Adamantyl N-benzylbenzamide: New series of depigmentation agents with tyrosinase inhibitory activity

Article abstract of DOI:10.1016/j.bmcl.2011.12.144

A new series of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety has been synthesized, and the depigmenting and tyrosinase inhibitory activities of the molecules were evaluated. The lipophilic character of the adamantyl moiety

Full text of DOI:10.1016/j.bmcl.2011.12.144

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2110–2113
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Adamantyl N-benzylbenzamide: New series of depigmentation agents
with tyrosinase inhibitory activity
Heung Soo Baek, Yong Deog Hong, Chang Seok Lee, Ho Sik Rho, Song Seok Shin, Young-Ho Park,
⇑
Yung Hyup Joo
Dermatological Drug Research, Medical Beauty Research Institute, AmorePacific Corporation R&D Center, 314-1 Bora-dong, Kiheung-gu, Yongin-si, Kyounggi-do 446-729, Republic
of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety has
been synthesized, and the depigmenting and tyrosinase inhibitory activities of the molecules were eval-
uated. The lipophilic character of the adamantyl moiety appeared to confer greater depigmentation
power on the benzamide derivatives as compared to those lacking adamantyl substitution. Molecular
modeling was applied in order to elucidate the interactions between ligands and tyrosinase that led to
inhibition.
Received 13 September 2011
Revised 19 December 2011
Accepted 21 December 2011
Available online 11 January 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Depigmentation
Tyrosinase inhibitor
Adamantane moiety
The role of melanin is to protect the skin from the harmful
effects of ultraviolet light and scavenging free radicals. In addition,
the quantity of melanin in keratinocytes is an important determi-
nant of skin color in humans. Excess production of melanins from
melanocytes can lead to hyperpigmentation, which can manifest as
melasma, freckles, and dark-spots.1,2
Melanin synthesis is accelerated by external stimuli such as
ultraviolet light and inflammation, and therefore melanin forma-
tion can be controlled by reducing harmful stimuli and blocking
signal transmission. However, there is a third means of control
through the suppression of tyrosinase, a key enzyme in melanin
biosynthesis.3–5
Tyrosinase inhibition is the main strategy for treating hyperpig-
mentation, and is widely applied to not only the treatment of
dermatological disorders but also to the preservation of food color
by the reduction of browning.6,7 Thus, there is considerable inter-
est in the development of new tyrosinase inhibitors with improved
potency for use as depigmenting agents. However, it has proven
difficult to develop tyrosinase inhibitors that have sufficient
clinical efficacy as well as in vitro efficacy. Indeed, most known
depigmenting agents currently in use have unsatisfactory efficacy
in humans, in addition to low stability, and skin irritation (Fig. 1).7,8
In order to obtain a significantly more effective agent, we
sought to develop a small molecule possessing both anti-melano-
genic activity and tyrosinase inhibition, which we anticipate will
possess substantial clinical efficacy in skin depigmentation.
There are many reports on polyhydroxy tyrosinase inhibitors
from various natural and synthetic sources, such as flavonoids,
aurones, stilbenes, benzyl benzoates, N-benzylbenzamides,
chalcones, biaryls, etc.4,9–14 Among natural sources, the extract of
Broussonetia kazinoki contains a 1,3-diphenylpropane skeleton
which gives rise to kazinols and broussonins, which have a
1,3-diaryl skeleton with polyhydroxyl and prenyl substituents.15
In our ongoing research into depigmenting agents, we took no-
tice of polyhydroxy compounds containing an adamantane moiety
and became interested in the influence of this group on melanin
formation. 16–18 Consequently, we used a kazinol mimic as our syn-
thetic starting point and proceeded by exchanging the C3-alkyl
chain for an alkylamide and introducing dihydroxyl and adamantyl
moieties in place of a prenyl group.
The adamantyl substituted benzamide derivatives were synthe-
sized via the route outlined in Scheme 1. First, alkylation of
hydroxybenzoic acid 1 under acidic conditions gave adamantyl
derivatives 2 in good yield. Then intermediates 2 were subjected
to N-hydroxysuccinimide (HOSu)/DCC coupling conditions,
followed by reaction with 2,4-dihydroxybenzylamine HCl salt to
afford the desired N-benzylbenzamides 3. A detailed procedure for
the synthesis of 5-adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-2,
4-dihydroxy-benzamide (3a) is presented in Ref. 19 in order to
illustrate an application of Scheme 1.
The benzamide analogues were tested for their ability to inhibit
melanogenesis in a murine melanoma cell line (B16) and evaluated
for mushroom tyrosinase inhibition activity.
The benzylbenzamides 3d–f lacking an adamantyl group on the
ring displayed submicromolar tyrosinase inhibition, which
⇑
Corresponding author.
E-mail addresses: yunghjoo@gmail.com, yunghyupjoo@hanmail.net (Y.H. Joo).
A
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.144

H. S. Baek et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2110–2113
2111
O
HO
OH
HO
HO
O
O
OH
OH
HO
OH
HO
HO
OH
O
Hydroquinone
Arbutin
Rucinol
Kojic acid
Figure 1. Structure of known depigmenting agents.
makes them over 30 times more potent than kojic acid.
Remarkably, masking the free OH with CH3 on ring A, as in
compounds 3e and 3f, did not diminish their inhibitory activities
(Table 1). In the presence of the sterically hindered adamantyl
group on ring A, compounds 3a–c exhibited lightly lower, but still
potent, tyrosinase inhibitions. Furthermore, compounds 3g and 3h
lacking the 2-OH substituent on ring A, showed activities similar to
those of compounds 3a–f. Despite the presence of the substituted
2,4-resorcinol structure on ring A, which resembles the potent
tyrosinase inhibitor rucinol, the adamantyl substitution did not
influence the tyrosinase inhibition activity. Therefore, based on
these SAR studies, the pharmacophore for this benzylbenzamide
series appeared to be contained in ring B. When substituents on
ring B were changed from 20,40-dihydroxy to 20,40-dimethoxy,
20-hydroxy, and 40-hydroxy, respectively, compounds 3i–k, lost
than compound 3a. Compound 3a, conversely, has a greater contri-
bution from hydrophobic interactions as compared with com-
pound 3d, making compound 3a less soluble. The docking scores
agreed well with the observed in vitro data in error bound analysis.
In addition, a
found, and the position of the aromatic ring was nearly identical to
that of superimposed -tyrosine. However, the binding mode of
p–p interaction between each ligand and His194 was
L
compound 3i was significantly different from the others, as shown
in Figure 2. It completely lost the important interaction between
the methoxy groups of the ligand and Cu(B), and the H-bonding
interaction with peroxide in the active site. The docking analysis
indicated that it was bound just outside of the binding pocket, on
the surface of the protein. This binding mode explains the loss of
tyrosinase inhibition activity in compound 3i.
Depigmenting activities for compounds 3d–f showed moderate
their tyrosinase inhibitory activities (<5% at 1
lM), indicating that
to good melanogenesis inhibition (IC50 = 10–30
lM), which are
the position and numbers of free hydroxyl groups on ring B are
critical for inhibitory activity in this benzylbenzamide series.
In order to understand the binding modes of compounds 3a and
3d with mushroom tyrosinase, docking studies were performed
using Surflex-Dock20 v.2.51 in the SYBYL-X 1.2 program (TRIPOS,
L.P. St. Louis, MO, USA). The crystal structure of the oxy form of
tyrosinase was obtained from the Protein Data Bank (PDB code
1wx2).21 The caddie protein (ORF378) and water molecules were
removed. Hydrogen atoms were added to the enzyme using SYBYL.
The docked conformations with the highest docking scores were
selected for further analysis of binding modes. The binding modes
of compounds 3a and 3d were quite similar to that of the superim-
similar to that of rucinol (IC50 = ꢀ20 M). Compared with the re-
l
sults of the tyrosinase inhibition study, the melanogenesis inhibi-
tion capacity of these compounds appeared to be relatively weak
in the cell-based environments. To improve depigmenting activity
of the compounds, we sought to change their physicochemical
properties, particularly hydrophobicity, which seemed to be crucial
to biological activity in the cell.
Our previous research indicated that the adamantyl group of
the diphenolic compound has some influence on melanin forma-
tion.17 Therefore, we selected this highly lipophilic group as a
means in increase hydrophobicity in ring A instead of t-butyl or
the naturally abundant prenyl group. Introduction of a 5-adaman-
tyl group to compounds 3d–f changed the lipophilicity parameter
posed L-tyrosine from Tyr98 of the caddie protein (ORF378) as
shown in Figure 2.
(DClogP = 4–5), and as a result, the melanogenesis inhibition of
For both docked ligands, interactions between the oxygen
atoms of the ligands and Cu(B) were found to interact within
2.6 Å. Moreover, both docked conformations formed an H-bonding
interaction with peroxide in the active site. In the binding pocket,
H-bonding interactions were also formed between each docked li-
gands and residues Asn191, and Ala202. Table 2 shows that com-
pound 3d has a stronger contribution from polar interactions
compounds 3a–c increased in a manner corresponding to the in-
crease of ClogP.22 Compounds 3b and 3c exhibited potent depig-
menting activities with IC50 = 1.8 and 1.1
making these compounds about 200 times more potent than kojic
acid. Although compound 3a showed 90% inhibition at 3 M, its
cytotoxicity was also quite high (62% viability at 10 M, 86% viabil-
M), and unfortunately its inhibitory activity was less than
lM, respectively,
l
l
ity at 1
l
A ring
R1
B ring
R4
R1
O
O
R1
O
'
2
a
b,c
N
H
OH
OH
R2O
R5
R2O
R2O
'
4
R3
R3
3a-3k
2
1
R1=H, OH, OMe
R2=H, Me
R3=H, 1-adamantyl
R4,R5=H, OH, OMe
Scheme 1. General reagents and conditions: (a) 1-Adamantanol, c-H2SO4/AcOH, CH2Cl2, rt; (b) HOSu, DCC, dioxane, rt; (c) Amine (salt), NaHCO3, H2O/50–60 °C, 2–4 h.

2112
H. S. Baek et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2110–2113
Table 1
Tyrosinase inhibitory and anti-melanogenic activity of polyphenolic benzamides 3a–k
Compounds R1
R2
R3
R4
R5
Tyrosinase inhibitiona (IC50
,
l
M) Melanogenesis inhibitiona (IC50
,
lM) Cytotoxicity [viability (%@ 10 lM,72 h)]
3a
3b
3c
3d
3e
3f
3g
3h
OH
OH
OMe Me Ad
H
Adb OH
OH
OH
OH
OH
OH
OH
OH
OH
1.1
0.8
0.9
0.9
0.3
0.4
0.9
1.4
<5%c
1.8
1.1
62 0.02{86 6.3}d
100 18
Me Ad
OH
OH
OH
OH
OH
OH
OH
95
7
OH
OH
H
Me
H
H
26.7
27.6
14.2
<5%c
<5%c
100
2
93 5.3
OMe Me
H
100
2
H
H
Ad
41 0.04{99 2.1}d
H
Me Ad
44 0.2{100 3.2}d
e
3i
3j
OH
OH
OH
H
H
H
Ad
Ad
Ad
OMe OMe <5%c
OH
H
—
—
—
—
H
OH
<5%c
<5%c
32
—
—
500
3k
Kojic acid
100 3.4
a
b
c
Value is the mean of at least two measurements.
1-Adamantyl.
% inhibition at 1 lM.
d
e
Figures in parentheses refer to viability % at 1
lM.
Not tested.
Figure 2. Docking positions of compounds 3a (green), 3d (blue), and 3i (yellow) with superimposed L-tyrosine (purple) from Tyr98 of the caddie protein (ORF378).
Altogether, greater lipophilicity of the molecule improved its
depigmenting effect in these compounds, but also seemed to cause
a decrease in cell viability.
Table 2
Docking scores and the contributions of polar interactions
In summary, we prepared a series of potent anti-melanogenic
agents while preserving tyrosinase inhibitory activity by modulat-
ing the physicochemical properties of the molecules. We deter-
mined that modulation of molecular lipophilicity by modification
via hydrophobic functional groups is important for enhanced
depigmenting activity without a concomitant increase in cytotox-
icity, and the selection of the position and numbers of OH is critical
for tyrosinase inhibitory activity. Among these analogues, com-
pound 3c was selected for in vivo efficacy evaluation and we are
investigating further modification of this scaffold as depigmenting
agent for practical use.
Compounds
Surflex-Dock scorea
Polar contribution
3a
3d
3i
6.98
5.81
4.02
2.25
3.15
1.02
a
Surflex-Dock score represents the binding affinity in units of ꢁlogKd.
5% at a 1 lM concentration. In compounds 3a, 3g and 3h, the
5-adamantyl group appeared to influence cell viability, and the
absence of the 2-OH on ring A seemed to negatively affect the
anti-melanogenesis activity when the 2,4-OH on B ring is present.

H. S. Baek et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2110–2113
2113
128.9, 116.0, 112.3, 105.9, 102.6, 96.8, 56.1, 55.4, 40.3, 38.4, 36.4, 35.8, 28.3:
HRMS (FABꢁ) [MꢁH]ꢁ calcd for C26H30NO5 436.2124 found 436.2119.
N-(2,4-Dihydroxy-benzyl)-2,4-dihydroxy-benzamide (3d): 1H NMR (300 MHz,
DMSO-d6) d 12.71 (s, 1H), 10.00 (s, 1H), 9.39 (s, 1H), 9.08 (s, 1H), 8.75 (m, 1H),
7.73 (d, 1H, J = 8.4 Hz), 6.89 (d, 1H, J = 8.7 Hz), 6.24 (m, 3H), 6.15 (d, 1H,
J = 8.7 Hz), 4.29 (d, 2H, J = 5.4 Hz): 13C NMR (125 MHz, DMSO-d6) d 168.8,
162.0, 161.9, 157.3, 155.7, 129.3, 115.4, 106.9, 105.9, 102.6, 102.3, 37.3: HRMS
(FABꢁ) [MꢁH]ꢁ calcd for C14H12NO5 274.0715 found 274.0713.
References and notes
1. Gupta, A. K.; Gover, M. D.; Nouri, K. N.; Taylor, S. J. Am. Acad. Dermatol. 2006, 55,
1048.
2. Dalton, S. R.; Gardner, T. L.; Libow, L. F.; Elston, D. M. J. Am. Acad. Dermatol.
2005, 52, 859.
3. Seo, S.-Y.; Sharma, V. K.; Sharma, N. J. Agric. Food Chem. 2003, 51, 2837.
4. Kim, Y.-J.; Uyama, H. Cell. Mol. Life Sci. 2005, 62, 1707.
5. Marmol, V. D.; Beermann, F. FEBS Lett. 1996, 381, 165.
6. Solano, F.; Briganti, S.; Picardo, M.; Ghanem, G. Pigment Cell Res. 2006, 19, 550.
7. Briganti, S.; Camera, E.; Picardo, M. Pigment Cell Res. 2003, 16, 101.
8. Smth, C. J.; O’Hare, K. B.; Alle, J. C. Pigment Cell Res. 1988, 1, 386.
9. Song, K.-K.; Huang, H.; Han, P.; Zhang, C.-L.; Shi, Y.; Chen, Q.-X. Biochem.
Biophys. Res. Commun. 2006, 342, 1147.
10. Fang, Y.; Chen, Y.; Feng, G.; Ma, L. Bioorg. Med. Chem. 2011, 19, 1167.
11. Cho, S. J.; Roh, J. S.; Sun, W. S.; Kim, S. H.; Park, K. D. Bioorg. Med. Chem. Lett.
2006, 16, 2682.
12. Khatib, S.; Nerya, O.; Musa, R.; Shmuel, M.; Tamir, S.; Vaya, J. Bioorg. Med. Chem.
2005, 13, 433.
13. Sapkota, K.; Roh, E.; Lee, E.; Ha, E.-M.; Yang, J.-H.; Lee, E.-S.; Kwon, Y.; Kim, Y.;
Na, Y. Bioorg. Med. Chem. 2011, 19, 2168.
14. Okombi, S.; Rival, D.; Bonnet, S.; Mariotte, A.-M.; Perrier, E.; Boumendjel, A. J.
Med. Chem. 2006, 49, 329.
N-(2,4-Dihydroxy-benzyl)-2-hydroxy-4-methoxy-benzamide (3e): 1H NMR
(300 MHz, DMSO-d6) d 12.91 (s, 1H), 9.40 (s, 1H), 9.12 (s, 1H), 8.86 (m, 1H),
7.85 (d, 1H, J = 8.7 Hz), 6.90 (d, 1H, J = 8.7 Hz), 6.44 (m, 2H), 6.28 (s, 1H), 6.16 (d,
1H, J = 8.1 Hz), 4.31 (d, 2H, J = 5.1 Hz), 3.76 (s,3H): 13C NMR (125 MHz,DMSO-
d6) d 168.7, 163.3, 162.2, 157.3, 155.7, 129.3, 129.1, 115.2, 108.1, 105.9, 105.7,
102.3, 101.1, 55.2, 37.3: HRMS(FABꢁ) [MꢁH]ꢁ calcd for C15H14NO5 288.0872
found 288.0871.
N-(2,4-Dihydroxy-benzyl)-2,4-dimethoxy-benzamide (3f): 1H NMR (300 MHz,
DMSO-d6) d 9.65 (s, 1H), 9.13 (s, 1H), 8.52 (m, 1H), 7.87 (d, 1H, J = 8.4 Hz), 6.93
(d, 1H, J = 8.7 Hz), 6.63 (m, 2H), 6.28(s, 1H), 6.16 (d, 1H, J = 8.1 Hz), 4.30 (d, 2H,
J = 5.7 Hz), 3.90 (s, 3H), 3.81 (s, 3H): 13C NMR (125 MHz, DMSO-d6) d 164.2,
162.9, 158.6, 157.5, 156.1, 132.5, 129.8, 115.9, 114.1, 105.9, 105.7, 102.6, 98.5,
56.0, 55.4, 38.4: HRMS (FABꢁ) [MꢁH]ꢁ calcd for C16H16NO5 302.1028 found
302.1028.
3-Adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-4-hydroxy-benzamide (3g): 1H
NMR (300 MHz, DMSO-d6) d 9.87 (s, 1H), 9.64 (s, 1H), 9.09 (s, 1H), 8.73 (m, 1H),
7.58 (m, 2H), 6.89 (d, 1H, J = 8.1 Hz), 6.77 (d, 1H, J = 7.8 Hz), 6.18 (m, 2H), 4.25
(m, 2H), 2.07 (s, 9H), 1.72 (s, 6H): 13C NMR (125 MHz, DMSO-d6) d 167.2, 159.0,
157.4, 155.9, 135.0, 129.9, 126.2, 126.0, 124.2, 116.2, 115.8, 106.0, 102.7, 38.0,
36.5, 36.2, 28.2: HRMS(FABꢁ) [MꢁH]ꢁ calcd for C24H26NO4 392.1862 found
392.1857.
15. Baek, Y. S.; Ryu, Y. B.; Curtis-Long, M. J.; Ha, T. J.; Rengasamy, R.; Yang, M. S.;
Park, K. H. Bioorg. Med. Chem. 2009, 17, 35.
16. Rho, H. S.; Baek, H. S.; Lee, B.-S.; Kim, J. H.; Kim, D. H.; Chang, I. S. Bull. Korean
Chem. Soc. 2006, 27, 115.
17. Rho, H. S.; Baek, H. S.; Ahn, S. M.; Yoo, J. W.; Kim, D. H.; Kim, H. G. Bioorg. Med.
Chem. Lett. 2009, 19, 1532.
18. Rho, H. S.; Goh, M.; Lee, J.; Ahn, S. M.; Yeon, J.; Yoo, D. S.; Kim, D. H.; Kim, H. G.;
Cho, J. Y. Bull. Korean Chem. Soc. 2011, 32, 1411.
3-Adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-4-methoxy-benzamide (3h): 1H
NMR (300 MHz, DMSO-d6) d 9.58 (s, 1H), 9.09 (s, 1H), 8.81 (t, 1H, J = 5.4 Hz),
7.73 (m, 2H), 7.02 (d, 1H, J = 8.4 Hz), 6.90 (d, 1H, J = 8.1 Hz), 6.18 (m, 2H), 4.26
(d, 2H, J = 5.7 Hz), 3.84 (s, 3H), 2.05 (s, 9H), 1.73 (s, 6H): 13C NMR (125 MHz,
DMSO-d6) d 166.8, 160.8, 157.4, 155.8, 137.0, 129.8, 126.5, 125.6, 116.1, 111.4,
106.0, 102.7, 55.3, 39.9, 38.0, 36.5, 36.4, 28.2: HRMS(FABꢁ) [MꢁH]ꢁ calcd for
19. Selected compounds were prepared as follows.
5-Adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dihydroxy-benzamide (3a):
5-Adamantan-1-yl-2,4-dihydroxybenzoic acid (0.606 g, 2.1 mmol), N-
hydroxy-succinimide (0.24 g, 2.1 mmol), and N,N’-dicyclohexyl-carbodiimide
(0.433 g, 2.1 mmol) were dissolved in 1,4-dioxane (5 mL) under nitrogen
atmosphere. The solution was stirred at ambient temperature for 12 h. The
C25H28NO4 406.2018 found 406.2019.
5-Adamantan-1-yl-N-(2,4-dimethoxy-benzyl)-2,4-dihydroxy-benzamide (3i):
1H NMR (300 MHz, DMSO-d6) d 12.48 (s, 1H), 9.92 (s, 1H), 8.86 (m, 1H), 7.48
(s, 1H), 7.07 (d, 1H, J = 8.1 Hz), 6.56 (m, 1H), 6.48 (m, 1H), 6.18 (m, 2H), 6.27 (s,
1H), 4.35 (d, 2H, J = 5.4 Hz), 3.80 (s, 3H), 3.73 (s, 3H), 2.03 (s, 9H), 1.71 (s, 6H):
13C NMR (125 MHz, DMSO-d6) d 169.1, 160.8, 159.5, 157.5, 128.4, 127.6, 125.7,
118.9, 106.3, 104.4, 103.7, 98.2, 55.3, 55.1, 40.2, 36.7, 36.6, 35.8, 28.3: HRMS
(FABꢁ) [MꢁH]ꢁ calcd for C26H30NO5 436.2124 found 436.2129.
5-Adamantan-1-yl-2,4-dihydroxy-N-(2-hydroxy-benzyl)-benzamide (3j): 1H
NMR (300 MHz, DMSO-d6) d 12.42 (s, 1H), 9.93 (s, 1H), 9.56 (s, 1H), 8.86 (m,
1H), 7.50 (s, 1H), 7.10 (m, 2H), 6.79 (m, 2H), 6.28 (s, 1H), 4.40 (d, 2H, J = 5.1 Hz),
2.03 (s, 9H), 1.71 (s, 6H): 13C NMR (125 MHz, DMSO-d6) d 169.3, 160.9, 159.4,
154.7, 128.1, 127.7, 125.8, 125.1, 118.7, 114.9, 106.2, 103.7, 40.2, 37.4, 36.6,
35.8, 28.3: HRMS (FABꢁ) [MꢁH]ꢁ calcd for C24H26NO4 392.1862 found
392.1859.
precipitate was filtered off and the filtrate added to
a solution of 2,4-
dihydroxybenzylamine HCl salt (0.406 g, 2.3 mmol) and NaHCO3 (0.177 g,
2.3 mmol) in H2O (2 mL). The reaction mixture was heated to 60 °C under
nitrogen and stirred for 2 h. After cooling to room temperature, 10% HCl
solution was added and the mixture extracted with EtOAc. The combined
organic layers were washed with brine, dried under anhydrous MgSO4, and
filtered, and the filtrate was evaporated in vacuo. The crude product was
purified by column chromatography (hexanes–EtOAc = 2:1) to yield compound
3a as a white solid (0.24 g, 30%): 1H NMR (300 MHz, DMSO-d6) d 12.41 (s, 1H),
9.91 (s, 1H), 9.40 (s, 1H), 9.09 (s, 1H), 8.83 (m, 1H), 7.47 (s, 1H), 6.89 (d, 1H,
J = 8.1 Hz), 6.26 (s, 2H), 6.16 (d, 1H, J = 8.1 Hz), 4.29 (m, 2H), 2.02 (s, 9H), 1.70
(s, 6H): 13C NMR (125 MHz, DMSO-d6) d 169.1, 160.8, 159.3, 157.3, 155.7,
129.4, 127.6, 125.8, 115.6, 106.3, 105.9, 103.6, 102.4, 40.2, 37.2, 36.5, 35.8,
28.3: HRMS (FABꢁ) [MꢁH]ꢁ calcd for C24H26NO5 408.1811 found 408.1810.
5-Adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-2-hydroxy-4-methoxy-benz-
amide (3b): 1H NMR (300 MHz, DMSO-d6) d 12.73 (s, 1H), 9.40 (s, 1H), 9.11 (s,
1H), 8.95 (m, 1H), 7.52 (s, 1H), 6.90 (d, 1H, J = 8.4 Hz), 6.43 (s, 1H), 6.28 (s, 1H),
6.17 (d, 1H, J = 8.4 Hz), 4.31 (d, 2H, J = 5.4 Hz), 3.79 (s, 3H), 2.00 (s, 9H), 1.71 (s,
6H): 13C NMR (125 MHz, DMSO-d6) d 169.1, 162.5, 160.1, 157.3, 155.7, 129.3,
128.9, 125.3, 115.5, 106.8, 105.9, 102.4, 100.3, 55.2, 40.4, 37.2, 36.5, 36.1, 28.3:
HRMS (FABꢁ) [MꢁH]ꢁ calcd for C25H28NO5 422.1967 found 422.1966.
5-Adamantan-1-yl-2,4-dihydroxy-N-(4-hydroxy-benzyl)-benzamide (3k): 1H
NMR (300 MHz, DMSO-d6) d 12.68 (s, 1H), 9.94 (s, 1H), 9.26 (s, 1H), 8.98 (m,
1H), 7.42 (s, 1H), 7.11 (d, 2H, J = 8.1 Hz), 6.70 (d, 2H, J = 8.1 Hz), 6.24 (s, 1H),
4.33 (m, 2H), 2.02 (s, 9H), 1.70 (s, 6H): 13C NMR (125 MHz, DMSO-d6) d 169.4,
160.9, 160.0, 156.2, 129.6, 128.6, 127.6, 125.3, 114.9, 105.9, 103.7, 41.6, 40.2,
36.6, 35.9, 28.3: HRMS (FABꢁ) [MꢁH]ꢁ calcd for C24H26NO4 392.1862 found
392.1863.
20. Jain, A. N. J. Med. Chem. 2003, 46, 499.
21. Matoba, Y.; Kumagai, T.; Yamamoto, A.; Yoshitsu, H.; Sugiyama, M. J. Biol. Chem.
2006, 281, 8981.
22. ClogP values were calculated by Chem Draw 12.0v. ClogP for compounds 3a–f:
5.68, 6.42, 5.89, 1.50, 1.13, 1.60.
5-Adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzamide (3c):
1H NMR (300 MHz, DMSO-d6) d 9.67 (s, 1H), 9.13 (s, 1H), 8.51 (m, 1H), 7.78 (m,
1H), 6.92 (d, 1H, J = 8.1 Hz), 6.66 (s, 1H), 6.27 (s, 1H), 6.16 (d, 1H, J = 8.1 Hz),
4.30 (d, 2H, J = 5.4 Hz), 3.93 (s, 3H), 3.88 (s, 3H), 1.98 (s, 9H), 1.71 (s, 6H): 13C
NMR (125 MHz, DMSO-d6) d 164.7, 161.8, 157.5, 156.9, 156.1, 129.9, 129.7,