Benzofuran-based hybrid compounds for the inhibition of cholinesterase activity, β amyloid aggregation, and Aβ neurotoxicity

Article abstract of DOI:10.1021/jm8002747

The complex etiology of Alzheimer's disease (AD) prompts scientists to develop multitarget strategies to combat causes and symptoms. We therefore designed, synthesized, and tested new hybrid molecules linking a benzofuran ring to a N-methyl-N-benzylamine through a heptyloxy chain, affording a series of potential multifunctional drugs for AD. The Cholinesterase inhibitory activity was extended to the inhibition of Aβ fibril formation for 1, 3, and 5. Compound 3 showed an additional neuroprotective effect.

Full text of DOI:10.1021/jm8002747

J. Med. Chem. 2008, 51, 2883–2886
2883
Chart 1. Design of Target Molecule 1
Benzofuran-Based Hybrid Compounds for
the Inhibition of Cholinesterase Activity, ꢀ
Amyloid Aggregation, and Aꢀ Neurotoxicity
Stefano Rizzo,† Ce´line Rivie`re,‡ Lorna Piazzi,†
Alessandra Bisi,† Silvia Gobbi,† Manuela Bartolini,†
Vincenza Andrisano,† Fabiana Morroni,§ Andrea Tarozzi,§
Jean-Pierre Monti,‡ and Angela Rampa*,†
Department of Pharmaceutical Sciences, Alma Mater Studiorum,
UniVersity of Bologna, Via Belmeloro 6, 40126 Bologna, Italy,
Laboratoire de Physique et Biophysique, GESVAB EA3675 ISVV,
UniVersity of Bordeaux 2, 146 Rue Le´o Saignat, 33076 Bordeaux
Cedex, France, and Department of Pharmacology, Alma Mater
Studiorum, UniVersity of Bologna, Via Irnerio 48,
40126 Bologna, Italy
the role of butyrylcholinesterase (BuChE) inhibition in AD has
received increasing attention from the medicinal chemistry and
the clinical points of view.6,7 Several lines of evidence indicate
that BuChE might be a co-regulator of the activity of the
neurotransmitter ACh.8 Remarkably, cortical levels of BuChE
show a significant increase in AD. In this respect, the research
efforts are focused on the development of selective inhibitors
that are necessary to clearly evaluate the role of the enzyme
and the therapeutic feasibility of its inhibition.9,10
Because of the complexity of AD and the involvement of
different enzymes in its progression, the modulation of a single
protein might not be sufficient to produce the desired efficacy.
Thus, researchers are now turning to the design of structures
that should be able to simultaneously interact with different
targets.11–14 With this new paradigm, two compounds binding
with very high selectivity to their respective targets are used as
the starting points and their structural elements are combined
to incorporate activity at both targets into a single molecule.
Our research group has been involved for many years in the
development of AChE and BuChE inhibitors as potential drugs
for AD.15–17 Since compounds containing a benzofuran moiety
have been identified as inhibitors of Aꢀ fibrils formation,18 we
report here a new hybrid molecule (1) based on the frameworks
of our AChE/BuChE inhibitors and of SKF-64346 (Chart 1).
The AChEI general formula (Chart 1) shows N-methyl-N-
benzylamine linked to a heteroaryl moiety through an heptyloxy
chain that allows the molecule to extend from the active anionic
site to the PAS, located at the bottom and at the top of the
gorge, respectively. In the design of the new molecule, the
heteroaryl moiety was substituted with the benzofuran ring
contained in SKF-64346, to introduce the inhibitory activity
toward Aꢀ fibril formation. With following acylation of this
newly introduced moiety (as in SKF-64346) a new series of
potential multi-target-directed compounds for AD was synthe-
sized (2-8) whose structures are reported in Table 1.
According to Scheme 1, 1 was synthesized starting from
4-benzofuran-2-yl-phenol19 and 1,7-dibromoheptane in the pres-
ence of K2CO3to afford the bromoheptane derivative 9, which
was then condensed with N-methyl-N-benzylamine to give the
final compound 1. Friedel-Craft acylation of 1, using tin(IV)
chloride and the selected acylchloride in dichloromethane, gave
the final compounds 2-8.
ReceiVed March 13, 2008
Abstract: The complex etiology of Alzheimer’s disease (AD) prompts
scientists to develop multitarget strategies to combat causes and
symptoms. We therefore designed, synthesized, and tested new hybrid
molecules linking a benzofuran ring to a N-methyl-N-benzylamine
through a heptyloxy chain, affording a series of potential multifunctional
drugs for AD. The cholinesterase inhibitory activity was extended to
the inhibition of Aꢀ fibril formation for 1, 3, and 5. Compound 3
showed an additional neuroprotective effect.
Alzheimer’s disease (ADa) is a progressive neurodegenerative
brain disorder that affects millions among the aging population
worldwide and is going to affect millions more in the next 20
years. AD is characterized by progressive memory loss and
severe cognitive decline associated with a degeneration of
cholinergic neurons in many areas of the CNS and with a
dramatic reduction of the neurotransmitters levels, among which
ACh is the most important one.1 One of the major neuropatho-
logical findings in AD is an abnormal extracellular accumulation
of ꢀ-amyloid peptide (Aꢀ), the main component of the senile
plaques that could be responsible for the onset of the disease.2
Aꢀ is a proteolytic fragment derived from the amyloid precursor
protein (APP), a transmembrane glycoprotein that is usually
processed by the enzyme R-secretase to generate in physiological
conditions small and soluble peptides. In AD affected brain a
second pathway, known as “amyloidogenic pathway”, takes
place involving the sequential action of ꢀ-secretase followed
by γ-secretase to generate two predominant Aꢀ peptides, either
40 or 42 amino acids in length,3 that are able to aggregate into
fibrils via soluble oligomers resulting, as generally accepted,
in neuronal toxicity. Consequently, many drug discovery
approaches are targeting the slowing and/or blocking of the
amyloid polymerization process.4,5
Current treatment of AD focuses on symptomatic aspects of
the pathology and is based on drugs increasing cholinergic
neurotransmission by inhibiting acetylcholinesterase (AChE),
like donepezil, rivastigmine, or galantamine. In recent times,
* To whom correspondence should be addressed. Phone: +39 0512099710.
Fax: +39 0512099734 . E-mail: angela.rampa@unibo.it.
†
Department of Pharmaceutical Sciences, University of Bologna.
‡
University of Bordeaux 2.
The inhibitory activities of the newly synthesized compounds
against both cholinesterases were studied using the method of
Ellman20 to determine the rate of acetylthiocholine or butyrylth-
iocholine hydrolysis in the presence of the inhibitor and are
§
Department of Pharmacology, University of Bologna.
a Abbreviations: AD, Alzheimer’s disease; ACh, acetylcholine; Aꢀ,
ꢀ-amyloid peptide; APP, amyloid precursor protein; AChE, acetylcholinest-
erase; BuChE, butyrylcholinesterase; AChEI, acetylcholinesterase inhibitors.
10.1021/jm8002747 CCC: $40.75
2008 American Chemical Society
Published on Web 04/18/2008

2884 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10
Table 1. Structures of the Studied Compounds
Letters
Figure 1. Compounds 1-8 Aꢀ25-35 fibril inhibition compared to that
of curcumin. The mean ( SD values from three independent experi-
ments are shown.
Scheme 1. Synthesis of the Studied Compoundsa
a Reagents: (i) Br(CH2)7Br, K2CO3; (ii) N-methyl-N-benzylamine; (iii)
RCOCl, SnCl4.
Table 2. AChE, BuChE, Aꢀ Fibril Formation Inhibitory Activities and
Aꢀ25-35 Peptide Neurotoxicity, Expressed as IC50
IC50 ( SEM (µM)a
AChE BuChE
32.6 ( 11.9 0.28 ( 0.02
IC50 (µM)b IC50 (µM)c
compd
Aꢀ25-35
Aꢀ25-35
1
2
3
4
5
6
7
8
7.0
ndd
17.4 ( 1.0
40.7 ( 3.5
127 ( 42
10.5 ( 1.3
127 ( 10
281 ( 95
177 ( 43
1.83 ( 0.12
38.1 ( 2.2
40.9 ( 1.1
1.82 ( 0.09
21.7 ( 1.6
89.1 ( 1.6
74.1 ( 0.2
Figure 2. Electron micrographs of fibrils of Aꢀ25-35 alone (A) and in
presence of the inhibitor 1 after the end of inhibitory activity
measurements (B). The bar represents 200 nm.
12.5
13.0
5.6
microscopy21 (Figure 1). The Aꢀ25-35 amino acid peptide, which
preserves the properties of neurotoxicity and aggregation, was
used.22,23 For the compounds exhibiting an inhibitory activity
at least equal to that of curcumin (compound reported to have
antiamyloidogenic properties24), IC50 values were calculated as
reported in Table 2. The neuroprotective effects of the most
interesting Aꢀ antiaggregating compounds were also determined
against the Aꢀ25-35 peptide induced toxicity in human neuronal-
like SH-SY5Y cells using a colorimetric MTT assay25,26 (Table
2 and Figure 3).
The anticholinesterase activity of the new molecules was
generally similar to that of rivastigmine, showing a better activity
toward BuChE than AChE. In detail, 2 and 5 showed the best
AChE inhibitory activity of the series (17.4 and 10.5 µM,
respectively), still keeping a fairly good BuChE inhibition (1.83
and 1.82 µM, respectively), probably as a consequence of a
higher affinity. There are differences in terms of topology
between AChE and BuChE, since in this latter enzyme Lys286
and Val288 line the gorge, compared to the large Phe of the
rivastigmine 3.03 ( 0.21 0.30 ( 0.01
a Human recombinant AChE and BuChE were used. IC50 values represent
the concentration of inhibitor required to decrease enzyme activity by 50%
and are the mean of two indipendent measurements, each performed in
triplicate (SEM ) standard error of the mean). b IC50 values defined as the
concentrations of inhibitor to inhibit the formation of Aꢀ25-35 fibrils to 50%
of the control value (reference compound: curcumin IC50 ) 10.0 µ M).
c IC50 values represent the concentration of compound resulting in 50%
inhibition of Aꢀ25-35 peptide toxicity in human neuronal SH-SY5Y cells.
The neuronal viability was determined by the MTT assay (as described in
Supporting Information) after 3 h of incubation with 10 µM Aꢀ25-35 peptide
in the presence or absence of different concentrations of the compounds
(1-30 µM). The values are the mean ( SD of at least two independent
experiments. d nd: IC50 not determined because less than 50% inhibition
was observed at the highest tested concentration (30 µM).
reported in Table 2, expressed as IC50 values. The inhibitory
activity of Aꢀ fibril formation was studied with an original in
vitro assay that uses UV-vis measurements and electron

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10 2885
corresponding residues of AChE, and this could allow bulky
compounds to better fit inside the gorge of BuChE and to
stabilize its occupancy probably by means of hydrophobic
interactions. In particular, 1 was found to possess a good BuChE
inhibitory activity (0.28 µM), about 100-fold higher than its
activity toward AChE. Several lines of evidence indicate that
BuChE might be a co-regulator of the activity of the neurotrans-
mitter ACh8 and that it might be important to inhibit this enzyme
in the treatment of AD. Several drugs that proved to be selective
BuChE inhibitors have been evaluated; for example, rivastig-
mine showed clinical efficacy without remarkable side effects.27
It is intriguing that specific BuChE inhibitors not only improve
cognition, presumably through an increase in acetylcholine
concentration, but also reduce levels of APP, which is the source
of Aꢀ peptide, the main component of plaques in AD. The effect
of these compounds on APP seems to be independent of their
ability to inhibit BuChE enzymatic activity, and it has been
suggested that it involves interactions with interleukin-1, a
proinflammatory molecule that has also been implicated in the
pathogenesis of AD.8
Figure 3. Compound 3 protects human neuronal SH-SY5Y cells from
Aꢀ25-35 peptide induced toxicity. The neuronal viability was determined
by the MTT assay (as described in Supporting Information) after 3 h
of incubation with 10 µM Aꢀ25-35 peptide in the presence or absence
of various concentrations of 3. The results are expressed as percent-
age of control cells. Values are reported as the mean ( SD of three
independent experiments: (/) p < 0.05, (//) p < 0.01 vs untreated
sample, ANOVA with Dunnett post hoc test.
Regarding Aꢀ fibril inhibition, 1 showed a higher potency
compared to that of the standard curcumin (IC50 ) 7 and 10
µM, respectively) and the highest one among the series.
Acylation of 1 with acetylchloride led to 2, whose activity was
surprisingly proaggregatory, whereas acylation of 1 with benzoyl
chloride retained the activity (3, IC50 ) 12.5 µM), suggesting
that the introduction of an aryl moiety in position 3 of the
benzofuran ring was tolerated. Modifications of 3 by the
introduction of a methyl group in the meta or para position on
the aryl group led respectively to 4 and 5 and resulted in a lower
activity for 4, whereas 5 retained the potency of the unsubstituted
3. In the opposite direction, the introduction of a methoxy group
in the meta position (6) resulted in a slightly lower but still
remarkable activity, though moving the methoxy group from
the meta to the para position (7) was considerably detrimental
for the activity. Moreover, the acylation of 1 with 3,4-
dimethoxybenzoyl chloride led to 8, which surprisingly proved
to have remarkable proaggregating activity.
hydrophobic properties (compare 3 with 1: 8.00 vs 6.80 log P)
and its ability to block the interaction of Aꢀ25-35 with the lipid
bilayer of the neuronal plasma membrane. It is therefore
reasonable to predict that there are adequate opportunities for
functionally important hydrophobic interactions between 3 and
the Aꢀ25-35 peptide. However, these preliminary results could
encourage further studies to elucidate the neuroprotective
mechanisms of 3.
In conclusion, because of the multifactorial nature of AD,
molecules that modulate the activity of a single protein target
are unable to significantly modify the progression of the disease.
Following this new paradigm, here we have reported a new
series of hybrid molecules based on the frameworks of our
AChE/BuChE inhibitors and of SKF-64346. Promising hits
proved to be 1, with very good inhibitory activity of BuChE
and Aꢀ aggregation, and 3, which turned out to inhibit AChE/
BuChE enzymes and showed remarkable inhibition of Aꢀ
aggregation and Aꢀ neurotoxicity. This multi-target-directed
compound could be considered as a new lead for further
optimization.
The assembly of Aꢀ aggregates, derived from Aꢀ oligomers,
into fibrils is toxic to neurons. The formation of Aꢀ is related
to protein misfolding, since the conformational transition to
ꢀ-sheet leads to a faster formation of aggregates.28 Thus,
compounds that are able to slow or block the amyloid polym-
erization process could be considered potential drugs for
inhibition of AD progression. During incubation of Aꢀ in the
presence of 1, only small bulk aggregates were visible and no
characteristic Aꢀ fibrils were observed in the electron micro-
graphs (Figure 2).
Acknowledgment. This work was supported by MiUR,
Rome (Grant FIRB RBNE03FH5Y).
Supporting Information Available: Details of syntheses and
biological evaluation of target compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Interestingly, 3 also showed a marked neuroprotective effect
against Aꢀ25-35 peptide induced neurotoxicity (Table 2). As
reported in Figure 3, treatment of SH-SY5Y cells with 3 at 10
and 30 µM significantly reduced the neuronal viability loss
evoked by Aꢀ25-35 peptide, in a dose-dependent manner, with
a maximum of inhibition of 63%. Since the same trend was
not observed with 1, these results prove that the modification
of 1 by introduction of an aryl moiety in the benzofuran ring is
crucial for the observed neuroprotective effects. Aꢀ25-35 peptide
contains a number of hydrophobic residues (i.e., Ile31, Ile32,
and Met35) that are critical for neurotoxicity and aggregation
processes.23,29 In this regard, recent studies have suggested that
unaggregated Aꢀ25-35 and Aꢀ31-35 peptides could initiate a
cascade of events leading to neurotoxicity solely after their
internalization within the neuronal cells.30 Neuroprotective
effects of 3 against Aꢀ25-35 toxicity could be ascribed to its
References
(1) Terry, A. V.; Buccafusco, J. J. The cholinergic hypothesis of age and
Alzheimer’s disease related cognitive deficits: recent challenges and
their implications for novel drug development. J. Pharmacol. Exp.
Ther. 2003, 306, 821–827.
(2) Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease:
progress and problems on the road to therapeutics. Science 2002, 297,
353–356.
(3) Selkoe, D. J. Normal and abnormal biology of the beta-amyloid
precursor protein. Annu. ReV. Neurosci. 1994, 17, 489–517.
(4) Talaga, P. ꢀ-Amyloid aggregation inhibitors for the treatment of
Alzheimer’s disease: dream or reality. Mini-ReV. Med. Chem. 2001,
1, 175–186.
(5) Estrada, L. D.; Soto, C. Disrupting ꢀ-amyloid aggregation for
Alzheimer’s disease treatment. Curr. Top. Med. Chem. 2007, 7, 115–
126.
(6) Greig, N. H.; Utsuki, T.; Yu, Q.; Zhu, X.; Holloway, H. W.; Perry,
T.; Lee, B.; Ingram, D. K.; Lahiri, D. K. A new therapeutic target in

2886 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10
Letters
Alzheimer’s disease treatment: attention to butyrylcholinesterase. Curr.
Med. Res. Opin. 2001, 17, 159–165.
(7) Giacobini, E. Acetyl- and butyrylcholinesterase inhibition by rivastig-
mine in cerebrospinal fluid of patiens with Alzheimer’s disease
correlates with cognitive benefit. J. Neural Transm. 2002, 109, 1053–
1065.
(8) Darvesh, S.; Hopkins, D. A.; Geula, C. Neurobiology of butyrylcho-
linesterase. Nat. ReV. Neurosci. 2003, 4, 131–138.
(9) Giacobini, E. Cholinesterase inhibitors: new roles and therapeutic
alternatives. Pharm. Res. 2004, 50, 433–440.
(19) Twyman, L. J.; Allsop, D. A short synthesis of the ꢀ-amyloid (Aꢀ)
aggregation inhibitor 3-p-toluoyl-2-[4′-(3-diethylaminopropoxy)-phen-
yl]-benzofuran. Tetrahedron Lett. 1999, 40, 9383–9384.
(20) Ellman, G. L.; Courtney, K. D.; Andres, V.; Featherstone, R. M. A
new rapid colorimetric determination of acetylcholinesterase activity.
Biochem. Pharmacol. 1961, 7, 88–95.
(21) Rivie`re, C.; Richard, T.; Quentin, L.; Krisa, S.; Me´rillon, J.-M.; Monti,
J.-P. Inhibitory activity of stilbenes on Alzheimer’s ꢀ-amyloid fibrils
in vitro. Bioorg. Med. Chem. 2007, 15, 1160–1167.
(22) Klegeris, A.; Walker, D. G.; McGeer, P. L. Activation of macrophages
by Alzheimer beta amyloid peptide. Biochem. Biophys. Res. Commun.
1994, 199, 984–991.
(23) Pike, C. J.; Walencewicz-Wasserman, A. J.; Kosmoski, J.; Cribbs,
D. H.; Glabe, C. G.; Cotman, C. W. Structure-activity analyses of
beta-amyloid peptides: contributions of the beta 25-35 region to
aggregation and neurotoxicity. J. Neurochem. 1995, 64, 253–265.
(24) Ono, K.; Hasegawa, K.; Naiki, H.; Yamada, M. Curcumin has potent
anti-amyloidogenic effects for Alzheimer’s beta-amyloid fibrils in vitro.
J. Neurosci. Res. 2004, 75, 742–750.
(25) Tarozzi, A.; Morroni, F.; Hrelia, S.; Angeloni, C.; Marchesi, A.;
Cantelli-Forti, G.; Hrelia, P. Neuroprotective effects of anthocyanins
and their in vivo metabolites in SH-SY5Y cells. Neurosci. Lett. 2007,
424, 36–40.
(26) Shearman, M. S.; Hawtin, S. R.; Tailor, V. J. The intracellular
component of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-
zolium bromide (MTT) reduction is specifically inhibited by beta-
amyloid peptides. J. Neurochem. 1995, 65, 218–227.
(27) Farlow, M.; Anand, R.; Messina, J., Jr.; Hartman, R.; Veach, J. A
52-week study of the efficacy of rivastigmin in patients with mild to
moderately severe Alzeimer’s disease. Eur. Neurol. 2000, 44, 236–
241.
(28) Bartolini, M.; Bertucci, C.; Bolognesi, M. L.; Cavalli, A.; Melchiorre,
C.; Andrisano, V. Insight into the kinetic of amyloid beta (1-42)
peptide self-aggregation: elucidation of inhibitors’ mechanism of
action. ChemBioChem 2007, 8, 2152–2161.
(10) Greig, N. H.; Utsuki, T.; Ingram, D. K.; Wang, Y.; Pepeu, G.; Scali,
C.; Yu, Q. S.; Mamczarz, J.; Holloway, H. W.; Giordano, T.; Chen,
D.; Furukawa, K.; Sambamurti, K.; Brossi, A.; Lahir, D. K. Selective
butyrylcholinesterase inhibition elevates brain acetylcholine, augments
learning and lowers Alzheimer beta-amyloid peptide in rodent. Proc.
Natl. Acad. Sci. U.S.A. 2005, 102, 17213–17218.
(11) Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging
drug discovery paradigm. J. Med. Chem. 2005, 48, 6523–6543.
(12) Youdim, M. B. H.; Buccafusco, J. J. Multi-functional drugs for various
CNS target in the treatment of neurodegenerative disorders. Trends
Pharmacol. Sci. 2005, 26, 27–35.
(13) Piazzi, L.; Cavalli, A.; Colizzi, F.; Belluti, F.; Bartolini, M.; Mancini,
F.; Recanatini, M.; Andrisano, V.; Rampa, A. Multi-target-directed
coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-
Alzheimer compounds. Bioorg. Med. Chem. Lett. 2008, 18, 423–426.
(14) Cavalli, A.; Bolognesi, M. L.; Minarini, A.; Rosini, M.; Tumiatti, V.;
Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat
neurodegenerative diseases. J. Med. Chem. 2008, 51, 347–372.
(15) Rampa, A.; Piazzi, L.; Belluti, F.; Gobbi, S.; Bisi, A.; Bartolini, M.;
Andrisano, V.; Cavrini, V.; Cavalli, A.; Recanatini, M.; Valenti, P.
Acetylcholinesterase Inhibitors: SAR and kinetic studies on ω-[N-
methyl-N-(3-alkylcarbamoyloxyphenyl)-methyl]-aminoalkoxyaryl de-
rivatives. J. Med. Chem. 2001, 44, 3810–3820.
(16) Belluti, F.; Rampa, A.; Piazzi, L.; Bisi, A.; Gobbi, S.; Bartolini, M.;
Andrisano, V.; Cavalli, A.; Recanatini, M.; Valenti, P. Cholinesterase
inhibitors: xanthostigmine derivatives blocking the acetylcholinest-
erase-induced ꢀ-amyloid aggregation. J. Med. Chem. 2005, 48, 4444–
4456.
(29) Johansson, A. S.; Bergquist, J.; Volbracht, C.; Pa¨ivio¨, A.; Leist, M.;
Lannfelt, L.; Westlind-Danielsson, A. Attenuated amyloid-beta ag-
gregation and neurotoxicity owing to methionine oxidation. Neuro-
Report 2007, 18, 559–563.
(30) Clementi, M. E.; Marini, S.; Coletta, M.; Orsini, F.; Giardina, B.;
Misiti, F. Abeta(31-35) and Abeta(25-35) fragments of amyloid beta-
protein induce cellular death through apoptotic signals: role of the
redox state of methionine-35. FEBS Lett. 2005, 579, 2913–2918.
(17) Piazzi, L.; Belluti, F.; Bisi, A.; Gobbi, S.; Rizzo, S.; Bartolini, M.;
Andrisano, V.; Recanatini, M.; Rampa, A. Cholinesterase inhibitors:
SAR and enzyme inhibitory activity of 3-[omega-(benzylmethylami-
no)alkoxy]xanthen-9-ones. Bioorg. Med. Chem. 2007, 15, 575–585.
(18) Howlett, D. R.; Perry, A. E.; Godfrey, F.; Swatton, J. E.; Jennings,
K. H.; Spitzfaden, C.; Wadsworth, H.; Wood, S. J.; Markwell, R. E.
Inhibition of fibril formation in ꢀ-amyloid peptide by a novel series
of benzofurans. Biochem. J. 1999, 340, 283–289.
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