Ketonethiosemicarbazones: Structure-activity relationships for their melanogenesis inhibition

Article abstract of DOI:10.1016/j.bmcl.2011.04.146

A series of 2-(1-phenylalkylidene)hydrazinecarbothioamides 2, 2-(1-phenylalkyl)hydrazinecarbothioamides 3, 2-(3,4-dihydronaphthalen-1(2H)- ylidene)hydrazinecarbothioamide (4), and 2-(1-(thiophen-2-yl)ethylidene) hydrazinecarbothioamide (5) were synthesize

Full text of DOI:10.1016/j.bmcl.2011.04.146

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3527–3530
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Ketonethiosemicarbazones: Structure–activity relationships for their
melanogenesis inhibition
Pillaiyar Thanigaimalai a, Ki-Cheul Lee a, Vinay K. Sharma a, Eunmiri Roh b, Youngsoo Kim b,
Sang-Hun Jung a,
⇑
a College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 305-764, Republic of Korea
b College of Pharmacy, Chungbuk National University, Cheongju 361-763, 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 series of 2-(1-phenylalkylidene)hydrazinecarbothioamides 2, 2-(1-phenylalkyl)hydrazinecarbothioa-
mides 3, 2-(3,4-dihydronaphthalen-1(2H)-ylidene)hydrazinecarbothioamide (4), and 2-(1-(thiophen-
2-yl)ethylidene)hydrazinecarbothioamide (5) were synthesized for their melanogenesis inhibition in
melanoma B16 cells. The SAR of these ketonethiosemicarbazones revealed that the benzylidene hydrogen
in aldehydethiosemicarbazones 1 can be replaced by hydrophobic moiety and substitutions with alkyl
group for the terminal amino hydrogen of ketonethiosemicarbazones improved the activity appreciably.
In addition, the double bond in thiosemicarbazones is an important factor for the increment of
hydrophobicity. Thus hydrophobic ketonethiosemicarbazones are excellent inhibitors of melanogenesis
like aldehydethiosemicarbazones.
Received 26 February 2011
Revised 30 April 2011
Accepted 30 April 2011
Available online 5 May 2011
Keywords:
Aldehydethiosemicarbazones
Ketonethiosemicarbazones
Melanogenesis inhibition
Melanoma B16
Ó 2011 Elsevier Ltd. All rights reserved.
Human skin exposure to ultraviolet (UV) irradiation can cause
sun tanning, photo aging and even photo carcinogenesis. Melanin
plays an important role in protecting the skin from UV damage.
However, the increased production and accumulation of melanin
in different specific parts of the human skin can leads to a large
number of dermatological disorders, which include acquired
hyperpigmentation such as melasma, freckles, postinflammatory
melanoderma, solar lentigo, and age spot.1,2 It is well known that
melanin is synthesized by a series of combination of enzymatic
and chemical reactions.3,4 Mainly, three melanocyte-specific en-
zymes such as tyrosinase, tyrosine related protein-1 (TYRP-1)
and tyrosine related protein-2 (TYRP-2) convert tyrosine to
melanin pigments.5 Among them, tyrosinase is involved in two rate
limiting steps of melanin synthesis, which are hydroxylation of
atives,22 oxadiazole,23 oxazolones24 and tetraketone derivative as
indicated in Figure 125 but unfortunately, only a few of these com-
pounds are used in practice because of their lower activity or se-
vere side effects. Therefore, it is still necessary to search and
discover novel melanogenesis inhibitors with higher activity and
lower side effects. Recently, our studies26,27 explored the struc-
ture–activity relationships (SAR) of a series of phenylthioureas
and aldehydethiosemicrbazones against melanogenesis in mela-
noma 16 cells. Most likely, the thiosemicarbazones (1, Fig. 2)
showed more potent activity than thioureas. The SAR of 1 showed
that the activity enhancement was mainly mediated by hydropho-
bic substitutions on the phenyl ring with chelating ability of thio-
semicarbazone unit in 1.
Taking above information into account for the activity improve-
ment, here, we further scrutinized the SAR in terms of defining the
roles of benzylidene hydrogen, substitutions for terminal amino
hydrogen and the double bond in 1. Therefore, here in the current
article we have designed and synthesized series of ketonethiose-
micarbazone (2a–l, 3a–c, 4, and 5) for evaluating their melanogen-
esis inhibition in melanoma B16 cells.
tyrosine and oxidation of 2,4-dihydroxyphenylalanine (L
-DOPA).6
Recently, it was reported to be associate with Parkinson’s and other
neurodegenerative diseases.7,8 Therefore, the inhibition of tyrosi-
nase is expected to provide effective therapeutic means for the
treatment of dermatological disorders9–11 and neurodegenerative
diseases.
A large number of tyrosinase inhibitors have been reported as
cosmetic agents like azelaic acid,12 hydroquinones,13,14 kojic acid,15
hydroxystilbene compounds like resveratrol,16–18 methyl ester of
gentisic acid,19 N-phenylthiourea derivatives,20,21 kojic acid deriv-
The synthesis of compounds 2a–l, 3a–c, 4, and 5 has been illus-
trated inSchemes 1 and 2. Briefly, according to Scheme 1, a number
of commercially available ketones 6a–i were treated with various
thiosemicarbazide 7a–d28–32 in anhydrous ethanol using catalytic
amount of glacial acetic acid at reflux temperature for 12 h to
provide appropriate ketonethiosemicarbazones 2a–l.33–40 The re-
duced thiosemicarbazones 3a–c41 were obtained by the reaction
⇑
Corresponding author.
E-mail address: jungshh@cnu.ac.kr (S.-H. Jung).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.146

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P. Thanigaimalai et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3527–3530
O
O
O
R1
OH
HO
HO
OH
OH
O
a) Hydroquinone R = -OH
b)Arbutin R = -O(b)-Glucose
Azilaic acid
Kojic acid
R6
R3
R4
O
R
N
R1
N
R1
HO
R2
R5
O R
X
O
R2
O
PTU analogs,
Kojic acid derivatives
Hydroxy stilbenes,
a) Resveratrol
b) Oxyresverotrol R1 = R2 = R3 = R5 = -OH
1 = R2 = R3 = -OH
R R1 = H, CH3
R2 = H, OH or OMe
X = O or S
R
R = various alkyl or
alkoxy
c) Gnetol
R1 = R2 = R5 = R6 = -OH
NH2
N
N
O
O
N
O
O
N
Br
O
O
O
Tetraketone derivative
Oxazolone derivatives
Oxodiazole derivatives
Figure 1. The structure of known melanization inhibitors.
H
R1
R1
H
H
H
H
H
H
N
N
N
NH2
N
N
R2
N
NH2
N
R2
N
N
N
O
R
R
H
R
H
S
S
S
S
N
NH2
H2N
(i)
(i)
+
3a-c
2a-l
1
S
1a: R =4 -H
1b: R = 4-CH3
1c: R = 4-OCH3
6j
4
H
N
7a
NH2
N
S
S
H
N
S
S
N
NH2
N
NH2
O
H2N
N
H
+
S
S
N
H
NH2
S
4
5
6k
7a
5
Figure 2. The structure of aldehydethiosemicarbazone 1 and ketonethiosemicar-
bazone analogs 2–5.
Scheme 2. Synthetic outline for the preparation of
4 and 5. Reagents and
conditions: (i) CH3COOH/ethanol, reflux 12 h.
R1
R1
H
N
H
H
H
(i)
N
N
N
R2
+
O
N
H2N
R
was determined by measuring absorbance values at 405 nm with
synthetic melanin as a standard.47 Data for % inhibition at 10
and IC50 values are mean values from three to five separate exper-
iments as shown in Table 1.
R
R
S
S
lM
6a-i
7a-d
2a-l
7a: R = -H
7b: R =-CH3
7c: R = -CHCH3
7d: R = -Ph
As we have mentioned earlier,26,27 the enhancement of activity
of aldehydethiosemicarbazones 1 was reconciled by the hydropho-
bic substitutions on the phenyl ring of 1. For defining the role of
benzylidene hydrogen, we improved the hydrophobicity in 1 by
placement of methyl group in three template analogs26,27 such as
inactive 2-benzylidenehydrazinecarbothioamide26 (1a, <10% inhi-
(ii)
R1
H
H
N
N
N
R2
R
H
S
3a-c
bition at 10
lidene)hydrazinecarbothioamide26 (1b, 64% inhibition at 10
IC50 = 6.8 M, C log P = 2.364) and
dene)hydrazinecarbothioamide27 (1c, 42% inhibition at 10
IC50 = 15.1
lM, IC50 = >10 lM, C log P = 1.865), 2-(4-methylbenzy-
Scheme 1. Synthetic outline for the preparation of
2 and 3. Reagents and
conditions: (i) CH3COOH/ethanol, reflux 12 h; (ii) NaBH4 in methanol, reflux 4 h.
l
M,
M,
l
2-(4-methoxybenzyli-
l
lM, C log P = 1.830). Expectedly, the resulting keton-
of 2a, 2b, or 2d with sodium borohydride at reflux condition for
4 h. Further, the analogs 442 and 543,44 were synthesized with
1,2,3,4-tetrahydronaphthalene-1-one (6j) or 2-acetylthiophene
(6k) using the same reaction condition for the preparation of 2
as indicated in Scheme 2. The substituents of compounds 2a–l,
3a–c, 4, and 5 were given in Table 1.
ethiosemicarbazones (2a–c) showed stronger activity than the cor-
responding aldehydethiosemicarbazones (1a–c). For instance,
analog 2a (>100% inhibition at 10
lM, IC50 = 2.30 lM,
C log P = 2.401) showed remarkable increment in activity com-
pared to 1a. Compound 2b (>100% inhibition at 10
IC50 = 0.84
than 1b and the methoxy analog 2c (>100% inhibition at 10
IC50 = 2.70
l
M,
M,
l
M, C log P = 2.900) exhibited eightfold more potent
For all synthesized analogs 2–5, the ability to inhibit the forma-
tion of melanin from melanoma B16 cells was determined under
l
l
M, C log P = 2.621) showed nearly sixfold enhanced
stimulus of
a
-MSH (100 nM) for 3 day incubation.45,46 The mela-
inhibition over 1c. These activity increments of 2a–c are the result
of increased hydrophobicity by the replacement of benzylidene
hydrogen in aldehydethiosemicarbazones 1 with methyl group.
noma B16 cells (CRL6323) were obtained from the ATCC (Manas-
sas, USA). The amount of melanin released into the culture media

P. Thanigaimalai et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3527–3530
3529
Table 1
The inhibitory activity of ketonethiosemicarbazones 2–5 on melanogenesis in melanoma B16 cells
a
Compd No:
R
R1
R2
% Inhibition at 10
l
M
IC50
(lM)
C log Pb
2a33–35
2b33,34,36
2c33,34,36
2d
4-H
–CH3
–CH3
–CH3
–H
-H
–H
–H
–H
–H
–H
–H
>100
>100
>100
>100
>100
>100
>100
96
2.30
0.84
2.70
2.6
2.9
2.0
2.401
2.900
2.621
3.429
3.727
3.877
3.150
3.239
4.102
3.315
3.844
5.099
1.269
1.768
2.297
2.945
2.181
4-CH3
4-OCH3
4-CH3
4-Cl
4-Br
4-OCH3
4-H
–CH2CH3
–CH2CH3
–CH2CH3
–CH2CH3
–CH(CH3)2
–Ph
–CH2CH3
–CH2CH3
–CH2CH3
–CH3
2e37
2f37
2g37
4.0
2h38
2i39,40
2j
3.7
4.9
2.0
4-H
–H
97
4-CH3
4-CH3
4-CH3
4-H
4-CH3
4-CH3
—
–CH3
–CH2CH3
–Ph
–H
–H
–H
>100
>100
>100
36
2k
1.9
0.79
>30
8.1
3.9
2.3
6.1
70
2l
3a41
3b
–CH3
–CH2CH3
—
61
3c
>100
>100
82
442
—
—
543,44
Kojic acid
Arbutin
—
—
180
a
IC50 values are obtained as mean from three to five independent experiments.
C log P values are calculated from Chemdraw Ultra 11.0 V.
b
In connection with the above result, the replacement of bulkier
the role of double bond in 2 is also an important factor for the
increment of hydrophobicity.
In addition, the fused ketonethiosemicarbazone 4 (>100% inhi-
bition at 10 lM, IC50 = 2.30 lM, C log P = 2.945) showed similar le-
hydrophobic substituents for benzylidene hydrogen would en-
hance the activity. Thus, the potent analog 1b among 1a–c were se-
lected for further modification. Primarily, ethyl analog 2d (>100%
inhibition at 10
lM, IC50 = 2.60
lM, C log P = 3.429) showed nearly
vel of activity as 2a. Interestingly, the phenyl group of 2a can be
three times more potent activity than 1b. Regardless of substitu-
tions on phenyl moiety of 1b, the similar trend was discerned as
shown in the following analogs such as 4-chloro (2e, >100% inhibi-
replaced by heterocyclic thiophenyl moiety as shown in 5 (86%
inhibition at 10
In summary,
hydrazinecarbothioamides
zinecarbothioamides (3),
l
M, IC50 = 6.1
series
2,
lM, C log P = 2.181).
a
of
2-(1-phenylalkylidene)
tion at 10
inhibition at 10
(2g, >100% inhibition at 10
analogs bearing isopropyl (2h, 96% inhibition at 10
IC50 = 3.7 M, C log P = 3.239) or phenyl (2i, 97% inhibition at
10 M, IC50 = 4.9 M, C log P = 4.102) in 1a also improved the
l
M, IC50 = 2.90
M, IC50 = 2.00
M, IC50 = 4.00
l
M, C log P = 3.727), 4-bromo (2f, >100%
M, C log P = 3.877) and 4-methoxy
M, C log P = 3.150). The
M,
2-(1-phenylalkyl)hydra-
l
l
2-(3,4-dihydronaphthalen-1(2H)
l
l
-ylidene)hydrazinecarbothioamide (4), and 2-(1-(thiophen-2-
yl)ethylidene)hydrazinecarbothioamide (5) were synthesized for
their melanogenesis inhibition in melanoma B16 cells. The SAR of
these ketonethiosemicarbazones revealed that the benzylidene
hydrogen in aldehydethiosemicarbazones 1 can be replaced by
hydrophobic moiety and substitutions with alkyl group for the ter-
minal amino hydrogen of ketonethiosemicarbazones improved the
activity appreciably. In addition, the double bond in thiosemicar-
bazones is an important factor for the increment of hydrophobic-
ity. Thus hydrophobic ketonethiosemicarbazones are excellent
inhibitors of melanogenesis like aldehydethiosemicarbazones.
l
l
l
l
activity. Thus, bulky hydrophobic group can replace the benzyli-
dene hydrogen in 1.
One of the terminal amino hydrogen (–C(@S)–NH2) of 2d was
replaced with methyl group as indicated in the analog 2j (>100%
inhibition at 10 lM, IC50 = 2.0 lM, C log P = 3.315) showed compa-
rable activity to 2d, which advice that the terminal amino hydro-
gen can be substituted by the hydrophobic group. In order to
find the optimum size of this substituent, ethyl (2k, >100% inhibi-
tion at 10
l
M, IC50 = 1.9
lM, C log P = 3.844) or phenyl (2l, >100%
Acknowledgment
inhibition at 10
lM, IC50 = 0.79
lM, C log P = 5.099) were intro-
duced in place of methyl in 2j. Among them, the phenyl (2l) analog
exhibited more potent inhibition against melanogenesis compared
to 2j–k. Therefore, the replacement of terminal amino hydrogen in
2d by large hydrophobic substituent like phenyl moiety favors
activity enhancement.
This work was supported by a Priority Research Centers Pro-
gram (2009-0093815) through the National Research Foundation
of Korea (NRF) funded by the Ministry of Education, Science and
Technology.
The reduction of double bond in 2a to afford the compound 3a
Supplementary data
(36% inhibition at 10
loss of inhibition potency. However, in analogs 3b (61% inhibition
at 10 M, IC50 = 8.1 M, C log P = 1.768) and 3c (>100% inhibition at
10 M, IC50 = 3.9 M, C log P = 2.269) the activity was gradually
lM, IC50 = >30 lM, C log P = 1.269) led to the
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.04.146.
l
l
l
l
enhanced which is due to increase in their hydrophobicity. The
reduced compounds 3a–c are conformationally quite different
from the corresponding compounds 2. The hydrophobic compound
3c (C log P = 2.297) has the comparable activity to 2d
(C log P = 3.429), unlike less hydrophobic 3a (C log P = 1.269) and
3b (C log P = 1.768) which showed significantly reduced activity
with their corresponding unsaturated analogs such as 2a
(C log P = 2.401) and 2b (C log P = 2.900). Thus, it can be concluded
that the hydrophobicity governs the activity of 2 and 3. Moreover,
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