Synthesis and evaluation of arylquinones as BACE1 inhibitors, β-amyloid peptide aggregation inhibitors, and destabilizers of preformed β-amyloid fibrils

Article abstract of DOI:10.1016/j.bmcl.2011.03.023

BACE1 activity, inhibition of Aβ aggregation, and disaggregation of preformed Aβ fibrils constitute the three major targets in the development of small-molecule lipophilic new drugs for the treatment of Alzheimer's disease (AD). Quinones are widely distributed among natural products and possess relevant and varied biological activities including antitumor and antibiotic, inhibition of HIV-1 reverse transcriptase, antidiabetic, or COX-inhibition, among others. We report herein the interaction of several arylquinones and their derivatives with the amyloidogenic pathway of the amyloid precursor protein processing. Our studies put forward that these compounds are promising candidates in the development of new drugs which are effective simultaneously towards the three major targets of AD.

Full text of DOI:10.1016/j.bmcl.2011.03.023

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2183–2187
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of arylquinones as BACE1 inhibitors, b-amyloid
peptide aggregation inhibitors, and destabilizers of preformed b-amyloid fibrils
Andrea Ortega a, Ángela Rincón b, Karim L. Jiménez-Aliaga a, Paloma Bermejo-Bescós a,
,
⇑
Sagrario Martín-Aragón a, María Teresa Molina c, Aurelio G. Csákÿ b,
⇑
a Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense, E28040 Madrid, Spain
b Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E28040 Madrid, Spain
c Instituto de Química Médica (CSIC), Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
BACE1 activity, inhibition of Ab aggregation, and disaggregation of preformed Ab fibrils constitute the
three major targets in the development of small-molecule lipophilic new drugs for the treatment of Alz-
heimer’s disease (AD). Quinones are widely distributed among natural products and possess relevant and
varied biological activities including antitumor and antibiotic, inhibition of HIV-1 reverse transcriptase,
antidiabetic, or COX-inhibition, among others. We report herein the interaction of several arylquinones
and their derivatives with the amyloidogenic pathway of the amyloid precursor protein processing.
Our studies put forward that these compounds are promising candidates in the development of new
drugs which are effective simultaneously towards the three major targets of AD.
Received 8 February 2011
Revised 5 March 2011
Accepted 8 March 2011
Available online 13 March 2011
Keywords:
Alzheimer’s disease
BACE1
Ó 2011 Elsevier Ltd. All rights reserved.
Ab fibrils
Amyloid aggregation
Quinones
Alzheimer’s disease (AD) is a progressive, neurodegenerative
disorder of the brain which affects 20–30 million individuals
worldwide and is recognized as the leading cause of dementia.1
Currently, there is no treatment available for AD and medical ther-
apies are usually limited to acetylcholinesterase inhibitors and
NMDA antagonists.2 The pathology of this neurodegenerative dis-
order uniquely manifests itself with the presence of extraneuronal
aggregation of plaques.3 The b-amyloid peptide (Ab) is the major
constituent of these senile plaques found in the brain of patients
with AD. Although the cause of AD remains unknown, a large body
of evidence is beginning to accumulate that highlights the central
role of Ab in the pathogenesis of the disease.4 Two aspartic prote-
inhibitors of this enzyme. Despite their high degree of biological
validation as drug targets, the aspartyl proteases have generally
proven to be difficult to inhibit with low-molecular weight, phar-
macologically tractable molecules. Most of the aspartyl protease
inhibitors in current clinical use today are peptidomimetics that
target the catalytic active site of the enzyme. These drugs have
demonstrated meager ability to cross the blood–brain barrier,
which may prove to be an obstacle to the use of such compounds
for treating diseases of the central nervous system, such as AD.6 In
addition to the active site, BACE1 contains additional binding pock-
ets that engage the substrate protein at locations distal to the site
of hydrolytic chemistry and can act as allosteric regulators of en-
zyme activity through conformational changes, to the active site
to effect augmentation or diminution of the enzyme’s catalytic
reactivity. These allosteric sites could represent an alternative tar-
get for small molecules and open new opportunities for the identi-
fication and development of potential inhibitors of BACE1.7
Since AD is a complex neurodegenerative disorder resulting
from multiple molecular abnormalities, strategies to develop drugs
that simultaneously affect multiple biological targets are being
proposed.8 Inhibiting Ab aggregation and destabilizing preformed
Ab fibrils constitutes another useful therapeutic approach for AD.9
As current therapies for AD are only palliative, the introduction
of disease-modifying small-molecule drugs would be a major ther-
apeutic breakthrough towards the treatment of this disease. There-
fore, the design and synthesis of new agents which simultaneously
ases, b-secretase (BACE1) and
c-secretase, are the key enzymes
that generate Ab from amyloid precursor protein (APP). In particu-
lar, the cleavage of the b-site of APP by BACE1 is the rate-limiting
initial step in Ab formation.
It is widely believed that halting the production of Ab peptide
by inhibition of BACE1 is an attractive therapeutic modality for
the treatment of AD.5 BACE1 is an aspartyl protease, and there is
significant effort in the pharmaceutical community to apply tradi-
tional design methods to the development of active site-directed
⇑
Corresponding authors. Tel.: +34 91 394 1767; fax: +34 91 394 1726 (P.B.B.);
tel.: +34 91 394 5030; fax: +34 91 394 5030 (A.G.C.).
E-mail addresses: bescos@farm.ucm.es (P. Bermejo-Bescós), csaky@quim.ucm.es
(A.G. Csákÿ).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.023

2184
A. Ortega et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2183–2187
inhibit BACE1, inhibit the aggregation of Ab, and disaggregate pre-
formed Ab fibrils could be highly welcome.
OH
OH
O
O
Ar1 Ar2
Ar1
Ph
Ph Ar
Ph
Quinones are widely distributed among natural products10 and
possess relevant and varied biological activities including
antitumor and antibiotic,11 inhibition of HIV-1 reverse transcrip-
tase,12 antidiabetic,13 or COX-inhibition,14 among others. The basic
knowledge on quinone studies has been used to design new anti-
cancer drugs, improving selectivity and providing a more rational
therapeutic application of them. The 1,4-naphthoquinone scaffold
has been identified as a new class of Hsp90 inhibitors which could
be useful for the treatment of cancer and numerous neurodegener-
ative disorders, including AD and Parkinson’s disease, in which
Ar2
OH
5
OH
6
O
3
O
4
3a, 4a, Ar1 = Ar2 = Ph
6, Ar = p-MeO-C6H4
3b, 4b, Ar1 = Ph, Ar2 = p-CF3-C6H4
3c, 4c, Ar1 = Ph, Ar2 = p-F-C6H4
3d, 4d, Ar1 = Ph, Ar2 = p-MeO-C6H4
3e, 4e, Ar1 = p-MeO-C6H4, Ar2 = p-F-C6H4
3f, 4f, Ar1 = Ar2 = = p-MeO-C6H4
protein aggregation is
a a
common etiology.15 Memoquin,
2,5-bis(diamino)-1,4-benzoquinone derivative, affects several
mechanisms relevant to AD: the formation of reactive oxygen spe-
cies, the processing and aggregation of Ab, acetylcholinesterase
activity and BACE1 activity. In animal models, it causes a remark-
able decrease in the formation of AD neurodegenerative hallmarks
and a significant reversal of behavioral deficits. Based on this un-
ique pharmacological profile, memoquin is a promising drug candi-
date for the treatment of AD.16 Also, it has been demonstrated
that the protective action of 1,4-benzoquinone against amylin fi-
bril-induced toxicity was most likely due to the binding interaction
between 1,4-benzoquinone and amylin aggregated/fibrillar spe-
cies.17 Moreover, 1,4-benzoquinone has been reported to effec-
tively attenuate fibrillogenesis and neurotoxic effect of Ab.18 It
has been shown that 1,4-benzoquinone was able to suppress the
OAc
OAc
OAc
Ar1 Ar2
Ar1 Ar2
Ar1
Ar2
OAc
7
OAc
8
OH
9
7a, Ar1 = Ar2 = p-MeO-C6H4
7b, Ar1 = Ph, Ar2 = p-CF3-C6H4
8a, Ar1 = Ar2 = Ph
8b, Ar1 = p-MeO-C6H4, Ar2 = Ph
9, Ar1 = p-MeO-C6H4, Ar2 = Ph
O
O
aggregation process of
a
-synuclein.19 Idebenone, (2-(10-hydrox-
Ar
ydecyl)-5,6-dimethoxy-3-methyl-cyclohexa-2,5-diene-1,4-dione),
a synthetic analog of coenzyme Q10, blocks the oxidative stress and
causes a depletion of ATP levels induced by Ab. Moreover, pretreat-
ment of rats with idebenone prevents the adverse behavioral
learning and memory effects induced by intracerebroventricular
infusion of Ab.20
Ar
R
O
R
O
10
11
10a, Ar = Ph, R = H
10b, Ar = p-OH-C6H4, R = H
10c, Ar = Ph, R = OH
10d, Ar = p-OH-C6H4, R = OH
10e, Ar = p-MeO-C6H4, R = OMe
11a, Ar = Ph, R = OH
11b, Ar = p-OH-C6H4, R = OMe
Based on these features, it was our interest to find out whether
several aryl-1,4-napththoquinones could interact with the amyloi-
dogenic pathway of the APP processing, particularly targeting at
BACE1 as well as at Ab aggregation and destabilizing preformed
Ab fibrils.21 In the search for new quinones with enhanced activi-
ties towards the three targets, we have considered herein the struc-
turally related 2,5-diaryl- or 2,6-diaryl-1,4-benzoquinones (Fig. 1).
Depending on the substitution pattern, arylated quinones have
been obtained only by a few general methods.22,23 Meerwein reac-
tions with aryldiazonium salts and oxidation of the corresponding
aromatics are among the most popular. Other methods such as the
Pummerer arylation and direct arylation protocols have also been
used for the installment of electron rich aryls or heteroaromatics.
When these reactions are carried out on mono-substituted 1,
4-benzoquinones, an issue of regioselectivity arises, as the aryla-
tion can lead to a 2,5- or to a 2,6-disubstituted 1,4-benzoquinone.
Most of these procedures take place with low regioselectivities and
give poor yields with electron-deficient aryl groups. In this respect,
transition-metal mediated cross-couplings are wider in scope than
other procedures.24 However, their application requires the previ-
ous selective functionalization of the starting quinone with a halo-
gen or a triflate group suitable for coupling. Thus, the development
of new synthetic methods leading to diarylated quinones in a reg-
ioselective fashion, suitable for the installment of both electron-
rich and electron-poor aromatics, is worthy.
Figure 1. Compounds considered in this Letter.
cently, it has been shown that the addition of arylboronic acids
to some electron-deficient alkenes can also be catalyzed by
dicationic Pd(II) species, which are cheaper than Rh(I)-catalysts.28
This method has been applied to the regioselective arylation of
the 2- and 3-positions of naphtho- and anthraquinones.29
Based on these results, in this paper we have developed a new
mild method for the direct arylation of 2-aryl-1,4-benzoquinones
(1) which permits the addition of either electron-rich or elec-
tron-poor arylboronic acids (2) under dicationic Pd(II)-catalysis
leading to 2,5-diaryl-1,4-benzoquinones (3) and to 2,6-diaryl-1,4-
benzoquinones (4) (Scheme 1). Good regioselectivities have been
achieved in some cases (Table 1).
Optimization of the palladium precursor, phosphine ligands,
protic or Lewis acidic additives and solvent–H2O combination
was carried out initially using 2-phenyl-1,4-benzoquinone 1a and
O
O
O
Ar2B(OH)2 (2)
i)
Quinones are well known for their Michael acceptor properties.
In connection with arylation methods by conjugate addition reac-
tions, the readily available non-toxic arylboronic acids are known
to react with a wide variety of electron-deficient systems under
transition-metal catalysis, mainly with Rh(I) species. Some scat-
tered reports of the Rh(I)-catalyzed addition of boronic acids to
quinones and their derivatives have been reported.25–27 More re-
Ar1
Ar1
Ar1
Ar2
Pd2+-cat
+
THF-H2O
FeCl3
Ar2
ii)
O
1
O
3
O
4
Scheme 1. Synthesis of compounds 3 and 4.

A. Ortega et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2183–2187
2185
Table 1
in the Table 2. For aggregation inhibition experiments, Ab (25–35)
peptide was dissolved at 1 mM in PBS and 10 M of the solution
was mixed with the quinone and incubated at 37 °C for 4 days.
For disaggregating experiments, 10 M Ab (25–35) peptide was
Synthesis of compounds 3 and 4
l
Entry
1
2
Methoda
3:4 ratiob, yieldc (%)
l
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
2a
2b
2c
2d
2a
2b
2c
2d
2a
2c
2d
2a
2c
2d
A
A
A
A
B
B
B
B
A
A
A
B
B
B
3a:4a = 85:15 (90)
3b:4b = 70:30 (70)
3c:4c = 65:35 (85)
3d:4d = 50:50 (60)
3a:4a = 20:80 (90)
3b:4b = 35:65 (70)
3c:4c = 30:70 (60)
3d:4d = 40:60 (60)
3d:4d = 70:30 (70)
3e:4e = 70: 30 (70)
3f: 4f = 50:50 (60)
3d:4d = 40:60 (70)
3e:4e = 30:70 (65)
3f:4f = 40:60 (60)
incubated at 37 °C for 4 days to generate fibrils. Preformed fibrils
were mixed with the quinones for 4 additional days at 37 °C. The
degree of Ab aggregation and disaggregation was determined using
thioflavin-T (Thio-T) fluorescence analyses. Excitation and
emission wavelengths were 448 and 483 nm, respectively. Sample
fluorescence was determined by subtracting the fluorescence of a
Thio-T blank. The assay for BACE1 activity was based on the
secretase-dependent cleavage of a specific fluorogenic substrate
(H-RE(EDANS)EVNLDAEFK(DABCYL)R-OH), which results in the re-
lease of a fluorescent signal. The level of secretase enzymatic activ-
ity was proportional to the fluorimetric reaction. BACE1 assay was
carried out at 37 °C using 0.24 U of human recombinant BACE1 en-
9
10
11
12
13
14
a
Method A: (i)
1
(1.0 equiv), 2 (3.0 equiv), Pd(OCOCF3)2 (5 mol %), dppben
zyme and 10
l
M substrate in 20 mM sodium acetate buffer (pH
(5.5 mol %), HBF4 (1.0 equiv), THF–H2O 8:2; (ii) FeCl3, CH2Cl2, rt, 1 h. Method B: (i) 1
(1.0 equiv), 2 (3.0 equiv), Pd(OCOCF3)2 (5 mol %), AgOTf (1.0 equiv), THF–H2O 10:1;
(ii) FeCl3, CH2Cl2, rt, 1 h.
4.5) in a final volume of 100
l
l. Wavelengths of excitation and
emission were 360 and 528 nm, respectively. The enzyme activity
assay was performed in the absence (control reaction), and in the
presence of the quinone. Before the addition of the substrate the
human recombinant BACE1 enzyme and the quinone were prein-
cubated at 37 °C for 1 h. The inhibition ratio of BACE1 activity
was calculated from the percentage of control after 1 h of incuba-
tion once the substrate was added. Data were expressed as the fifty
percent inhibitory concentration (IC50).
b
Determined by integration of the 1H NMR (CDCl3, 300 MHz) of the reaction
crudes.
c
Combined isolated yields. Compounds 3 and 4 were separated by column
chromatography (hexane/DCM = 20: 80).
phenylboronic acid 2a. This led to optimum conditions for the reg-
ioselective synthesis of compounds 3 or 4, which were obtained as
mixtures with variable amounts of the corresponding hydroqui-
nones 5, 6. Without any separation, the reaction crudes were oxi-
dized to afford compounds 3 and 4.
The synthesis of the 2,5-diaryl-1,4-benzoquinones 3a–3c was
favored by treatment of quinones 1 with the arylboronic acids 2
(3.0 equiv) in the presence of Pd(OCOCF3)2 (5 mol %), 1,
2-bis(diphenylphosphino)benzene (dppben, 5.5 mol %) and HBF4
(1.0 equiv) as the optimum reagent combination for generating
the catalytically active dicationic Pd(II)-species at room tempera-
ture in THF–H2O (8:2) as solvent (Table 1, entries 1–3). However,
low regioselectivity was observed for the reaction with the elec-
tron-rich boronic acid 3d (Table 1, entry 4).
On the other hand, the synthesis of the 2,6-diaryl-1,4-benzoqui-
nones 4a–d was favored under ligandless (no phosphine) condi-
tions. Thus, reaction of quinones 1 with the arylboronic acids 2
(3.0 equiv) in the presence of Pd(OCOCF3)2 (5 mol %), and AgOTf
(1.0 mol %) at room temperature in THF–H2O (10:1) allowed the
regioselective synthesis of the 2,6-diaryl-1,4-benzoquinones 4
after oxidation of the crude reaction mixtures (Table 1, entries
5–8).
Similar trends were observed when the reactions were carried
out on quinone 1b by either method (Table 1, entries 9–14).
Reduction of compounds 3a or 4d (NaBH4, MeOH, rt, 1 h) gave
compounds 5 and 6, respectively. Compounds 7a, 7b, 8a, and 8b
were prepared respectively by reductive acetylation of 3f, 3b, 4a
The BACE1 inhibitory activity of the quinones and their effect of
Ab aggregation are given in Table 2.
We found21 that several 2-aryl and 3-aryl-1,4-naphthoquinones
(10a–10d, 11a) were selective for BACE1 inhibition, with no effect
on Ab aggregation or disaggregation. On the other hand, quinone
10e showed BACE1 inhibition and also inhibited Ab aggregation,
but had no effect on disaggregation of preformed Ab fibrils. Com-
pound 11b was active on the three targets.
Concerning benzoquinones and their reduced derivatives, since
no neurotoxicity of compounds 3b, 3f, 4a, 4d, 5, 6, 7a, 7b, 8a, 8b
and 9 was found up to 20
inhibition of Ab aggregation and disaggregation of Ab aggregates
was performed at concentration of 20 M. Those compounds
lM, initial screening of compounds for
l
exhibiting inhibitory or disaggregating activity at least of a 50%
were further analyzed to determine their IC50 values.
For the analysis of the data from inhibition of amyloid aggrega-
tion, we began by considering the 2,6-diarylbenzoquinones 4a and
4d which differed only by a p-methoxy group on one of the phenyl
rings. We observed that both displayed a similar activity. Then, we
compared the activity of 4d with that of its reduced form, the
hydroquinone 6. This showed a decreased inhibitory activity, dis-
playing the highest IC50 value among all the 1,4-benzoquinones
tested. The inhibitory activity was completely lost upon mono-
or diacetylation (compounds 9 and 8b, respectively). Comparison
of 4a with 8a showed a similar effect. Therefore, acetylation of
the hydroxyl groups of the hydroquinone molecule was definitely
detrimental for the inhibitory activity since it could involve a loss
of hydrogen bond donors. Indeed, many studies indicate that
hydrogen bonds are crucial in the interactions between polyphe-
nols and proteins.30 Next, switching to the 2,5-diaryl series, we
observed that, opposite to 2,6-diphenyl-1,4-benzoquinone (4a),
2,5-diphenyl-1,4-benzoquinone (3a) was toxic to SH-SY5Y neuro-
and 4d (Zn, Ac2O, NaOAc,
by selective hydrolysis of the less hindered acetyl group of 8b
(K2CO3, MeOH, 0 °C, 5 h).
D, 90 min). Compound 9 was prepared
The mitochondrial-dependent reduction of MTT to formazan
(described in Supplementary data) was used to exclude a cytotoxic
effect of the 1,4-benzoquinones (1,4-BQ) in SH-SY5Y neuroblas-
toma cells. Non-cytotoxic concentrations of these compounds for
brain cells must be tested since they would be eventually adminis-
tered to organisms if active. For that purpose, these 1,4-benzoqui-
nones were previously tested for cell viability in the SH-SY5Y cell
line which is widely used for studies of neuroprotection and neuro-
toxicity. We found that several 1,4-benzoquinones (4b, 3c, 3d, 3e
blastoma cells at 20 lM. However, toxicity was reduced either by
making both aryl rings electron-rich (3f) or by making one of the
aryl rings electron-poor (3b). Compound 3f exhibited the lowest
IC50 value of all compounds studied, while 3b showed a consider-
ably higher IC50 value than 3f. This puts forward that trifluorome-
thylation of one of the aryls reduces the protective activity against
aggregation. As previously observed for the 2,6-diarylated com-
pounds, the diacetylated 2,5-diarylhydroquinones 7a and 7b
and 4e) showed cytotoxicity up to 20
carded for the in vitro assays accomplished in the present work.
Percentages of cell death at 20 M for those compounds are shown
lM, therefore, they were dis-
l

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A. Ortega et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2183–2187
Table 2
BACE1 inhibitory activity, inhibition of Ab aggregation and disaggregation of Ab fibrils
Compound
Cell death at 20
lM (%)
BACE1 inhibitory activity IC50
(
lM)
Effect on Ab aggregation, IC50 (lM)
Inhibition of Ab aggregation
Disaggregation of Ab fibrils
10a
10b
10c
10d
10e
11a
11b
3b
3c
Non-toxic
Non-toxic
Non-toxic
Non-toxic
Non-toxic
Non-toxic
Non-toxic
Non-toxic
78.08
9.33
8.22
12.56
16.09
11.21
8.98
10.31
6.52
Non-tested
Non-tested
Non-tested
23.26
11.43
Non-tested
13.41
Non-tested
15.96
9.10
23.92
12.12
Non-active
Non-active
Non-active
Non-active
22.55
Non-active
16.59
14.19
Non-tested
Non-tested
Non-tested
6.37
9.28
Non-tested
9.56
Non-tested
>50
17.83
Non-active
>50
Non-active
Non-active
Non-active
Non-active
Non-active
Non-active
Non-active
Non-active
Non-active
5.05
12.31
Non-tested
Non-tested
Non-tested
7.15
9.00
Non-tested
7.87
Non-tested
14.28
8.24
>50
>50
3d
3e
3f
56.29
66.22
Non-toxic
Non-toxic
100
Non-toxic
62.50
Non-toxic
Non-toxic
Non-toxic
Non-toxic
Non-toxic
Non-toxic
Non-toxic
4a
4b
4d
4e
5
6
7a
7b
8a
8b
9
20.01
11.15
11.29
Non-active
Non-active
Non-active
showed no inhibitory activity. However, 2,5-diphenylhydroqui-
none (5) showed no inhibitory activity, in contrast to the 2,6-diaryl
series (6). As for disaggregation activity of Ab aggregates (or fi-
brils), we observed that in the 2,6-series reduction of the quinone
preserved the activity, as observed when comparing 4d with 6,
while in the 2,5-series quinone 3f was considerably more active
than hydroquinone 5. However, trifluoromethylation of the benzo-
quinone molecule on a phenyl ring, as shown in 3b, led to the loss
of activity, probably due to steric hindrance in the process of bind-
ing to amyloid protein. No activity was found for the acetylated
derivatives in any case.
In conclusion, our studies put forward that 2,6-diaryl-1,4-ben-
zoquinones are promising candidates in the development of
small-molecule lipophilic new drugs for the treatment of neurode-
generative diseases targeting simultaneously BACE1 activity, inhi-
bition of Ab aggregation, and disaggregation of preformed Ab
fibrils.
Acknowledgments
Andrea Ortega (PhD fellow) thanks the government of Chile and
the ‘Universidad Católica del Norte’ (Antofagasta, Chile) for a grant
(MECESUP program, UCN0604). Projects CTQ2009-14124-C02-01,
CTQ2010-16170 and SAF2009-10399 from the Spanish govern-
ment are gratefully acknowledged for financial support.
With respect to BACE1 inhibition, all compounds tested were
active towards BACE1 inhibition at
2,6-diarylbenzoquinones 4a and 4d, whose IC50 values are 11.43
and 13.41 M, respectively, indicated that introduction of a p-
lM range. Comparison of the
l
methoxy group was slightly detrimental for the activity. This effect
was also observed in the 2,5-series, with compound 3f displaying
the highest IC50 value among all the quinones tested. Opposite to
the effect on Ab aggregation, trifluoromethylation of the benzoqui-
none molecule on a phenyl ring (3b) provided the highest inhibi-
Supplementary data
Supplementary data (experimental protocols for the synthesis
of compounds 3–9, pharmacological assays, and characterization
of new compounds) associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.03.023.
tory activity, with an IC50 value of 6.52 lM. Acetylation of the
reduced form of 3b was not favorable for the activity, since 7b
approximately displayed an IC50 value which doubled that of 3b.
However, as shown by the pairs 3f & 7a, 4a & 8a, 4d & 8b and 4d
& 9, acetylation did not affect significantly the activity in the rest
of cases. Last, hydroquinone 6 was slightly more active than the
parent quinone (4d), while 5 was considerable less active than 6.
Our studies revealed that, together with the 3-aryl-1,4-naph-
thoquinone 11b, the 2,6-diaryl-1,4-benzoquinones 4a and 4d were
the most effective compounds among those studied in altering
simultaneously an important effect in the AD neurotoxic cascade:
inhibition of amyloid aggregation and disaggregation of preformed
Ab fibrils. These 1,4-benzoquinones (4a and 4d) were particularly
effective in the inhibition of Ab aggregation in comparison with
11b, while the latter was more effective on disaggregation of pre-
formed Ab fibrils. In addition, the 2,5-diaryl-1,4-benzoquinone 3b,
which was also active against the three targets, showed the best
activity towards BACE1 inhibition, although it was less effective
both in the inhibition of Ab aggregation and the disaggregation
of preformed Ab fibrils than compounds 4a and 4d.
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