Identification of indoline-2-thione analogs as novel potent inhibitors of α-melanocyte stimulating hormone induced melanogenesis

Article abstract of DOI:10.1248/cpb.59.1285

Based on the hits, 3,4-dihydroquinazoline-2-thione (1) and benzimidazole-2-thione (2), a series of indole-2-thione (3) and indole-2-thiol inhibitors (4) of melanogenesis were designed, synthesized and evaluated in melanoma B16 cells under the stimulant of α-melanocyte stimulating hormone (α-MSH). The indole-2-thione compounds (3a-g) exhibited an effective inhibitory activity on melanin synthesis. The Structure-Activity Relationship (SAR) studies of 2 have revealed that in potent inhibitor 3a (>100% inhibition at 30μM, IC₅₀=1.40μM) the role of nitrogen (3-N) at 3-position is insignificance. In addition, the hydrophobic substituents of 3 were better than the hydrophilic one. However, conversion of thione (-C=S, 3) to thiol (-C-SH, 4) led to decrease in the potency.

Full text of DOI:10.1248/cpb.59.1285

October 2011
Regular Article
Chem. Pharm. Bull. 59(10) 1285—1288 (2011)
1285
Identification of Indoline-2-thione Analogs as Novel Potent Inhibitors of
a
-Melanocyte Stimulating Hormone Induced Melanogenesis
Pillaiyar THANIGAIMALAI,a Ki-Cheul LEE,a Vinay Kumar SHARMA,a Niti SHARMA,a Eunmiri ROH,b
Youngsoo KIM,b and Sang-Hun JUNG*,a
a College of Pharmacy and Institute of Drug Research and Development, Chungnam National University; Daejeon
305–764, Korea: and b College of Pharmacy, Chungbuk National University; Cheongju 361–763, Korea.
Received July 4, 2011; accepted July 26, 2011; published online July 28, 2011
Based on the hits, 3,4-dihydroquinazoline-2-thione (1) and benzimidazole-2-thione (2), a series of indole-2-
thione (3) and indole-2-thiol inhibitors (4) of melanogenesis were designed, synthesized and evaluated in
melanoma B16 cells under the stimulant of a-melanocyte stimulating hormone (a-MSH). The indole-2-thione
compounds (3a—g) exhibited an effective inhibitory activity on melanin synthesis. The Structure–Activity Rela-
tionship (SAR) studies of 2 have revealed that in potent inhibitor 3a (ꢀ100% inhibition at 30 mM, IC50ꢀ1.40 mM)
the role of nitrogen (3-N) at 3-position is insignificance. In addition, the hydrophobic substituents of 3 were
better than the hydrophilic one. However, conversion of thione (–CꢀS, 3) to thiol (–C–SH, 4) led to decrease in
the potency.
Key words melanogenesis inhibitor; benzimidazole-2-thione; inoline-2-thione; indole-2-thiol
In human, melanin is the primary pigment responsible for severe side effects.11) Therefore, it is necessary to develop
hair and skin color, which is produced from melanocytes ideal melanogenesis inhibitors with higher activity and lower
through the process called melanogenesis.1,2) Melanin pro- side effects.
tects the skin from sun related injuries. However, the extra
As part of our effort to discover new hypopigmenting
accumulation of melanin in different parts of the skin can agents, the random screening yielded 3,4-dihydroquinazo-
cause diverse hyperpigmentary disorders such as melasma, line-2-thione (1, Fig. 2, ꢀ100% inhibition at 10 mM, IC50ꢁ
freckles and age spot.3,4) The biosynthesis of melanin is con- 0.8 mM) as a potent inhibitor of melanogenesis in melanoma
trolled at many different levels by a variety of proteins and B16 cells under the stimulus of a-melanocyte stimulating
enzymes such as tyrosinase, tyrosinase related protein-1 hormone (a-MSH) through cAMP pathway.13) Unlike other
(TRP-1) and TRP-2, which are known to be involved in the hypopigmenting agents, this compound 1 had no effect on ty-
melanogenesis pathway. Several factors affect the activities rosinase enzyme.13) As a continued effort to develop a more
of these enzymes and related proteins including, a-melano- potent analog, we subsequently explored the Structure–
cyte stimulating hormone (a-MSH), fibroblast growth factor Activity Relationship (SAR) of 1 in previous reports.14—16)
(FGF), endothelin-1 and UV light.5,6)
This resulted in the identification of benzimdazole-2(3H)-
The production of melanin is controlled by a key regula- thione analog 2 (Fig. 2, ꢀ100% inhibition at 10 mM, IC50ꢁ
tory tyrosinase, copper containing multifunctional enzyme.7) 1.5 mM)16) as equipotent to compound 1. Here, in the current
Thus, the inhibition of tyrosinase is expected to provide ef- report, we further scrutinized the SAR of 2 in terms of de-
fective therapeutic means for the treatment of dermatological fining the role of nitrogen at 3-position (3-N) and thione
disorders.8—10) Majority of currently known hypopigmenting (–CꢁS) in 2. Hence, a series of indoline-2-thiones 3, and in-
agents act directly or indirectly on this enzyme via several dole-2-thiols 4 were designed, synthesized (Fig. 2) and evalu-
mechanisms.8,11,12) The chemical agents, including N- ated for their hypopigmenting activity in melanoma B16 cell
phenylthiourea (PTU), hydroquinone, kojic acid, and arbutin line under the stimulus of a-MSH.
(Fig. 1), have been used as hypopigmenting agents, but none
Chemistry The compounds 3 and 4 were prepared ac-
are completely satisfying because of their lower activity or cording to Chart 1. Briefly; intermediate 6 was synthesized
by the Wolff–Kishner reduction of isatin 5.17) The compound
8 was obtained in one pot by sequential treatment of 6 with
Fig. 2. The Target Structures of Melanogenesis Inhibitors 1—4
The substituents of 3 and 4 are indicated in Table 1.
Fig. 1. Chemical Structures and Activity of Known Hypopigmenting
Agents
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: jungshh@cnu.ac.kr

1286
Vol. 59, No. 10
appropriate aldehydes in the presence of piperidine at reflux (4a—g) were confirmed by IR with a characteristic S–H
condition for 3—5 h to yield 718—23) and then with sodium stretching vibration at near 2560—2565 cmꢂ1 as a broad and
borohydride at room temperature.21) Meanwhile carbonyl diffuse band, and the 1H-NMR spectra with a clear singlet for
compound 6 was treated with phosphorous pentasulfide benzylic proton have strongly supported the presence of in-
(P2S5) in the presence of sodium carbonate at room tempera- dolethiol form.
ture to obtain the indoline-2-thione 9.24,25) The compound 326)
was obtained by the treatment of indoline-2-thione (9) with Results and Discussion
various aldehydes using the same condition as for the prepa-
As described previously, the inhibitory ability of a new se-
ration of 7. Interestingly, the benzylideneindole-2-thiones ries of compounds 8a—g, 3a—g and 4a—g were assayed on
may exist as either Z or E isomer depending on the sub- melanoma B16 cells under the stimulus of a-MSH (100 nM)
stituents at the C-3 position of the 3-benzylideneindoline-2- for 3 d incubation period.14,15) Melanoma B16 cells
thione. The previous study26) determined E and Z isomers (CRL6323) were obtained from ATCC (Manassas, U.S.A.).
1
based on chemical shift of vinyl-H in H-NMR as chemical The amount of melanin released into the culture media was
shift of E-isomer (dꢁ6.95—7.26) of benzylideneindole-2- determined by measuring the absorbance at 405 nm with syn-
thiones is less de-shielded compared to Z-isomer (dꢁ7.30— thetic melanin as the standard.27) The data for % inhibition
7.50). Thus, in the current study, we observed that the com- and IC50 values are given in Table 1.
pound 3a—g are E-isomers with their chemical shift values
As shown in the Table 1, all carbonyl compounds, 8a—g,
of vinyl-H in the range of 6.95—7.26.
did not show any notable inhibition however, the thiones
The reduction of 3 with sodium borohydride gave the tar- (3a—g) were found to be more potent against melanogenesis
get compound 4. The compound 4 could also be obtained by as we reported in our earlier studies.14—16) Accordingly, 3-
treating the intermediate 8 with Lawesson’s reagent under re- benzylideneindoline-2-thione (3a, ꢀ100% inhibition at
fluxing condition in toluene. The similar result was also ob- 30 mM, IC50ꢁ1.40 mM) displayed 50-fold more potent in-
served in previous findings.24,25) All the thiol compounds hibitory activity than kojic acid, a well known hypopigment-
ing agent, and similar potency to the lead 2 (IC50ꢁ1.40 mM)
in melanoma B 16 cell line. This implies that the nitrogen at
3-position of 2 does not have any specific role against
melanogenesis. In an attempt to further improve the potency,
we then examined a series of analogs with various hydropho-
bic substituent at 4-position on benzylidene side chain of 3a.
Accordingly, the compound with methyl (3b, ꢀ100% inhibi-
tion at 30 mM, IC50ꢁ3.2 mM), ethyl (3c, ꢀ100% inhibition at
30 mM, IC50ꢁ2.5 mM) or chloro (3d, ꢀ100% inhibition at
30 mM, IC50ꢁ1.4 mM) showed comparable activity to that of
3a. This study confirms that the presence of hydrophobic
substituent on the benzylidene side chain of 3 does not have
any influence on their activity enhancement. Conversely, the
hydrophilic substituents led to decreased activity as indicated
Reagents and condition: (a) NH2NH2·H2O, 6 N HCl; (b) P2S5, Na2CO3, THF; (c)
R1-CHO, piperidine, ethanol; (d) NaBH4, ethanol, reflux; (e) Lawesson’s reagent,
toluene, reflux; (f) R1-CHO, piperidine, reflux; (g) NaBH4, ethanol, reflux. *Note:
Substituents are indicated in Table 1.
in the methoxy derivative (3e, 87% inhibition at 30 mM,
Chart 1. Synthetic Outline for the Preparation of 3 and 4
Table 1. The Melanogenesis Inhibitory Activity of 8a—g, 3a—g, and 4a—g
% of inhibition
at 30 mM
IC50
% of inhibition
at 30 mM
IC50
Entry No:
R1
Entry No:
R1
a)
a)
(mM)a)
(mM)a)
8a20)
8b20)
8c22)
8d20)
8e20)
8f22)
8g23)
3a24)
3b
Ph
ꢃ10
ꢃ10
ꢃ10
ꢃ10
ꢃ10
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
1.40
5.20
2.50
1.40
1.40
3e26)
3f
4-OCH3Ph
1-Naphthyl
Cyclohexyl
Ph
4-CH3Ph
4-CH3CH2Ph
4-ClPh
4-OCH3Ph
1-Naphthyl
Cyclohexyl
87
ꢀ100
ꢀ100
53
6.70
3.40
3.60
4-CH3Ph
4-CH3CH2Ph
4-ClPh
4-OCH3Ph
1-Naphthyl
Cyclohexyl
Ph
4-CH3Ph
4-CH3CH2Ph
4-ClPh
3g
4a24)
24.20
14.03
12.15
14.34
18.23
15.62
ꢀ30
0.80
70
4b
4c
4d
4e
4f
4g
1
85
89
79
55
ꢃ10
ꢃ10
ꢀ100
ꢀ100
ꢀ100
ꢀ100
ꢀ100
59
3c
ꢃ10
ꢀ100
3d26)
2
Kojic acid
a) The values of percentage of inhibitions have taken as a mean value from 3—5 independent experiments.

October 2011
1287
Synthesis of Thioindole (9)24,25) 0.06 mol of P2S5 and 0.06 mol of
Na2CO3 were suspended in 20 ml of anhydrous THF at 0 °C and the mixture
was stirred for 20 min. Oxoindole (0.05 mol) 1 was dissolved in 25 ml anhy-
drous THF and added drop wise to this mixture. This was stirred at 0 °C for
30 min, allowed to adapt to room temperature, and stirred overnight. The
IC50ꢁ6.7 mM), showing less activity than 3a—d.
Furthermore, the importance of phenyl group is demon-
strated with the derivative of naphthyl (3f, ꢀ100% inhibition
at 30 mM, IC50ꢁ3.4 mM) or cyclohexyl (3g, ꢀ100% inhibition
at 30 mM, IC50ꢁ3.6 mM). These results illustrated that the reaction mixture was poured into ice-cold water and extracted with ethyl
acetate (3ꢄ50 ml). The organic layer was washed with brine (3ꢄ20 ml) and
overall lipophilicity of compounds 3 favors melanogenesis
inhibition in the melanoma B16 cells.
We next attempted further modification of the thione
dried over anhydrous Na2SO4. Evaporation of the solvent gave the crude
compound, which was purified by silica gel column chromatography. Yield
83%; yellow solid; mp 146—148 °C.
Synthesis of 3-Benzylideneindoline-2-thione (3a)24) A reaction mix-
ture of indole-2-thione (9, 1 eq), benzaldehyde (1.2 eq), and piperidine
(0.1 eq) in ethanol (1—2 ml/1 mmol) was stirred at 90 °C for 3—5 h. After
the reaction was completed, the mixture was cooled to ambient temperature
then poured into water and extracted with methylene chloride. The resulting
organic phase was washed with brine, dried over Na2SO4 and evaporated
under reduced pressure. The crude material was then purified by column
chromatography to give 3a. Yield 71%, a yellow waxy solid.
group of 3, and the results are summarized in Table 1. In
compound 4a (53% inhibition at 30 mM, IC50ꢁ24.2 mM), the
activity decreased nearly 20 fold to the corresponding thione
3a. The same trend has also been observed in the analogs, 4b
(85% inhibition at 30 mM, IC50ꢁ14.0 mM), 4c (89% inhibition
at 30 mM, IC50ꢁ12.1 mM), 4d (79% inhibition at 30 mM,
IC50ꢁ14.3 mM), 4e (55% inhibition at 30 mM, IC50ꢁ18.2 mM),
4f (59% inhibition at 30 mM, IC50ꢁ15.6 mM) and 4g (ꢃ10%
inhibition at 30 mM, IC50ꢁꢀ30 mM). From the above study, it
can be concluded that the thiones (3) are more favorable than
thiols (4) for their melanogenesis inhibitory activity and the
benzylidene side chain of 3 is an essential motif for retaining
intact indoline-2-thione function.
(E)-3-(4-Methylbenzylidene)indoline-2-thione (3b) Using the same
reaction condition for the preparation of 3a, compound 3b was obtained
from the reaction of 9 with p-tolualdehyde (1.2 eq). Yield 67%; yellow waxy
1
solid; IR (neat) 3258, 3174, 1686, 1583, 1503, 1487, 1444, 1437 cmꢂ1; H-
NMR (CDCl3) d: 2.43 (s, 3H, Ar-CH3), 6.92 (d, Jꢁ8.4 Hz, 1H, Ar-H), 7.02
(t, Jꢁ8.0 Hz, 1H, Ar-H), 7.22—7.44 (m, 6H, –CꢁCH–, Ar-H), 7.89 (d,
Jꢁ8.4 Hz, 1H), 8.27 (d, Jꢁ8.0 Hz, 1H, Ar-H). HR-MS Calcd for C16H13NS
m/z 251.0769, Found 251.0771.
(E)-3-(4-Ethylbenzylidene)indoline-2-thione (3c) Using the same re-
action condition for the preparation of 3a, compound 3c was obtained from
Conclusion
Based on the hits, 1 and 2, a series of novel inhibitors (3, the reaction of 9 with p-ethylbenzaldehyde (1.2 eq). Yield 68%; yellow waxy
1
solid; IR (neat) 3376, 1684, 1584, 1505, 1488, 1465,1436, 1410 cmꢂ1; H-
4) of melanogenesis were designed, synthesized and evalu-
ated in melanoma B16 cells under the stimulus of a-MSH.
The selected compounds (3a—g) exhibited an effective in-
NMR (CDCl3) d: 1.08 (t, Jꢁ5.2 Hz, 3H, CH3), 2.46 (q, Jꢁ5.6 Hz, 2H, CH2),
6.30 (d, Jꢁ8.4 Hz, 1H, Ar-H), 6.58 (t, Jꢁ7.6 Hz, 1H, Ar-H), 6.86 (m, 2H,
Ar-H), 7.11—7.22 (m, 3H, –CꢁCH–, Ar-H), 7.84 (d, Jꢁ8.4 Hz, 1H, Ar-H),
hibitory activity on melanin synthesis without any cytotoxic-
ity in melanoma B 16 cells (data not shown). The SAR stud-
ies of 2 have revealed that in potent inhibitor 3a (ꢀ100% in-
hibition at 30 mM, IC50ꢁ1.40 mM) the role of nitrogen (3-N) at
3-position is insignificant. However, conversion of thione
(–CꢁS, 3) to thiol (–C–SH, 4) led to decrease in the in-
hibitory potency. Detailed mechanistic studies directed to-
wards identification of the molecular target of these indoline-
2-thiones as hypopigmenting agents are ongoing and will be
reported in due course.
8.30 (d, Jꢁ8.0 Hz, 1H, Ar-H), 8.59 (bs, 1H, NH). HR-MS Calcd for
C17H15NS m/z 265.0925, Found 265.0922.
(E)-3-(4-Chlorobenzylidene)indoline-2-thione (3d)26) Using the same
reaction condition for the preparation of 3a, compound 3d was obtained
from the reaction of 9 with p-chlorobenzaldehyde (1.2 eq). Yield 63%; yel-
low solid; mp 133—135 °C.
(E)-3-(4-Methoxybenzylidene)indoline-2-thione (3e)26) Using the
same reaction condition for the preparation of 3a, compound 3e was
obtained from the reaction of 9 with p-anisaldehyde (1.2 eq). Yield 69%;
yellow solid; mp 169—171 °C.
(E)-3-(Naphthalen-1-ylmethylene)indoline-2-thione (3f) Using the
same reaction condition for the preparation of 3a, compound 3f was ob-
tained from the reaction of 9 with 1-naphthaldehyde (1.2 eq). Yield 62%;
yellow waxy solid; IR (neat) 3256, 1682, 1593, 1538, 1497, 1434 cmꢂ1; 1H-
NMR (CDCl3) d: 6.69 (d, Jꢁ7.6 Hz, 1H, Ar-H), 7.11—7.23 (m, 4H,
–CꢁCH–, Ar-H), 7.36—7.51 (m, 4H, Ar-H), 7.58 (d, Jꢁ8.0 Hz, 1H, Ar-H),
7.74 (d, Jꢁ7.6 Hz, 1H, Ar-H), 7.86—7.89 (m, 1H, Ar-H), 8.29 (d, Jꢁ8.4 Hz,
1H, Ar-H). HR-MS Calcd for C19H13NS m/z 287.0769, Found 287.0773.
(E)-3-(Cyclohexylmethylene)indoline-2-thione (3g) Using the same
reaction condition for the preparation of 3a, compound 3f was obtained from
the reaction of 9 with cyclohexylcarboxaldehyde (1.2 eq). Yield 68%; light
yellow solid; mp 123—125 °C; IR (neat) 3397, 1680, 1590, 1557, 1503,
Experimental
Chemistry Melting points (mp) were determined on Electro thermal 1A
9100 MK2 apparatus and were uncorrected. All commercial chemicals were
used as obtained and all solvents were purified by the standard procedures
prior to use. Thin layer chromatography was performed on E Merck silica
gel GF-254 pre-coated plates and the identification was done with UV light
and colorization with 10% phosphomolybdic acid spray followed by heating.
Flash column chromatography was performed with E Merck silica gel
(230—400 mesh). Infra red spectrum was recorded by using (neat sample
without solvent or KBr) FT-IR spectrum with Nicolet-380 models. NMR
spectra were measured against the peak of tetramethylsilane by Varian Unity
Inova 400 NMR (400 MHz) spectrometer. High resolution-mass spectrum
(HR-MS) was recorded on API2000 mass spectrometer (PE Sciex, Toronto,
Canada).
1
1454 cmꢂ1; H-NMR (CDCl3) d: 0.82—1.92 (m, 10H, C6H10), 2.21 (m, 1H,
C6H11), 6.99 (d, Jꢁ8.4 Hz, 1H, –CHꢁCH–), 7.08 (t, Jꢁ7.8 Hz, 1H, Ar-H),
7.34 (t, Jꢁ8.4 Hz, 1H, Ar-H), 7.67 (d, Jꢁ8.0 Hz, 1H, Ar-H), 8.22 (d,
Jꢁ8.4 Hz, 1H, Ar-H), 8.28 (br s, 1H, NH). HR-MS Calcd for C15H17NS m/z
243.1082, Found 243.1079.
Synthesis of Oxoindole (6)17) The solution of isatin 5 (14 g, 0.10 mol)
in hydrazine monohydrate (60 ml, 1.2 mol) was refluxed at 140 °C for 4 h.
The reaction mixture was poured into ice cold water and acidified by 6 N
HCl. After standing at room temperature for 2 d, 7.5 g of pure oxo-indole
crystals was obtained. Yield 60%; light yellow solid; mp 126—128 °C.
General Synthetic Procedure for the Preparation Compounds 818—23)
A reaction mixture of oxoindole, 6 (1 eq), an appropriate benzaldehyde
(1.2 eq), and piperidine (0.1 eq) in ethanol (1—2 ml/1 mmol) was stirred at
90 °C for 3—5 h. As soon as the reaction was completed, the mixture was
cooled to ambient temperature and treated with NaBH4 (2 eq). The mixture
was then stirred for additional 1 h at 90 °C. The reaction mixture was cooled
and the solvent removed under reduced pressure. Precipitate or oily com-
pounds were purified by silica gel column chromatography to produce ap-
propriate derivative.
Synthesis of 3-Benzyl-1H-indole-2-thiol (4a)24) Method A (Known
Procedure): To the ethanolic solution of 3 (0.5 g, 1 mmol) added NaBH4
(2 eq) portion wise over 10 min at room temperature. Then the reaction mix-
ture was allowed to reflux for 2 h with stirring. Solvent was evaporated from
the mixture and poured into water than extracted with methyelene chloride
(50 ml). This resulting organic phase was evaporated under reduced pressure
and purified by column chromatography to yield 4a.
Method B: Compound 4a was also obtained from the intermediate 8a
(1 eq) by the reflux with Lawesson’s reagent (1.2 eq) in toluene (30 ml) for
overnight. After evaporation under reduced pressure, the residue was diluted
with water and extracted with methylene chloride. The organic layer was
washed with brine and dried over Na2SO4. The resulting organic phase was
evaporated under reduced pressure and the crude product was purified by
column chromatography to yield 4a. The product from Method B has the

1288
Vol. 59, No. 10
same characteristics as one obtained from Method A.
References
Yield 68%; light yellow solid; mp 145—147 °C; IR (neat) 3356, 2560,
1622, 1555, 1494, 1465, 1434 cmꢂ1; 1H-NMR (CDCl3) d: 3.91 (s, 2H, CH2),
6.88—6.99 (m, 2H, Ar-H), 7.22—7.42 (m, 5H, Ar-H), 7.64 (d, Jꢁ8.0 Hz,
1H, Ar-H), 8.08 (d, Jꢁ8.4 Hz, 1H, Ar-H), 8.08 (br s, 1H, NH). HR-MS
Calcd for C15H13NS m/z 239.0769, Found 239.0766.
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3-(4-Methylbenzyl)-1H-indole-2-thiol (4b) Yield 59%; yellow semi-
1
solid; IR (neat) 3354, 2562, 1624, 1556, 1504, 1488, 1466 cmꢂ1; H-NMR
(CDCl3) d: 2.37 (s, 3H, Ar-CH3), 3.98 (s, 2H, CH2), 6.99—7.12 (m, 2H, Ar-
H), 7.23—7.57 (m, 4H, Ar-H), 7.69 (d, Jꢁ8.0 Hz, 1H, Ar-H), 8.10 (d,
Jꢁ8.4 Hz, 1H, Ar-H), 8. Twelve (br s, 1H, NH). HR-MS Calcd for C16H15NS
m/z 253.0925, Found 253.0927.
3-(4-Ethylbenzyl)-1H-indole-2-thiol (4c) Yield 64%; yellow semisolid;
IR (neat) 3354, 2564, 1622, 1538, 1498, 1440 cmꢂ1 1H-NMR (CDCl3) d:
;
1.01 (t, Jꢁ5.6 Hz, 3H, CH3), 2.42 (q, Jꢁ5.6 Hz, 2H, Ar-CH2), 3.97 (s, 2H,
CH2), 6.98—7.13 (m, 2H, Ar-H), 7.26—7.53 (m, 4H, Ar-H), 7.71 (d,
Jꢁ8.4 Hz, 1H, Ar-H), 8.11 (d, Jꢁ8.4 Hz, 1H, Ar-H), 8.11 (br s, 1H, NH).
HR-MS Calcd for C17H17NS m/z 267.1082, Found 267.1085.
3-(4-Chlorobenzyl)-1H-indole-2-thiol (4d) Yield 59%; yellow solid;
1
mp 119—121 °C; IR (neat) 3353, 2562, 1620, 1505, 1488, 1465 cmꢂ1; H-
NMR (CDCl3) d: 3.99 (s, 2H, CH2), 7.01—7.12 (m, 2H, Ar-H), 7.22 (d,
Jꢁ8.0 Hz, 2H, Ar-H), 7.49 (d, Jꢁ8.0 Hz, 2H, Ar-H), 7.73 (d, Jꢁ8.4 Hz, 1H,
Ar-H), 8.07 (d, Jꢁ8.4 Hz, 1H, Ar-H), 8.10 (br s, 1H, NH). HR-MS Calcd for
C15H12ClNS m/z 273.0379, Found 273.0375.
3-(4-Methoxybenzyl)-1H-indole-2-thiol (4e) Yield 49%; Yellow solid;
1
mp 144—146 °C; IR (neat) 3350, 2563, 1622, 1547, 1537, 1456 cmꢂ1; H-
NMR (CDCl3) d: 3.72 (s, 3H, OCH3), 3.92 (s, 2H, CH2), 6.55 (d, Jꢁ8.0 Hz,
2H, Ar-H), 6.94 (d, Jꢁ8.4 Hz, 2H, Ar-H), 7.09 (t, Jꢁ8.0 Hz, 1H, Ar-H),
7.23 (t, Jꢁ8.0 Hz, 1H, Ar-H), 7.53 (d, Jꢁ8.4 Hz, 1H, Ar-H), 7.68 (d,
Jꢁ8.4 Hz, 1H, Ar-H), 8.07 (br s, 1H, NH). HR-MS Calcd for C16H15NOS
m/z 269.0874, Found 269.0871.
3-(Naphthalen-1-ylmethyl)-1H-indole-2-thiol (4f) Yield 69%; yellow
16) Lee J. H., Thanigaimalai P., Lee K. C., Bang S. C., Kim M. S., Sharma
V. K., Yun C. Y., Roh E., Kim Y., Jung S. H., Chem. Pharm. Bull., 58,
918—921 (2010).
solid; mp 96—98 °C; IR (neat) 3354, 2563, 1623, 1538, 1497, 1348 cmꢂ1
;
1H-NMR (CDCl3) d: 4.55 (s, 2H, CH2), 6.71 (d, Jꢁ8.0 Hz, 1H, Ar-H),
7.11—7.20 (t, Jꢁ8.0 Hz, 1H, Ar-H), 7.22—26 (t, Jꢁ8. 0 Hz, 1H, Ar-H),
7.36—7.48 (m, 4H, Ar-H), 7.64 (d, Jꢁ8.4 Hz, 1H, Ar-H), 7.66 (d, Jꢁ8.0 Hz,
1H, Ar-H), 7.78 (d, Jꢁ8.4 Hz, 1H, Ar-H), 8.02 (br s, 1H, NH), 8.11 (d,
Jꢁ8.4 Hz, Ar-H). HR-MS Calcd for C19H15NS m/z 289.0925, Found
289.0922.
17)
Carlo F. J., J. Am. Chem. Soc., 66, 1420—1436 (1944).
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(2009).
3-(Cyclohexylmethyl)-1H-indole-2-thiol (4g) Yield 55%; yellow vis-
20) Cheng L., Liu L., Wang D., Chen Y. J., Org. Lett., 11, 3874—3877
(2009).
1
cous solid; IR (neat) 3354, 2560, 1622, 1537, 1496, 1505, 1442 cmꢂ1; H-
NMR (CDCl3) d: 0.93—1.82 (m, 11H, C6H11), 2.58 (d, Jꢁ4.6 Hz, 2H, CH2),
6.98 (t, Jꢁ7.6 Hz, 1H, Ar-H), 7.19 (d, Jꢁ8.0 Hz, 1H, Ar-H), 7.55 (d,
Jꢁ8.4 Hz, 1H, Ar-H), 8.01 (d, Jꢁ8.4 Hz, 1H, Ar-H), 8.18 (br s, 1H, NH).
HR-MS Calcd for C15H19NS m/z 245.1238, Found 245.1236.
21) Zhang W., Go M. L., Bioorg. Med. Chem., 17, 2077—2090 (2009).
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24) Hino T., Suzuki T., Takeda S., Kano N., Ishii Y., Sakai A., Nakagawa
M., Chem. Pharm. Bull., 21, 2739—2748 (1973).
Acknowledgements This work was supported by Priority Research
Centers Program (2009-0093815) through the National Research Foundation
of Korea (NRF) funded by the Ministry of Education, Science and Technol-
ogy.
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