Novel 3-substituted N-methylcarbazole–imidazolium salt derivatives: Synthesis and cytotoxic activity

Article abstract of DOI:10.1111/cbdd.13178

A series of novel 3-substituted N-methylcarbazole–imidazolium salt derivatives has been prepared and evaluated in vitro against a panel of tumor cell lines (Hep G-2, Hela and PC12). The results suggest that the presence of substituted 2-methyl-imidazole or imidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl or 4-bromophenacyl group were important for improving cytotoxic activity. Compounds 17, 18, 27, and 28 with 4-bromophenacyl and naphthylacyl groups displayed good activities with IC₅₀ values of 0.09–7.20?μm against three tumor cell lines investigated and more active than DDP. Compound 35 exhibited cytotoxic activity selectively against Hela cell.

Full text of DOI:10.1111/cbdd.13178

Article type: Research Article
Novel 3-substituted N-methylcarbazole–imidazolium salt
derivatives: Synthesis and cytotoxic activity
1
2
1
1
1
Yan-Hua Li | Bei Zhou | Yi-Min Shi | Yu-Peng Xun | Yun-Han Yang | Li-Juan
1
Yang
1
School of Chemistry and Environment, Key Laboratory of Ethnic Medicine Resource Chemistry,
State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming,
650500, P. R. China. Tel./Fax.: +86-871-65910017.
2
Key Laboratory for Forest Resources Conservation and Utilisation in the Southwest Mountains of
China, Ministry of Education, Southwest Forestry University, Kunming, 650224, P. R. China
Correspondence
Li-Juan Yang, School of Chemistry and Environment, Key Laboratory of Ethnic Medicine Resource
Chemistry, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University,
Kunming, P. R. China.
Email: yangljyang@sina.com
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
1
0.1111/cbdd.13178
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A series of novel 3-substituted N-methylcarbazole–imidazolium salt derivatives has been prepared
and evaluated in vitro against a panel of tumor cell lines (Hep G-2, Hela and PC12). The results
suggest that the presence of substituted 2-methyl-imidazole or imidazole ring and substitution of the
imidazolyl-3-position with a naphthylacyl or 4-bromophenacyl group were important for improving
cytotoxic activity. Compounds 17, 18, 27 and 28 with 4-bromophenacyl and naphthylacyl groups
displayed good activities with IC values of 0.09–7.20 μM against three tumor cell lines investigated
5
0
and more active than DDP. Compound 35 exhibited cytotoxic activity selectively against Hela cell.
KEYWORDS
N-methylcarbazole, imidazolium salts, synthesis, cytotoxic activity, structure-activity
relationship
1
| INTRODUCTION
Innovation for pharmacological hybrid compounds served as a hot and challenging point over recent
decades. Heteroatom structure unit attracted attention because of its population in medicine,
[
1-6]
pesticides, materials and other fields of broad application prospects.
Due to the large conjugated
system and the ability of strong intramolecular electron transformation, the special rigid fused ring
[
7-9]
structure of the carbazole compounds show many unique biological activities and performances.
Previous studies found that many carbazole derivatives have good antitumor and anticonvulsant
activities, such as carbazole compound LCY-2-CHO (Scheme 1) with a significant anti-inflammatory
activity which can not only inhibit platelet aggregation, neutrophil threshing and the production of
NO in macrophages and smooth muscle cells, but also induce death of malignant hematopoietic
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[
10,11]
cell.
points in heterocyclic biochemical pharmacology.
Meanwhile, imidazolium salt is a class of five-membered aromatic heterocycles that are widely
Therefore, design and synthesis of novel carbazole derivatives for potential usage are hot
[
12]
[
13,14]
present in natural products and synthetic drugs.
The biological activity of the imidazolium salt
[
15-17]
[18-23]
derivatives has been widely reported in the previous literature,
especially antitumor activity.
For example, two new imidazolium halides (Scheme 1), Lepidiline A and Lepidiline B, isolated from
the roots of Lepidium meyenii, showed interesting potent cytotoxic activity against the human cancer
[
24]
cell lines UMUC3, PACA2, MDA231 and FDIGROV. In our previous research, we have reported
the synthesis of a series of novel imidazolium salt derivatives and their potential antitumor
[
25-30]
activity.
SCHEME 1
[
31,32]
Molecular hybridization served as an effective way to develop new drugs.
The establishment
of multi-functional carbazole-imidazolium salts is a good approach to obtain novel structure tumor
[
33]
suppressor compounds. In the present research, a series of novel N-methylcarbazole–imidazolium
salt derivatives with good antitumor activity has been designed and synthesized. To the best of our
knowledge, no reports concerning antitumor activity of 3-substituted N-methylcarbazole–imidazole
hybrid compounds have been found in the literature. The purpose was to explore the antitumor
activity of carbazole-based imidazolium salts, with the final target of developing novel potent
antitumor compounds.
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2
| MATERIALS AND METHODS
2
2
.1 | Chemistry
.1.1 | General
Melting points were obtained on a XT-4 melting-point apparatus and were uncorrected. Proton
1
nuclear magnetic resonance ( H-NMR) spectra were recorded on a Bruker Avance 400 spectrometer
13
1
at 400 MHz. Carbon-13 nuclear magnetic resonance ( C{ H}-NMR) was recorded on Bruker Avance
400 spectrometer at 100 MHz. Chemical shifts are reported as δ values in parts per million (ppm)
relative to tetramethylsilane (TMS) for all recorded NMR spectra. Low-resolution Mass spectra were
recorded on a VG Auto Spec-3000 magnetic sector MS spectrometer. High Resolution Mass spectra
were taken on AB QSTAR Pulsar mass spectrometer. Silica gel (100-200 & 200-300 mesh) for
column chromatography and silica GF254 for TCL were produced by Qingdao Marine Chemical
Company (China). All air- or moisture- sensitive reactions were conducted under an argon
atmosphere. Starting materials and reagents used in reactions were obtained commercially from
Acros, Aldrich, Fluka and were used without purification, unless otherwise indicated.
2.1.2 | Synthesis of 9-methyl-9H-carbazole (2)
NaH (60% dispersion, 14.37 mmol) was combined with DMF (50 mL) and cooled to 0 °C bath.
Carbazole (1, 2.00 g, 11.97 mmol) was added to the stirring slurry in portions. After 30 minutes MeI
(
2.04 g, 14.36 mmol) was added slowly. The reaction was stirred at ambient temperature for 2 h. The
heterogeneous reaction mixture was quenched with NH Cl (sat. aq), diluted with EtOAc, then washed
4
sequentially with brine. The organic extracts were dried (Na SO ) and concentrated. The residue was
2
4
chromatographed on silica gel (petroleum ether 60-90 °C : ethyl acetate = 10:1) to afford the
products 2 (1.99 g, 86%) as white powder. See Supporting Information file for characterization data.
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2.1.3 | Synthesis of 9-methyl-9H-carbazole-3-carbaldehyde (3)
POCl (3.09 mL, 33.15 mmol) was slowly added to a solution of DMF (4.26 mL, 55.25 mmol) while
3
the temperature was maintained below 40 °C. Then, carbazole 2 (2.00 g, 11.05 mol) was added
dropwise to this reaction mixture at below 40 °C, over a period of 15 min. The resulting mixture was
warmed and stirred at 80 °C for 24 h. The reaction mixture was then Cooled to room temperature and
slowly dropwised ice water and carefully quenched with a solution of sodium hydroxide. The organic
material was separated, and the aqueous layer was extracted with ethyl acetate. It was washed with
brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated, and the residue
was chromatographed on silica gel (petroleum ether 60-90 °C : ethyl acetate = 10:1) to afford the
products 3 (1.89 g, 82%) as white powder. See Supporting Information file for characterization data.
2.1.4 | Synthesis of (9-methyl-9H-carbazol-6-yl)methanol (4)
To a stirred solution of compound 2 (2.00 g, 9.57 mmol) in MeOH (25 mL) at 0 °C was added
NaBH (0.44 g, 11.48 mmol) in small portions over a period of 20 minutes, and then at ambient
4
temperature for 2 h. Reaction progress was monitored by TLC. A small amount of dilute
hydrochloric acid (1N) was added and the mixture was stirred for 15 min before rotary evaporation.
The solvent was evaporated under reduced pressure and the residue was chromatographed on silica
gel (petroleum ether 60-90 °C : ethyl acetate = 5:1) to afford the product 3 (1.94 g, 96%) as white
powder. See Supporting Information file for characterization data.
2.1.5 | Synthesis of N-methylcarbazole-imidazole compounds (6-8)
To a solution of compound 4 (2.11 g, 10 mmol) in dichloromethane (50 mL) was added
methanesulfonyl chloride (1.16 mL, 15 mmol) and triethylamine (4.18 mL, 30 mmol) at 0 °C. The
resulting mixture was stirred at room temperature for 2 h. After quenching the reaction with water
(
50 mL), the layers were separated. The organic phase was dried over anhydrous magnesium sulfate
and concentrated, and used for the next synthetic step. A mixture of the previous methanesulfonate
and imidazole or substituted imidazole (15 mmol) and K CO (4.14 g, 30 mL ) was stirred in 1,4-
2
3
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dioxane (30 ml) at reflux for 24–48 h (monitored by TLC). After cooling to room temperature, the
solvent was concentrated, and the residue was diluted with EtOAc (20 mL). The organic layer was
washed with water (20 mL) and brine (20 mL), dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by column chromatography (silica gel, petroleum ether 60–
90, ethyl acetate = 2:1 →1 :2) to afford 6-8 in 64-73% yield (two steps) as white powder.
3-((1H-Imidazol-1-yl)methyl)-9-methyl-9H-carbazole (6)
o
-1
Yield 64%. White powder, mp 116-117 C. IR ν (cm ): 3447, 3103, 2337, 1597, 1491, 1436, 1356,
max
1
1
323, 1275, 1249, 1223, 1124, 1075, 1004, 866, 813, 751, 710, 658, 621, 559. H NMR (400 MHz,
CDCl ): δ7.91 (1H, d, J = 7.8 Hz), 7.75 (1H, s), 7.46 (1H, s), 7.38-7.34 (1H, s), 7.23 (1H, d, J = 8.2
3
Hz), 7.17 (1H, d, J = 8.4 Hz), 7.14-7.10 (2H, m), 6.96 (1H, s), 6.79 (1H, s), 5.07 (2H, s), 3.63 (3H, s).
13
1
C{ H} NMR (100 MHz, CDCl ): δ 141.3, 140.6, 137.2, 129.4, 126.3, 126.1, 125.3, 122.9, 120.3,
3
+
1
2
19.7, 119.2, 119.2, 108.9, 108.7, 51.3, 29.1. HRMS (ESI-TOF) m/z Calcd for C H N [M+H]
17
15
3
62.1339, found 262.1338.
-Methyl-3-((2-methyl-1H-imidazol-1-yl)methyl)-9H-carbazole (7)
9
Yield 73%. Yellow oil. IR νmax (cm-1): 3446, 2931, 2330, 1602, 1525, 1493, 1424, 1356, 1330,
1
1
273, 1249, 1124, 1068, 987, 850, 748, 673, 561. H NMR (400 MHz, CDCl ): δ7.93 (1H, d, J = 7.8
3
Hz), 7.68 (1H, s), 7.40-7.36 (1H, m), 7.27 (1H, d, J = 8.2 Hz), 7.22 (1H, d, J = 8.4 Hz), 7.15-7.11
1H, m), 7.09-7.06 (1H, m), 6.86 (1H, d, J = 1.3 Hz), 6.75 (1H, d, J = 1.3 Hz), 5.05 (2H, s), 3.69 (3H,
(
1
3
1
s), 2.29 (3H, s). C{ H} NMR (100 MHz, CDCl ): δ144.8, 141.4, 140.6, 126.8, 126.5, 126.2, 124.8,
3
123.0, 122.3, 120.4, 119.9, 119.2, 119.0, 108.9, 108.7, 50.3, 29.2, 13.2. HRMS (ESI-TOF) m/z Calcd
+
for C H N [M+H] 276.1495, found 276.1493.
18
18
3
3-((1H-Benzo[d]imidazol-1-yl)methyl)-9-methyl-9H-carbazole (8)
o
-1
Yield 73%. White powder, mp 224-225 C. IR ν (cm ): 3446, 3084, 2323, 1600, 1492, 1457, 1432,
max
1
1
361, 1327, 1265, 1180, 1122, 1064, 1002, 869, 801, 746, 623, 559, 427. H NMR (400 MHz,
CDCl ): δ8.02 (1H, d, J = 7.8 Hz), 7.97 (1H, s), 7.84-7.82 (1H, m), 7.50-7.46 (1H, m), 7.40-7.31 (4H,
3
13
1
m), 7.29-7.26 (1H, s), 7.25-7.21 (2H, m), 5.49 (2H, s), 3.81 (3H, s). C{ H} NMR (100 MHz,
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CDCl ): δ144.1, 143.3, 141.5, 140.9, 134.1, 126.3, 125.7, 125.3, 123.2, 123.1, 122.3, 122.3, 120.5,
3
1
20.4, 119.7, 119.3, 110.3, 109.1, 108.8, 49.6, 29.3. HRMS (ESI-TOF) m/z Calcd for C H N
21
18
3
+
[
M+H] 312.1495, found 312.1495.
.1.6 | Synthesis of N-methylcarbazole–imidazolium salts (9-38)
A mixture of compound 6-8 (2.0 mmol) and phenacyl bromides or alkyl halides (1.2 mmol) was
2
stirred in THF (5 ml) at 68 oC for 12-48 h. An insoluble substance was formed. After completion of
the reaction as indicated by TLC, the precipitate was filtered, and washed with ethyl acetate (30-50
ml), then dried to afford imidazolium salts 9-38 in 64-96% yields. See Supporting Information file
for characterization data of all new compounds.
1
-((9-Methyl-9H-carbazol-3-yl)methyl)-3-(2-(naphthalen-2-yl)-2-oxoethyl)-1H-imidazol-3-
ium bromide (18)
o
-1
White powder, yield: 92%, mp 200-201 C. IR ν (cm ): 3380, 3077, 2322, 1692, 1627, 1599, 1566,
max
1
1
494, 1472, 1438, 1362, 1334, 1253, 1159, 1125, 1041, 860, 812, 725. H NMR (400 MHz, DMSO):
δ9.37 (1H, s), 8.82 (1H, s), 8.38 (1H, s), 8.20-8.10 (3H, m), 8.06-8.03 (3H, m), 7.84-7.82 (1H, m),
7.75-7.62 (5H, m), 7.52-7.49 (1H, m), 7.27-7.24 (1H, m), 6.25 (2H, s), 5.74 (2H, s), 3.90 (3H, s).
13
1
C{ H} NMR (100 MHz, DMSO): δ191.3, 141.1, 140.6, 137.2, 135.5, 132.0, 131.0, 130.5, 129.7,
129.3, 128.8, 127.9, 127.4, 126.4, 126.2, 124.8, 124.4, 123.2, 122.2, 122.1, 121.7, 121.0, 120.2,
+
1
19.1, 109.8, 109.5, 55.6, 52.7, 29.1. HRMS (ESI-TOF) m/z Calcd for C H N O [M–Br] 430.1914,
29
24
3
found 430.1915.
2
-Methyl-1-((9-methyl-9H-carbazol-3-yl)methyl)-3-(2-(naphthalen-2-yl)-2-oxoethyl)-1H-
imidazol-3-ium bromide (28)
o
-1
White powder, yield: 95%, Mp 283-284 C. IR ν (cm ): 3443, 3065, 2957, 2325, 1687, 1626, 1594,
max
1
1
531, 1472, 1362, 1333, 1254, 1182, 1126, 1068, 861, 815, 738, 564,481. H NMR (400 MHz,
DMSO): δ8.83 (1H, s), 8.27 (1H, s), 8.20-8.18 (2H, m), 8.12 (1H, d, J = 8.7 Hz), 8.07-8.01 (2H, m),
.91 (1H, d, J = 2.0 Hz), 7.76-7.71 (4H, m), 7.65-7.63 (1H, m), 7.56-7.49 (2H, m), 7.26 (1H, t, J =
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7

1
3
1
1
1
1
4.7 Hz), 6.24 (2H, s), 5.68 (2H, s), 3.91 (3H, s), 2.70 (3H, s). C{ H} NMR (100 MHz, DMSO): δ
91.2, 145.7, 141.1, 140.5, 135.5, 132.0, 131.1, 130.8, 129.7, 129.4, 128.7, 127.9, 127.4, 126.3,
25.9, 124.6, 123.4, 122.9, 122.2, 121.6, 121.6, 120.3, 119.1, 109.9, 109.5, 54.6, 51.5, 29.2, 9.8.
+
HRMS (ESI-TOF) m/z Calcd for C H N O [M–Br] 444.2070, found 444.2072.
3
0
26
3
1
-((9-Methyl-9H-carbazol-3-yl)methyl)-3-(2-(naphthalen-2-yl)-2-oxoethyl)-1H-
benzo[d]imidazol-3-ium bromide (38)
o
-1
White powder, yield: 95%, Mp 239-240 C. IR ν (cm ): 3446, 3131, 2338, 1682, 1601, 1564, 1489,
max
1
1
8
359, 1255, 1219, 1185, 1123, 1063, 992, 864, 819, 771. H NMR (400 MHz, DMSO): δ9.88 (1H, s),
.93 (1H, s), 8.47 (1H, s), 8.21-8.07 (7H, m), 7.70-7.61 (7H, m), 7.50 (1H, s), 7.25 (1H, s), 6.57 (2H,
1
3
1
s), 6.06 (2H, s), 3.89 (3H, s). C{ H} NMR (100 MHz, DMSO): δ191.2, 143.3, 141.1, 140.6, 135.5,
1
1
32.3, 132.0, 131.1, 130.9, 130.6, 129.7, 129.4, 128.7, 127.9, 127.4, 126.9, 126.6, 126.4, 126.2,
23.6, 123.3, 122.2, 121.6, 121.1, 120.3, 119.1, 114.1, 109.9, 109.5, 53.3, 50.8, 29.1. HRMS (ESI-
+
TOF) m/z Calcd for C H N O [M–Br] 480.2070, found 480.2072.
3
3
26
3
2.1.7 | X-single crystal data of 36
C H N O ·Br·H O, M = 558.46, a = 16.3192 (19) Å, b = 10.1075 (12) Å, c = 15.5850 (19) Å, α =
3
0
26
3
2
2
3
9
0°, β = 94.662 (2)°, γ = 90°, V = 2562.2 (5) Å , T = 100 (2) K, space group P21/c, Z = 4, μ (MoKα)
-1
=
1.642 mm , 25263 reflections measured, 6339 independent reflections (R = 0.0844). The final R
int
1
2
values were 0.0475 (I > 2σ (I)). The final wR (F ) values were 0.1201 (I > 2σ (I)). The final R values
1
2
2
were 0.0943 (all data). The final wR (F ) values were 0.1507 (all data). The goodness of fit on F was
0.884. See Supporting Information file for crystallographic data in CIF.†
2.2 | Cytotoxicity assay
o
The assay was in five kinds of cell lines (Hep G-2, Hela, PC12). Cells were cultured at 37 C under a
humidified atmosphere of 5% CO in RPMI 1640 medium supplemented with 10% fetal serum and
2
dispersed in replicate 96-well plates. Compounds were then added. After 48 h exposure to the
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compounds, cells viability were determined by the [3-(4,5- dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide] (MTT) cytotoxicity assay by measuring the absorbance at 570 nm with
a microplate spectrophotometer. Each test was performed in triplicate.
3
| RESULTS AND DISCUSSION
3.1 | Chemistry
SCHEME 2
To prepare N-methylcarbazole imidazole salt derivatives, we used commercially available imidazole
derivatives that were alkylated with (9-methyl-9H-carbazol-6-yl) methanol, which was synthesized
from readily available starting materials as shown in Scheme 2. Carbazole 1 was used as the starting
material, and MeI was slowly added in the presence of the dry DMF and NaH to get N-methyl-
substituted carbazole compound 2 in a yield of 86%. Followed by the introduction of a formyl group
at the 5-position under the classical Vilsmeier-Haack condition to give formylated N-
methylcarbazole compound 3 (82% yield). The carbonyl group was then reduced to a hydroxyl group
in an alcoholic solution of NaBH to give the (9-methyl-9H-carbazol-6-yl)methanol 4 in 96% yield.
4
Key intermediate methanesulfonate compound 5 was obtained with methanesulfonyl chloride.
Methanesulfonate was substituted by various imidazoles (imidazole, 2-methyl-imidazole and
benzimidazole) to give N-methylcarbazole-imidazole compounds 6-8 with 64–73% yields (two
steps). Finally, thirty N-methylcarbazole–imidazolium salt derivatives 9–38 were prepared with
excellent yields by reaction of N-methylcarbazole-imidazole compounds 6-8 with the corresponding
alkyl and phenacyl bromides in refluxing THF (64-96% yields). The structures and yields of N-
methylcarbazole–imidazolium salt derivative are listed in Table 1.
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TABLE 1
To confirm the structures of the N-methylcarbazole–imidazolium salt derivatives, imidazolium salt
3
6 was selected as a representative compound (in CH CN) and characterized by X-ray
3
[
34]
crystallography (the Cambridge crystallographic data centre (CCDC) 1570371),
as shown in
Scheme 3.
SCHEME 3
3.2 | Biological evaluation structure−activity relationship analysis
The effects on the cytotoxicity of all newly synthesized N-methylcarbazole–imidazolium salt
derivatives was evaluated in vitro against a panel of tumor cell lines according to procedures
[35]
described in the literature.
The panel consisted of human liver carcinoma (Hep G-2), human
cervical carcinoma (Hela) and rat pheochromocytoma (PC12). Cisplatin (DDP) was used as the
reference drug. The results are listed in Table 1.
As shown in Table 1, the structures of the hybrids have a noticeable influence on the inhibitory
activities. N-Methylcarbazole–imidazole compounds 6-8 lacked activity at the concentration of 40
μM or showed poor activity. However, their imidazolium salts 9–38 displayed higher cytotoxic
activities.
Most of the N-Methylcarbazole–imidazolium salts had certain antitumor activities compared with
DDP. When the imidazole ring was substituted with imidazole (9-18), the salt derivatives 9, 12, 15–
20 had relatively good activities. In particular, compounds 17 and 18 with 4-bromophenacyl and
naphthylacyl groups had IC values of 0.09–1.80 μM against three tumor cell lines investigated and
5
0
more active than DDP (up to 163-fold lower than DDP). When the imidazole ring was substituted
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with 2-methylimidazole (19–28), the salt compounds 19-28 also had excellent activities. For
example, compound 23 with 4-bromobenzyl group had IC value of 0.33 μM against PC12 cell, and
50
compound 27 with 4-bromophenacyl group had IC value of 1.05 μM against Hela cell. When the
50
imidazole ring was substituted with benzimidazole (29–38), compounds also showed a certain
selectivity. Notably, compound 35 exhibited cytotoxic activity selectively against Hela cell with IC50
values 680-fold lower than DDP.
Comparing the substituent at position-3 of imidazole, compounds 17 and 27 with 4-bromophenacyl
groups as well as compounds 18 and 28 with naphthylacyl groups displayed excellent activities with
IC values of 0.09–7.20 μM against three tumor cell lines investigated. When it was substituted with
50
benzyl groups, the activity was slightly worse than the phenacyl groups.
The results suggest that the existence of substituted 2-methyl-imidazole or imidazole ring and
substitution of the imidazolyl-3-position with a naphthylacyl or 4-bromophenacyl group were
important for improving cytotoxic activity. The structure-activity relationship (SAR) results were
illustrated in Scheme 4.
SCHEME 4
4
| CONCLUSION
In summary, a series of novel 3-substituted N-methylcarbazole–imidazolium salt derivatives has
been prepared and evaluated in vitro against a panel of tumor cell lines (Hep G-2, Hela and PC12).
Compounds 17, 18, 27 and 28 with 4-bromophenacyl and naphthylacyl groups displayed good
activities with IC values of 0.09–7.20 μM against three tumor cell lines investigated and more active
5
0
than DDP (up to 163-fold lower than DDP). Compound 35 exhibited cytotoxic activity selectively
against Hela cell with IC values 680-fold lower than DDP. Carbazole-based imidazolium salts 17,
5
0
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18, 25 26, 27, 28 and 35 can be considered promising leads for further structural modifications
guided by the valuable information derivable from our detailed SARs.
CONFLICT OF INTERESTS
The authors declare no conflict of interest.
ACKNOWLEDGMENTS
This work was supported by Natural Science Foundation of China (21762051 and 21562048),
Innovative Team of Yunnan Minzu University (L.J. Yang) and Key Laboratory of Resource Clean
Conversion in Ethnic Regions of Yunnan. Authors thank Dr. Cui Yang in Yunnan Minzu University
for biological evaluation.
SUPPORTING INFORMATION
Additional Supporting Information (Details of experimental procedure, spectral data and copies of all
novel compounds. CCDC 1570371 crystallographic data in CIF) may be found online in the
supporting information tab for this article.
SCHEME TITLES
SCHEME 1 Molecular hybridization of novel carbazole-imidazolium salt derivatives.
SCHEME 2 Synthesis of imidazole compounds 6–8 and N-methylcarbazole–imidazolium salts
9
-38.
SCHEME 3 X-ray crystal structure of compound 36.
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SCHEME 4 Structure-activity relationship of N-Methylcarbazole–imidazolium salt derivatives.
TABLE TITLES
TABLE 1 Structures, yields and cytotoxic activities of N-methylcarbazole–imidazolium compounds
6-38
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TABLE 1 Structures, yields and cytotoxic activities of N-methylcarbazole–imidazolium compounds
-38
6
b
a
Yields
%)
Cytotoxic activities in vitro (IC50, M )
2
Entry Compd. Imidazole ring
R
(
Hep G-2
>40
Hela
>40
PC12
>40
3.22
0.76
0.11
>40
>40
>40
>40
>40
3.42
1.21
0.09
0.09
>40
2.96
0.27
>40
0.39
>40
1.09
0.94
3.65
1.11
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
6
imidazole
–
–
–
64
73
73
92
92
90
85
92
88
91
7
2-methyl-imidazole
benzimidazole
imidazole
>40
26.63
>40
8
>40
9
benzyl
4.75
2.07
>40
8.98
7.02
4.14
7.88
1.38
>40
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
imidazole
4-methylbenzyl
4-nitrobenzyl
2-bromobenzyl
4-bromobenzyl
naphthylmethyl
phenacyl
imidazole
imidazole
1.15
1.39
1.26
19.00
2.09
1.15
1.80
14.56
1.39
13.60
2.46
1.62
1.17
3.18
1.29
1.18
1.32
imidazole
imidazole
0
1
2
3
4
5
6
7
8
9
0
1
2
3
imidazole
1.31
1.36
1.39
0.95
1.43
0.80
1.33
1.27
5.81
1.30
1.06
6.62
1.05
7.20
imidazole
4-methoxyphenacyl 93
imidazole
4-bromophenacyl
naphthylacyl
benzyl
96
92
83
91
64
84
92
87
92
imidazole
2-methyl-imidazole
2-methyl-imidazole
2-methyl-imidazole
2-methyl-imidazole
2-methyl-imidazole
2-methyl-imidazole
2-methyl-imidazole
2-methyl-imidazole
2-methyl-imidazole
2-methyl-imidazole
4-methylbenzyl
4-nitrobenzyl
2-bromobenzyl
4-bromobenzyl
naphthylmethyl
phenacyl
4-methoxyphenacyl 94
4-bromophenacyl
naphthylacyl
90
95
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2
2
2
2
2
2
3
3
3
3
4
5
6
7
8
9
0
1
2
3
4
29
30
31
32
33
34
35
36
37
38
DDP
benzimidazole
benzimidazole
benzimidazole
benzimidazole
benzimidazole
benzimidazole
benzimidazole
benzimidazole
benzimidazole
benzimidazole
benzyl
86
90
92
83
91
64
89
>40
1.70
8.01
1.15
1.39
>40
>40
>40
>40
>40
3.10
>40
>40
4-methylbenzyl
4-nitrobenzyl
2-bromobenzyl
4-bromobenzyl
naphthylmethyl
phenacyl
9.92
>40
>40
0.06
>40
>40
>40
>40
4.36
0.02
>40
>40
>40
4-methoxyphenacyl 94
>40
4-bromophenacyl
naphthylacyl
96
95
>40
16.20
21.57
14.75
31.62
13.61
3
a
Cytotoxicity as IC for each cell line, is the concentration of compound which reduced by 50% the optical density
5
0
of treated cells with respect to untreated cells using the MTT assay.
b
Data represent the mean values of three independent determinations.
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SCHEME 1
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SCHEME 2
SCHEME 3
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SCHEME 4
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