Aminostyrylbenzofuran derivatives as potent inhibitors for Aβ fibril formation

Article abstract of DOI:10.1016/j.bmcl.2008.08.111

The synthesis of a novel series of aminostyrylbenzofuran derivatives 1a-w and their inhibitory activities for Aβ fibril formation were described. All the synthesized compounds were evaluated by thioflavin T (ThT) assay and displayed potent inhibitory activities for Aβ fibril formation. Among them, compounds 1i and 1q exhibited excellent inhibitory activities (IC₅₀ = 0.07 and 0.08 μM, respectively) than those of Curcumin (IC₅₀ = 0.80 μM) and IMSB (IC₅₀ = 8.00 μM) as reference compounds. Both compounds were selected as promising candidates for further biological evaluation.

Full text of DOI:10.1016/j.bmcl.2008.08.111

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5591–5593
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Aminostyrylbenzofuran derivatives as potent inhibitors for Ab fibril formation
Ji Hun Byun a,b, HyeYun Kim a, YoungSoo Kim a, Inhee Mook-Jung c, Dong Jin Kim a,
a,
Won Koo Lee b, , Kyung Ho Yoo
*
*
a Life Sciences Research Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea
b Department of Chemistry and Interdisciplinary Program of Integrated Biotechnology, Sogang University, Seoul 121-742, Republic of Korea
c Department of Biochemistry and Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a novel series of aminostyrylbenzofuran derivatives 1a–w and their inhibitory activities
for Ab fibril formation were described. All the synthesized compounds were evaluated by thioflavin T
(ThT) assay and displayed potent inhibitory activities for Ab fibril formation. Among them, compounds
Received 25 June 2008
Revised 28 August 2008
Accepted 29 August 2008
Available online 3 September 2008
1i and 1q exhibited excellent inhibitory activities (IC50 = 0.07 and 0.08
Curcumin (IC50 = 0.80 M) and IMSB (IC50 = 8.00 M) as reference compounds. Both compounds were
selected as promising candidates for further biological evaluation.
lM, respectively) than those of
l
l
Keywords:
Alzheimer’s disease
Ab42 fibrils
Ó 2008 Elsevier Ltd. All rights reserved.
Aminostyrylbenzofurans
Inhibitory activity
Alzheimer’s disease (AD) is a neurodegenerative disorder of the
brain that is characterized by dementia, cognitive impairment, and
memory loss.1,2 A major hallmark of AD is the formation and accu-
mulation of fibrillar b-amyloid (Ab) peptides in the brain.3–6 Of the
two most abundant forms of Ab, Ab42 are aggregated into oligo-
mers, protofibrils, and fibrils more readily than relatively soluble
Ab40.7,8
I
HO
OH
HO2C
CO2H
IMSB
O
O
Preventing of Ab fibril formation in the brain are currently being
targeted as potential therapies for AD.9–11 Various promising
approaches to develop ligands exhibiting specific high binding
affinity to Ab fibrils have been proposed. Hence, several series of
inhibitors such as E,E-1-iodo-2,5-bis-(3-hydroxycarbonyl-4-methoxy)-
styrylbenzene (IMSB),12,13 (1E,6E)-1,7-bis(4-hydroxy-3-methoxy-
phenyl)-1,6-heptadiene-3,5-dione (Curcumin),14,15 4-N-methyl-
amino-40-hydroxystilbene (SB-13),16 and benzofuran analogues17–19
were designed, and these compounds were found to interfere with
the fibrillization of Ab as determined by thioflavin T (ThT) assay.
In this paper, the structural modification by the introduction of
styryl conjugated system of IMSB and Curcumin into benzofuran
nucleus was designed as shown in Figure 1.
HO
OH
OMe
R1
R2
MeO
Curcumin
R3
O
R4
1a-w
Figure 1. Structures of IMSB, Curcumin, and aminostyrylbenzofuran derivatives.
Scheme 1. Ethyl 2-benzofuran carboxylates 4 were obtained by
first Casiraghi formylation20 of phenol derivatives 2 with para-
formaldehyde and magnesium chloride, and subsequent Perkin-
typed intramolecular Aldol condensation21 of 3 (3a,b,d,f,g,i,k:
com. avail.). Reduction of ester group of 4 with aluminum chloride
followed by bromination with phosphorus tribromide gave the
bromomethylbenzofurans 6, which were reacted with tri-
ethylphosphite by Arbuzov reaction22 to give the corresponding
compounds 7, respectively. Subsequent Horner–Emmons olefin-
We report here the synthesis and evaluation of a novel series of
aminostyrylbenzofuran derivatives 1a–w with potent inhibitory
activities for Ab fibril formation.
Aminostyrylbenzofurans 1a–o,v,w with varying R1, R2, R3, and
R4 groups were prepared by the sequence of reactions shown in
* Corresponding authors. Tel.: +82 2 705 8449; fax: +82 2 701 0967 (W.K.L.), tel.: +82
2 958 5152; fax: +82 2 958 5189 (K.H.Y.).
E-mail addresses: wonkoo@sogang.ac.kr (W.K. Lee), khyoo@kist.re.kr (K.H. Yoo).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.08.111

5592
J. H. Byun et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5591–5593
O
R1
R1
R2
R1
R2
R1
R2
O
O
ii
iv
i
iii
H
R2
O
O
OH
OH
OH
3a: R1=H, R2=H; 3b: R1=MeO, R2=H
3d: R1=Me, R2=H; 3e: R1=F, R2=H
3f: R1=Cl, R2=H; 3g: R1=Br, R2=H
3h: R1=I, R2=H; 3i: R1=H, R2=MeO
3k: R1=H, R2=Me; 3l: R1=H, R2=F
3m: R1=H, R2=Cl; 3n: R1=H, R2=Br
3o: R1=H, R2=I
2e: R1=F, R2=H
2h: R1=I, R2=H
2l: R1=H, R2=F
2m: R1=H, R2=Cl
2n: R1=H, R2=Br
2o: R1=H, R2=I
4
5
R1
R1
R1
R2
v
vi
R3
R2
R2
O
O
PO(OEt)2
O
Br
R4
1a-o,v,w
6
7
1b: R1=MeO, R2=H, R3=NMe2, R4=H
1i: R1=H, R2=MeO, R3=NMe2, R4=H
1c: R1=HO, R2=H, R3=NMe2, R4=H
1j: R1=H, R2=HO, R3=NMe2, R4=H
vii
Scheme 1. Reagents and conditions: (i) paraformaldehyde, MgCl2, Et3N, CH3CN, molecular sieve, reflux, 18 h, 34–58% (for 3e,h,l–o); (ii) ethyl bromoacetate, K2CO3, DMF,
molecular sieve, reflux, 1.5 h, 61–77%; (iii) LiAlH4, THF, 0 °C, 20 min, 90–92%; (iv) PBr3, DMF, 0 °C, 1 h; (v) PO(OEt)3, reflux, 4 h, 74–95% (for two steps from 5); (vi) NaHMDS,
benzaldehyde, 0 °C to rt, 1 h, 36–80%; (vii) BBr3, CH2Cl2, ꢀ78 °C to rt, 3 h, 50%.
O
O
ii
iii
i
H
HO
HO
HO
R6
Boc
R6
R6
R6
Boc
N
N
H
N
H
N
9a: R6=H
10a: R6=H
11a: R6=H
8b: R6=Me
9b: R6=Me
10b: R6=Me
11b: R6=Me
R1
R2
R1
R2
iv
v
R6
NBoc
R3
O
O
12a: R1=MeO, R2=H, R6=H
12b: R1=MeO, R2=H, R6=Me
12c: R1=H, R2=MeO, R6=H
12d: R1=H, R2=MeO, R6=Me
1p: R1=MeO, R2=H, R3=NH2
1q: R1=MeO, R2=H, R3=NHMe
1t: R1=H, R2=MeO, R3=NH2
1u: R1=H, R2=MeO, R3=NHMe
1r: R1=HO, R2=H, R3=NH2 HCl
vi
1s: R1=HO, R2=H, R3=NHMe HCl
Scheme 2. Reagents and conditions: (i) LiAlH4, THF, 0 °C, 24 h, 65% (for 9b); (ii) (Boc)2O, dioxane+H2O, rt, 6 h, 98% (for 10a), 85% (for 10b); (iii) MnO2, CH2Cl2, rt, 12 h, 81% (for
11a), 84% (for 11b); (iv) 7, 1 M NaHMDS, 0 °C to rt, 2 h, 47–57%; (v) TFA, CH2Cl2, 0 °C to rt, 24 h, 97–99%; (vi) BBr3, CH2Cl2, ꢀ78 °C to rt, 3 h, 98%.
ation23 for only trans configuration of 7 with the appropriate
benzaldehydes was achieved to give the title compounds 1.
Hydroxyl compounds 1c and 1j were obtained from methoxy com-
pounds 1b and 1i by demethylation using boron tribromide,
respectively.24
The synthesis of terminal primary and secondary amino-
styrylbenzofurans 1p–u were outlined in Scheme 2. Reduction of
carboxylic acid group of 8b with lithium aluminum hydride25 fol-
lowed by Boc-protection26 of 9 (9a: com. avail.) led to the com-
pounds 10, which were oxidized with magnesium dioxide to
yield the aldehydes 11. Compounds 11 were coupled with 7 by
Horner–Emmons olefination in the presence of sodium hexameth-
yldisilazane to give compounds 12. Deprotection of 12 provided
the title compounds 1, and compounds 1p and 1q were demethy-
lated using boron tribromide to yield the compounds 1r and 1s,
respectively.
the synthesized compounds were evaluated by thioflavin T (ThT)
assay.27
Shown in Table 1, 9 compounds displayed better inhibitory
activities (IC50 = 0.07–0.53 lM) than those of Curcumin
(IC50 = 0.80 lM) and IMSB (IC50 = 8.00 lM) as reference com-
pounds. In particular, compounds 1i (R1 = H, R2 = MeO,
R3 = NMe2) and 1q (R1 = MeO, R2 = H, R3 = NMe2) exhibited
10-fold superior inhibitory activities (IC50 = 0.07 and 0.08 lM,
respectively) to Curcumin. In general, compounds 1c–h having
R1 substituents possessed slightly potent activities as com-
pared to compounds 1j–o with R2 substituents, except 1b.
Electronic effect according to electron-donating or -withdraw-
ing of substituents at benzofuran nucleus did not make any
significant difference of inhibitory activity. R3 and R4 substitu-
ents at aminobenzene ring also did not show a meaningful
trend.
Table 1 shows the in vitro inhibitory activities (IC50 values) of
aminostyrylbenzofurans 1a–w for Ab42 fibril formation together
with those of Curcumin and IMSB as reference compounds. All
In conclusion, aminostyrylbenzofuran derivatives showed
excellent inhibitory activities for Ab42 fibril formation. Especially,
1i and 1q exhibited 10-fold better inhibitory activities than Curcu-

J. H. Byun et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5591–5593
5593
Table 1
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1a
1b
H
H
H
H
H
H
H
H
H
MeO
HO
Me
F
Cl
Br
I
H
H
H
H
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NH2
NHMe
NH2ꢁHCl
NHMeꢁHCl
NH2
NHMe
NMe2
NMe2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
MeO
MeO
2.30
0.81
0.16
0.13
1.98
0.20
0.47
0.17
0.07
3.62
3.44
2.19
3.21
1.34
2.80
0.82
0.08
2.95
2.16
5.44
0.80
0.16
0.53
0.80
8.00
MeO
HO
Me
F
Cl
Br
I
H
H
H
H
1c
1d28
1e
1f
1g
1h
1i28
1j
1k
1l
1m
1n
1o
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1p
MeO
MeO
HO
HO
H
H
MeO
H
1q28
1r
1s
1t
1u
1v
1w
Curcumin
IMSB
MeO
MeO
H
MeO
a
ThT assay. IC50 was calculated from non-linear regression by Graphpad Prism
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software.
concentration of Ab42 (Bachem) was 25
lM. The excitation and emission
wavelengths were 450 and 482 nm with 10 nm slit (LS-55 luminescence
spectrometer: Perkin-Elmer).
min. Above results demonstrate that the introduction of styryl con-
jugated system into benzoxazole nucleus led to the potent inhibi-
tors, and these informations will helpful for designing AD
treatments.
28. Selected data.
1d: Mp: 188.0–189.0 °C; IR (KBr): 3437, 1600, 1518, 1359, 1184, 814 cmꢀ1
;
1H
NMR (CDCl3, 400 MHz) d 7.43 (d, 2H, J = 8.8 Hz), 7.32 (d, 1H, J = 8.3 Hz), 7.28 (s,
1H), 7.23 (d, 1H, J = 16.1 Hz), 7.04 (d, 1H, J = 8.3 Hz), 6.79 (d, 1H, J = 16.1 Hz),
6.72 (d, 2H, J = 8.8 Hz), 6.50 (s, 1H), 3.00 (s, 6H), 2.42 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 156.2, 153.1, 150.4, 132.4, 130.4, 129.6, 127.9, 125.1, 124.9, 120.3,
112.3, 112.2, 110.1, 103.0, 40.4, 21.3; MS m/z 277 (M+).
Acknowledgments
1i: Mp: 194.5–195.5 °C; IR (KBr): 3437, 1602, 1489, 1356, 1146, 1107,
We are grateful to the Ministry of Science and Technology
(MOST) and Ministry of Commerce, Industry and Energy (MCIE)
of Korea for financial support.
820 cmꢀ1 1H NMR (CDCl3, 400 MHz) d 7.43 (d, 2H, J = 8.8 Hz), 7.33 (d, 1H,
;
J = 9.0 Hz), 7.23 (d, 1H, J = 16.1 Hz), 6.97 (d, 1H, J = 2.5 Hz), 6.84 (dd, 1H, J = 2.6,
8.8 Hz), 6.79 (d, 1H, J = 16.1 Hz), 6.72 (d, 2H, J = 8.8 Hz), 6.52 (s, 1H), 3.85 (s,
3H), 3.01 (s, 6H); 13C NMR (CDCl3, 100 MHz) d 157.0, 155.9, 150.4, 149.7, 130.5,
130.0, 127.9, 124.8, 112.3, 112.1, 111.0, 103.4, 103.1, 55.9, 40.4; MS m/z 293
(M+).
References and notes
1q: Mp: 174.0–175.0 °C; IR (KBr): 3409, 1602, 1519, 1201, 1183, 819 cmꢀ1 1H
;
NMR (CDCl3, 400 MHz) d 7.38 (d, 2H, J = 8.6 Hz), 7.33 (d, 1H, J = 8.9 Hz), 7.2 (d,
1H, J = 16.1 Hz), 6.97 (d, 1H, J = 2.5 Hz), 6.83 (dd, 1H, J = 2.6, 8.8 Hz), 6.77 (d, 1H,
J = 16.1 Hz), 6.61 (d, 2H, J = 8.5 Hz), 6.51 (s, 1H), 3.85 (s, 3H), 2.88 (s, 3H), 1.55
d 156.8, 155.8, 149.7, 149.3, 130.5,
130.0, 128.0, 125.8, 112.4, 112.4, 111.0, 103.4, 103.0, 55.9, 30.5; MS m/z 279
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3. Gandy, S. J. Clin. Invest. 2005, 115, 1121.
(s, 3H); 13C NMR (CDCl3, 100 MHz)
4. Hardy, J.; Selkoe, D. J. Science 2002, 297, 353.
(M+).