The title compound (clear flakes) was prepared in a yield of
2-acetyl-5-(4-cyanobenzyloxy)phenol (2l) 55%: mp 93.2°C–94.5°C (ethanol), lit. mp 93°C–94°C.7 1H
The title compound (white powder) was prepared in a yield NMR (600 MHz, CDCl3) δ 7.92 (d, J =8.9 Hz, 2H), 7.44–7.36
of 73%: mp 145.9°C–147.6°C (ethanol), lit. mp 147°C–148- (m, 4H), 7.34 (d, J =7.2 Hz, 1H), 6.99 (d, J =8.9 Hz,2H),
°C.4 1H NMR (600 MHz, CDCl3) δ12.70 (s, 1H), 7.66 (d, J=8.2 5.11 (s, 2H), 2.54 (s, 3H); 13C NMR (151 MHz, CDCl3)
Hz, 2H), 7.64 (d, J =8.9 Hz, 1H), 7.51 (d, J =8.2 Hz, 2H), 6.49 δ 196.74, 162.57, 136.13, 130.57, 130.48, 128.67, 128.22,
(dd, J =8.9, 2.5 Hz, 1H), 6.43 (d, J =2.5 Hz, 1H), 5.13 (s, 2H), 127.44, 114.50, 70.10, 26.34; APCI-HRMS m/z: calcd for
2.54 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 202.65, 165.06, C15H15O2 (MH+), 227.1067, found 227.1063.
164.34, 141.23, 132.48, 132.45, 127.53, 118.48, 114.38,
112.01, 107.83, 101.85, 68.91, 26.25; APCI-HRMS m/z: calcd 2-Propanoyl-5-benzyloxyphenol (3b)
for C16H14NO3 (MH+), 268.0968, found 268.0982.
The title compound (clear needles) was prepared in a yield of
62%: mp 112.0°C–113.4°C (ethanol), lit. mp 113°C– 114°C.8
1H NMR (600 MHz, CDCl3) δ12.81 (s, 1H), 7.65 (d, J=9.6Hz,
1H), 7.42–7.31 (m, 5H), 6.50 (dd, J =7.0, 2.5 Hz, 2H), 5.07
2-Acetyl-5-[4-(trifluoromethyl)benzyloxy]
phenol (2m)
The title compound (clear needles) was prepared in a yield (s, 2H), 2.93 (q, J =7.3 Hz, 2H), 1.21 (t, J =7.3 Hz, 3H); 13C
of 39%: mp 85.6°C–87.0°C (ethanol). 1H NMR (600 MHz, NMR (151 MHz, CDCl3) δ 205.34, 165.13, 164.87, 135.87,
CDCl3) δ 12.70 (s, 1H), 7.66 (d, J =8.2 Hz, 2H), 7.64 (d, 131.44, 128.67, 128.27, 127.50, 113.46, 108.01, 101.93,
J=8.9Hz, 1H), 7.51(d, J=8.2Hz, 2H), 6.49(dd, J=8.9,2.5Hz, 70.15, 31.15, 8.48; APCI-HRMS m/z: calcd for C16H17O3
1H), 6.43 (d, J =2.5 Hz, 1H), 5.13 (s, 2H), 2.54 (s, 3H); 13C (MH+), 257.1172, found 257.1170.
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