Design and synthesis of curcumin derivatives as tau and amyloid β dual aggregation inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.08.092

Alzheimer's disease (AD) is the most common form of dementia. In an AD patient's brain, senile plaques and neurofibrillary tangles, the abnormal aggregates of amyloid β (Aβ) peptide and tau protein, are observed as the two major hallmarks of this disease.

Full text of DOI:10.1016/j.bmcl.2016.08.092

Accepted Manuscript
Design and synthesis of curcumin derivatives as tau and amyloid β dual aggre-
gation inhibitors
Michiaki Okuda, Ichiro Hijikuro, Yuki Fujita, Takayuki Teruya, Hirochika
Kawakami, Takashi Takahashi, Hachiro Sugimoto
PII:
S0960-894X(16)30925-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.08.092
BMCL 24218
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
22 June 2016
28 August 2016
30 August 2016
Please cite this article as: Okuda, M., Hijikuro, I., Fujita, Y., Teruya, T., Kawakami, H., Takahashi, T., Sugimoto,
H., Design and synthesis of curcumin derivatives as tau and amyloid β dual aggregation inhibitors, Bioorganic &
Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.08.092
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Bioorganic & Medicinal Chemistry Letters
jo u r n a l h o m e p a g e : w w w . e ls e v i e r . c o m
Design and synthesis of curcumin derivatives as tau and amyloid β dual
aggregation inhibitors
Michiaki Okudaa,b,*, Ichiro Hijikuroc,1, Yuki Fujitaa,b, Takayuki Teruyab,2, Hirochika Kawakamib,3, Takashi
Takahashid, and Hachiro Sugimotoa
aGraduate School of Brain Science, Doshisha University, 4-1-1 Kizugawadai, Kizugawa, Kyoto, 619-0225, Japan
bPharma Eight Co., Ltd., Creation Core Kyoto Mikuruma, 448-5 Kajii-cho, Kamigyo-ku, Kyoto 602- 0841, Japan
cChemGenesis Inc. 4-10-2, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan
dYokohama College of Pharmacy, Natural Product Chemistry & Pharmaceutical Research Center, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa 245-
0066, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Alzheimer’s disease (AD) is the most common form of dementia. In an AD patient’s brain,
senile plaques and neurofibrillary tangles, the abnormal aggregates of amyloid β (Aβ) peptide
and tau protein, are observed as the two major hallmarks of this disease. To develop a new drug
for treatment of AD, we have designed and synthesized a series of curcumin derivatives and
evaluated their inhibitory activities against both tau and Aβ aggregation. In this study, we
describe the development of the more potent aggregation inhibitor 3-[(1E)-2-(1H-indol-6-
yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)
phenyl]
ethenyl]-1H-pyrazole
Keywords:
(compound 4, PE859). This compound has a better pharmacokinetic profile and pharmacological
efficacy in vivo than curcumin, making it suitable as a drug for AD.
Alzheimer’s disease
Tau
Amyloid β
Aggregation inhibitor
Curcumin
2016 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD), a neurodegenerative disease, is the
most common form of dementia. The number of worldwide
patients with dementia today is estimated at 44 million, and more
than half of them are AD.1 The currently available drugs for AD
are limited to symptomatic treatment such as the
acetylcholinesterase inhibitors, Donepezil, rivastigmine, and
galantamine, and the N-methyl-d-aspartate (NMDA) receptor
antagonist memantine.2 Therefore, new fundamental therapeutic
approaches are required.
Aβ, especially Aβ oligomers, show neurotoxicity.7 Aβ further
aggregates and eventually forms SP. Therefore, Aβ is widely
believed to be fundamental in the onset or progression of AD. In
fact, many of the following therapeutic studies on Aβ cascade are
ongoing: the inhibition of Aβ production, promotion of Aβ
clearance, and inhibition of Aβ aggregation;8 however, recent
clinical trials targeting Aβ have not yet been successfully
developed. In contrast, tau is a microtubule-associated protein
that plays a fundamental role in the stabilization of microtubules.
In AD and tauopathies, hyperphosphorylated tau proteins
dissociate from microtubules and aggregate into NFT. The NFT
formation correlates with the progression of neuronal dysfunction,
and the severity of AD is positively related to the number of
NFTs.9 Furthermore, oligomeric tau is more toxic than other
forms, just like Aβ.10
Pathologically, senile plaques (SP) composed of amyloid β
(Aβ) peptide and neurofibrillary tangles (NFT) composed of tau
4
protein are known as the two major hallmarks of AD.3, SP
appear in the brain several years prior to the onset of AD.5 Aβ is
generated from an amyloid precursor protein (APP) through
proteolytic cleavage by β-secretase and γ-secretase.6 Aggregated
We proposed that a dual inhibitor on both Aβ and tau cascades
should be more effective in treating AD than existing inhibitors
of Aβ or tau alone. Thus, we have designed and synthesized
curcumin derivatives and performed screenings for more potent
inhibitors on both Aβ and tau aggregation. The seed compound
curcumin, 1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-
3,5-dione, is the main component in the rhizome of Curcuma
longa, also known as turmeric. Although curcumin has a simple
structure with two phenolic functional groups connected by a
conjugated β-diketone system, it exhibits a variety of biological
activities. For example, curcumin is an anti-inflammatory,11
_____________
 Corresponding author. Tel.: +81-774-65-7498; fax: +81-774-65-7498;
e-mail: jt-liaay@mail.doshisha.ac.jp
1 Farnex Inc., 4259-3 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa
226-8510, Japan
2 Okinawa Institute of Science and Technology Graduate University,
1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa, 904-0495, Japan
3 Ig-M Co., Ltd. 4-1-1, Minatojima-nakamachi, Chuo-ku, Kobe, Hyogo
650-0046, Japan

Scheme 1
antioxidant,12 anti-cancer,13 anti-HIV integrase,14 anti-
compounds had higher inhibitory activities than curcumin.
Symmetric structures may decrease the inhibitory activities
composed of asymmetric compounds. For example, the
symmetric compound with the structure of 1f (compound 1j; data
not shown) had lower activities than 1f, which had IC50 values of
4.6 μM for Aβ aggregation and >10 μM for tau aggregation.
angiogenic,15 and antibacterial compound.16 Additionally,
curcumin has inhibitory effects on the pathology of AD, such as
γ-secretase
activity,17
β-secretase
upregulation,18
Aβ
aggregation,19 and tau aggregation.20 Although curcumin has such
therapeutic activities, it is unsuitable for clinical use due to its
poor solubility, stability, and bioavailability.21 We developed the
novel curcumin derivative PE859 (3-[(1E)-2-(1H-indol-6-
yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy) phenyl]
ethenyl]-1H-pyrazole, compound 4) as a potent inhibitor of both
tau and Aβ aggregation with a good pharmacokinetic profile.
Previously, we introduced the inhibitory effect of PE859 on tau
aggregation.22 In this study, we described the development of
PE859 through the structure–activity relationships study of
curcumin and its derivatives.
Table 1. Structure and inhibition data of curcumin and
compounds 1a–i.
O
O
R1
OH
C
H CO
3
3
Aggregation Inhibition
IC50 (µM)
HO
HO
R1
Aβ
Tau
OCH3
OH
Inhibitory activity against tau and Aβ aggregation was
determined using a thioflavin T (ThT) fluorescence assay.23 ThT
specifically binds to the β-sheet structure of the protein. It is
reported that curcumin breaks the β-sheet structure of Aβ
aggregates.24 Several studies of curcumin analogues as Aβ and
tau aggregation inhibitors are published25,26 and these curcumin
analogues are presumed to break the β-sheet structure of Aβ or
tau aggregates, like curcumin. In our assay, curcumin had IC50
values of 5.4 μM for Aβ aggregation and 3.0 μM for tau
aggregation (Table 1).
Curcumin
5.4 ± 0.3
3.0 ± 0.4
OH
OCH3
1a
1b
1c
1d
1e
1f
5.4 ± 0.3
1.9 ± 0.3
2.1 ± 0.2
1.6 ± 0.2
1.3 ± 0.2
0.92 ± 0.4
1.8 ± 0.4
1.1 ± 0.3
0.69 ± 0.04
0.71 ± 0.04
0.52 ± 0.11
0.91 ± 0.09
0.60 ± 0.05
0.58 ± 0.04
0.92 ± 0.03
0.32 ± 0.02
OCH3
OH
OH
OCH3
OCH3
A series of asymmetric curcumin derivatives 1a–i (Table 1),
2a–f (Table 2), 3a–e (Table 3) were synthesized in two steps as
indicated in Scheme 1. Common starting material, acetylacetone
was reacted with each aromatic aldehyde (Ar1-CHO) in the
presence of boron oxide, trialkyl borate (tributyl borate or
triisopropyl borate) followed by the addition of amine (n-
butylamine or piperidine), and then treated with 1M HCl/brine to
obtain the corresponding mono-substituted intermediates.27,28
This reaction sequence was repeated for the intermediates and
each aromatic aldehyde (Ar2-CHO) to obtain 1a–i, 2a–f, 3a–e in
low to moderate yields. Pyrazole 4 (PE859, table 4) was
synthesized from 3e and hydrazine monohydrate in acetic acid in
75% yield.29,30
HO
OCH3
OH
OCH3
OH
OCH3
1g
1h
HO
OCH3
First, we synthesized curcumin derivatives where the hydroxyl
and methoxy substituents on one of the two aromatic rings were
changed (1a–i, Table 1). The results indicated that the inhibitory
activity on Aβ aggregation decreased when these substituents
were located in ortho positions each other (curcumin, 1a, 1b, and
1c) and that location of the hydroxyl substituent in ortho
positions with a carbon chain linker decreased the inhibitory
activities (1d vs. 1e or, 1f; 1g vs. 1h; 1i vs. 1c). Interestingly, all
OH
1i
0.93 ± 0.05
1.4 ± 0.3
HO
OCH3
Next, we synthesized derivatives where the aromatic ring was
replaced with other cyclic structures (2a–f, Table 2). These
results suggest that a bicyclic structure (2a–c) may increase

inhibitory activities, especially in tau aggregation, relative to the
monocyclic structures (2d–f).
The pharmacokinetic profiles of curcumin and 3e (Fig. 1) were
compared. Each compound was orally administered to rats at 50
mg/kg and concentrations in plasma were measured for up to 3 h
(Fig. 1a). The Cmax of 3e was found to be 1/20 lower than that of
curcumin (5.7 ± 3.3 ng/mL at 30 min and 125 ± 65 ng/mL at 15
min). Additionally, the concentration of 3e in the brain was 1/13
of the concentration of curcumin (Fig. 1b). These results suggest
that further structural change on 3e is required for a better
pharmacokinetic profile.
Table 2. Structure and inhibition data of compounds 2a–2f.
O
O
R2
OH
C
H CO
3
3
Aggregation Inhibition
IC50 (µM)
HO
HO
R2
Aβ
Tau
OCH3
The central diketone of curcumin is unstable in an aqueous
solution; the modification of this moiety improves the aqueous
stability.32 Additionally, the C–C bond of a β-diketone moiety is
enzymatically cleaved in vivo.33 Other studies on curcumin
derivatives indicate that the modification of the central diketone
moiety improves its pharmacokinetic profile34 and brain
permeability.35 Thus, we substituted the diketone in 3e with a
pyrazole (4, Table 4). Compound 4 had IC50 values of 1.2 μM for
Aβ aggregation and 0.66 μM for tau aggregation.
Curcumin
5.4 ± 0.3
3.0 ± 0.4
OH
O
O
2a
2b
2c
2d
2e
3.7 ± 1.4
0.59 ± 0.07
0.42 ± 0.10
2.2 ± 0.3
> 10
1.2 ± 0.2
0.42 ± 0.12
0.44 ± 0.03
1.4 ± 0.1
> 10
H
N
Table 4. Structure and inhibition data of compound 4
(PE859).
N
Aggregation Inhibition
IC50 (µM)
O
2f
0.76 ± 0.14
2.0 ± 0.01
Structure
Aβ
Tau
The results reported in Tables 1 and 2 were combined to
synthesize derivative 3a (Table 3). The moieties used in 1f and
2c were selected because these compounds had higher inhibitory
activities than curcumin. As a result, compound 3a had IC50
values of 0.52 μM for Aβ aggregation and 0.23 μM for tau
aggregation.
4
1.2 ± 0.2
0.66 ± 0.13
The plasma concentration of 4, after oral administration to rats
Previous reports have demonstrated that curcumin is subject to
conjugation of glucuronide or sulfate with hydroxyl substituents
on aromatic rings in the body.31 To protect compounds from
being metabolized, various residues were introduced to the
phenolic hydroxyl group of 3a (3b–3e, Table 3). In these
compounds, only 3e had the same level of inhibitory activities as
3a.
at 50 mg/kg, was 466 ± 123 ng/mL after 3 h, and the
concentration was still increasing (Fig. 1a). Previously, we
reported pharmacokinetics of compound 4 in mice,22 and the Tmax
of 4 occurred at 6 h in that study. After 3 h of administration,
brains were collected and concentrations of these compounds
were measured (Fig. 1b). The concentration of 4 in the brain was
~300 times higher than that of 3e and 20 times higher than that of
curcumin. To compare the metabolic stability of 3e and 4 in the
body, they were intravenously administered at 5 mg/kg and the
concentrations in plasma were measured up to 3 h (Fig. 1c). The
concentration of 4 maintained a higher level than that of 3e.
These results suggest that this modification drastically improved
its pharmacokinetic profile in vivo and that 4 has a better
pharmacokinetic profile than curcumin.
Table 3. Structure and inhibition data of compounds 3a–3e.
OCH3
O
O
H
N
Aggregation Inhibition
IC50 (µM)
3
R
R''
R3
Aβ
Tau
The efficacy of 4, in vivo, was next confirmed (Fig. 2). In the
in vivo study, we compared the efficacy of 4 to those of curcumin
and methylene blue (MB). MB is one of the best-known tau
aggregation inhibitors and phase 2 clinical trials of MB in AD
have been completed.36 Additionally, MB inhibits Aβ
aggregation in vitro.37 In our ThT fluorescence assay, MB had
IC50 values of 1.4 μM for tau aggregation and 0.50 μM for Aβ
aggregation. We administered these compounds orally to JNPL3
human tau P301L transgenic mice. In JNPL3 mice, tau proteins
abnormally aggregate and accumulate as sarkosyl-insoluble tau
in the brain.38 After a four-week administration, 4 significantly
reduced the amount of sarkosyl-insoluble tau in the brain at doses
of 20 and 40 mg/kg/day. In contrast, MB and curcumin showed
no effect on the amount of sarkosyl-insoluble tau, even at 40
mg/kg/day. These results suggest that 4 has a more potent effect
than curcumin and MB.
HO－
3a
0.52 ± 0.04
0.23 ± 0.06
H CO－
3b
3c
3d
3e
0.61 ± 0.52
2.5 ± 0.2
0.70 ± 0.05
0.42 ± 0.01
0.61 ± 0.04
0.33 ± 0.09
3
O
O
O
5.4 ± 0.2
N
O
0.47 ± 0.02

Figure 2. Inhibitory activities on tau aggregation by 4, curcumin
(Cur), and methylene blue (MB) in vivo. Each compound was
orally administered to JNPL3 human tau P301L transgenic mice
for four weeks, and sarkosyl-insoluble tau in the brain was
measured. Mean ± standard error, n = 15–16. *P < 0.05 vs.
Vehicle (Veh).
Acknowledgments
This work was financially supported by the grants of New Energy
and Industrial Technology Development Organization in Japan (no.
051039) and the Kansai Bureau of Economy, Trade and Industry in
Japan (no. 20R5022). The authors would like to thank Enago
(www.enago.jp) for the English language review.
References and notes
1.
World Alzheimer Report 2014. Alzheimer’s Disease International.
2014.
2.
National Institute on Aging, Alzheimer’s disease fact sheet. 2011.
http://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-
fact-sheet.
3.
4.
Masters, C.L.; Multhaup, G.; Simms, G.; Pottgiesser, J.; Martins, R.N.;
Beyreuther, K. EMBO J. 1985, 4, 2757.
Wischik, C. M.; Novak, M.; Thøgersen, H. C.; Edwards, P. C.;
Runswick, M. J.; Jakes, R.; Walker, J. E.; Milstein, C.; Roth, M.; Klug,
a Proc. Natl. Acad. Sci. U. S. A. 1988, 85, 4506.
Figure 1. Pharmacokinetic profile of curcumin, 3e, and 4. (a)
The concentration of compounds 3a, 4, and curcumin in plasma
after oral administration to SD rats at 50 mg/kg. (b) The
concentration of the compounds in the brain at 3 h after oral
administration. (c) The concentration of 3e and 4 in plasma after
intravenous administration to SD rats at 5 mg/kg. Mean ± SD, n
= 3.
5.
6.
7.
Braak, H.; Braak, E. Acta Neuropath. 1991, 82, 239.
Sinha, S.; Lieberburg, I. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 11049.
Lambert, M.P.; Barlow, A.K.; Chromy, B.A.; Edwards, C.; Freed, R.;
Liosatos, M.; Morgan, T.E.; Rozovsky, I.; Trommer, B.; Viola, K.L.;
Wals, P.; Zhang, C.; Finch, C.E.; Krafft, G.A.; Klein, W.L. Proc. Natl.
Acad. Sci. U S A. 1998, 95, 6448.
In conclusion, compound 4 is the best candidate for an AD
drug, as determined by this study. This compound is a more
potent both tau and Aβ dual aggregation inhibitor than curcumin
8.
9.
Pharmaceutical Research and Manufacturers of America, “Medicines
in Development for Older Americans,” 2015.
in vitro. Furthermore, this compound has
a
better
pharmacokinetic profile and potent pharmacological effect than
curcumin in vivo.
Arriagada, P.V.; Growdon, J.H.; Hedley-Whyte, E.T.; Hyman, B.T.
Neurology 1992, 42, 631.
10. Lasagna-Reeves, C.A; Castillo-Carranza, D. L.; Sengupta, U.; Clos, A.
L.; Jackson, G. R.; Kayed, R. Mol. Neurodegener. 2011, 6, 39.
11. Huang, M.T.; Lysz, T.; Ferraro, T.; Abidi, T.F.; Laskin, J.D.; Conney,
A.H. Cancer Res. 1991, 51, 813.

12. Sharma, O.P. Biochem. Pharmacol. 1976, 25, 1811.
M.; Yu, X.; Duff, K.; Hardy, J.; Corral, A.; Lin, W.L.; Yen, S.H.;
Dickson, D.W.; Davies, P.; Hutton, M. Nat. genet. 2000, 25, 402.
13. Aggarwal, B.B.; Kumar, A.; Bharti, A.C. Anticancer Res. 2003, 23,
363.
14. Mazumder, A.; Raghavan, K.; Weinstein, J.; Kohn, K.W.; Pommier,
Supplementary data
Y. Biochem. Pharmacol. 1995, 49, 1165.
Supplementary data (synthetic procedures for curcumin derivatives
reported in this letter and procedures for ThT fluorescence assay,
pharmacokinetic study and in vivo study) is available via the Internet
at http://
15. Thaloor, D.; Singh, A.K.; Sidhu, G.S.; Prasad, P.V.; Kleinman, H.K.;
Maheshwari, R.K. Cell Growth Differ. 1998, 9, 305.
16. Schraufstatter, E.; Bernt, H. Nature 1949, 164, 456.
17. Narlawar, R.; Baumann, K.; Schubenel, R.; Schmidt, B. Neurodegener.
Dis. 2007, 4, 88.
18. Shimmyo, Y.; Kihara, T.; Akaike, A.; Niidome, T.; Sugimoto, H.
Neuroreport 2008, 19, 1329.
19. Yang, F.; Lim, G.P.; Begum, A.N.; Ubeda, O.J.; Simmons, M.R.;
Ambegaokar, S.S. J. Biol. Chem. 2005, 280, 5892.
20. Ma, Q. L.; Zuo, X.; Yang, F.; Ubeda, O. J.; Gant, D. J.; Alaverdyan,
M.; Teng, E.; Hu, S.; Chen, P. P.; Maiti, P.; Teter, B.; Cole, G. M.;
Frautschy, S. A. J. Biol. Chem. 2013, 288, 4056.
21. Belkacemi, A.; Doggui, S.; Dao, L.; Ramassamy, C. Expert Rev Mol
Med 2011, 13, e34.
22. Okuda, M.; Hijikuro, I.; Fujita, Y.; Wu, X.; Nakayama, S.; Sakata, Y.;
Noguchi, Y.; Ogo, M.; Akasofu, S.; Ito, Y.; Soeda, Y.; Tsuchiya, N.;
Tanaka, N.; Takahashi, T.; Sugimoto, H. PLoS One 2015, 10.
23. Levine, H. Protein Sci. 1993, 2, 404.
24. Zhao, L. N.; Chiu, S. W.; Benoit, J.; Chew, L. Y.; Mu, Y. J. Phys.
Chem. B 2012, 116, 7428.
25. Endo, H.; Nikaido, Y.; Nakadate, M.; Ise, S.; Konno, H. Bioorganic
Med. Chem. Lett. 2014, 24, 5621.
26. Narlawar, R.; Pickhardt, M.; Leuchtenberger, S.; Baumann, K.; Krause,
S.; Dyrks, T.; Weggen, S.; Mandelkow, E.; Schmidt, B.
ChemMedChem 2008, 3, 165.
27. Pabon, H. Recl. des Trav. Chim. des Pays-Bas 1964, 83, 379.
28. Masuda, T.; Matsumura, H.; Oyama, Y.; Takeda, Y.; Jitoe, A.; Kida,
A.; Hidaka, K. J. Nat. Prod. 1998, 61, 609.
29. Flynn, D. L.; Belliotti, T. R.; Boctor, A. M.; Connor, D. T.; Kostlan, C.
R.; Nies, D. E.; Ortwine, D. F.; Schrier, D. J.; Sircar, J. C. J. Med.
Chem. 1991, 34, 518.
30. Selvam, C.; Jachak, S. M.; Thilagavathi, R.; Chakraborti, A. K.
Bioorganic Med. Chem. Lett. 2005, 15, 1793.
31. Ravindranath, V.; Chandrasekhara, N. Toxicology 1980, 16, 259.
32. Chakraborti, S.; Dhar, G.; Dwivedi, V.; Das, A.; Poddar, A.;
Chakraborti, G.; Basu, G.; Chakrabarti, P.; Surolia, A.; Bhattacharyya,
B. Biochemistry 2013, 52, 7449.
33. Grogan, G. Biochem. J 2005, 388, 721.
34. Liang, G.; Shao, L.; Wang, Y.; Zhao, C.; Chu, Y.; Xiao, J.; Zhao, Y.;
Li, X.; Yang, S. Bioorg. Med. Chem. 2009, 17, 2623.
35. Liu, Y.; Dargusch, R.; Maher, P.; Schubert, D. J. Neurochem. 2008,
105, 1336.
36. Wischik, C.; Staff, R. J Nutr Heal. Aging 2009, 13, 367.
37. Necula, M.; Breydo, L.; Milton, S.; Kayed, R.; van derVeer, WE.;
Tone, P.; Glabe, CG. Biochemistry 2007, 46, 8850.
38. Lewis, J.; McGowan, E.; Rockwood, J.; Melrose, H.; Nacharaju, P.;
Van, Slegtenhorst, M.; Gwinn-Hardy, K.; Paul, Murphy, M.; Baker,

Curcumin
Compound 4
O O
O O
OCH3
N
NH
H
N
e
e
M
M
O
O
H3CO
OCH3
N
O
HO
OH
H
H
O
O
1.2 µM
5.4 µM
3.0 µM
Aβ aggregaꢀon IC50
Tau aggregaꢀon IC50
0.66 µM
276 ng/g-ꢀssue
13 ng/g-ꢀssue
Brain concentraꢀon
(50 mg/kg p.o., at 3h)