European Journal of Medicinal Chemistry 45 (2010) 4692e4696

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European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Short communication

Synthesis and antimicrobial activities of novel 1H-dibenzo[a,c]carbazoles

from dehydroabietic acid
Wen Gu*, Shifa Wang
Department of Forestry Chemical Engineering, College of Chemical Engineering, Nanjing Forestry University, 149, Longpan Road, Nanjing 210037, PR China

a r t i c l e i n f o a b s t r a c t

Article history: A series of novel 1H-dibenzo[a,c]carbazole derivatives were synthesized in good yield through reaction
Received 28 May 2010 of methyl 7-oxo-dehydroabietate with a variety of substituted phenylhydrazines. The structures of the
Received in revised form newly synthesized compounds were confirmed by IR, 1H NMR, MS spectral studies and elemental
18 July 2010
analysis. All compounds were investigated for their activity against four bacteria (Bacillus subtilis,
Accepted 19 July 2010
Available online 24 July 2010
Staphylococcus aureus, Escherichia coli and Pseudomonas fluorescens) and three fungi (Trichophyton
rubrum, Candida albicans and Aspergillus niger). Among the compound tested, 6d, 6e, 6f and 6m exhibited
pronounced antibacterial activities and 6e and 6m also showed moderate antifungal activities. Partic-
Keywords:
1H-dibenzo[a,c]carbazole
ularly, 6d exhibited stronger antibacterial activity against B. subtilis comparable to positive control.
Dehydroabietic acid Ó 2010 Elsevier Masson SAS. All rights reserved.
Synthesis
Antibacterial activity
Antifungal activity

1. Introduction antiviral, antioxidant, gastroprotective and Kþ channel-opening

The rapid development of multi-drug resistant microbial
pathogens has made the treatment of infectious diseases an
escalating problem. Consequently, there is a pressing need to
develop new and efficacious antimicrobial agents [1,2]. As an
important class of natural alkaloids, carbazole derivatives have
been isolated from different sources such as some genera of higher
plants, blueegreen algae, actinomycetes and filamentous fungi.
Widespread interests of chemists have been attracted to these
structures due to their biological activities and potential applica-
tions as pharmacological agents [3]. A large number of natural and
synthetic carbazole derivatives have been reported to exhibit
diverse biological activities such as antimicrobial [4e8], antitumor
[9e11], antiviral [12], anti-inflammatory [13], antimalarial [14],
antidiarrhoeal [15] and other biological properties such as
immunosuppression [16], neuroprotection [17] and pancreatic
lipase inhibition [18].
Dehydroabietic acid (DHA, 1) is an abietane diterpene that can
be readily obtained from disproportionated rosin. DHA and
a number of its derivatives have been reported to possess a broad
spectrum of biological properties such as antimicrobial, antitumor,
* Corresponding author. Tel.: þ86 25 8542 8369; fax: þ86 25 8542 7396.
E-mail address: njguwen@163.com (W. Gu).
activities [19e24]. Therefore, the compound is proved to be a useful
starting material for physiologically or pharmacologically impor-
tant products. In light of these findings, it is supposed that the
introduction of carbazole moiety to DHA may produce derivatives
with considerable antimicrobial activity. Herein, we report the
synthesis of a series of new 1H-dibenzo[a,c]carbazoles starting
from DHA. Their in vitro antimicrobial activities against several test
microorganisms are also presented.
2. Chemistry
The synthesis of the carbazole derivatives (6) was performed in
a manner as outlined in Scheme 1. Dehydroabietic acid (1) was
converted into methyl dehydroabietate (2) by the esterification
reaction using known procedure. Further the ester was oxidized
by CrO3 to give the key intermediate methyl 7-oxo-dehydro-
abietate (3) [24]. Diazotization of different substituted anilines (4)
followed by reduction by SnCl2 afforded the corresponding
substituted phenylhydrazine hydrochlorides (5) [25]. Finally, the
2,3,4,4a,9,13c-Hexahydro-7-isopropyl-1,4a-dimethyl-1H-dibenzo[a,c]
carbazole-1-carboxylic acid methyl ester derivatives (6aem) were
obtained in moderate to good yields from compound 3 and
different phenylhydrazine hydrochlorides (5) with the presence of
hydrochloric acid through Fischer indole reaction [26].

0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.07.038
 W. Gu, S. Wang / European Journal of Medicinal Chemistry 45 (2010) 4692e4696
NH 2
NaNO2 , HCl
R R
4 NHNH 2·HCl
1) SOCl2 CrO 3
HOAc/Ac2 O
2) MeOH
CO 2H CO 2Me
1 2
R=H ( 6a) 12-CH3
12-F (6d ) 10-F
10-Cl (6g) 12-Br
12-OCH3 (6j ) 10-OCH 3
12-NO 2 (6m )
Scheme 1. Synthetic route of carbazole derivatives from dehydroabietic acid.
3. Antimicrobial studies
All the newly synthesized carbazole derivatives were screened
for their antibacterial and antifungal activity. Seven strains were
used as test microorganisms including four bacteria: Bacillus subtilis
CGMCC1.1162 (Bs), Escherichia coli CGMCC1.1571 (Ec), Pseudomonas
fluorescens CGMCC1.1828 (Pf) and Staphylococcus aureus
CGMCC1.1361 (Sa), and three fungi: Trichophyton rubrum ATCC10218
(Tr), Candida albicans CGMCC2.2086 (Ca) and Aspergillus niger
CGMCC3.316 (An). The four bacteria and the fungi C. albicans, A. niger
were obtained from China General Microbiological Culture Collec-
tion Center (CGMCC), China, while T. rubrum was from American
Type Culture Collection (ATCC), USA. The antimicrobial activity was
assessed in terms of minimum inhibitory concentrations (MICs) by
a modified microdilution method [27]. Compounds were dissolved
in 20% DMSO and serial double dilutions of each compound (50 mL)
were prepared in 96 well micro-trays. The same amount of test
microorganism in Martin’s (for bacteria) or PD (for fungi) broth
(w105 colony forming unit (CFU)/ml) was added to each well to give
a final volume of 100 mL. Amikacin sulfate and ketoconazole were
included as positive control, and 20% DMSO was used as negative
control. After incubation at 37  C for 24 h (for bacteria) or 28  C for
48 h (for fungi), the trays were examined for growth of the test
microbes. The MIC was defined as the lowest concentrations of
compound at which microbial growth was inhibited. All assays were
performed in duplicate.
4. Results and discussion
4.1. Analysis of spectra
The structures of synthetic carbazole derivatives were
confirmed on the basis of elemental analysis, IR, MS and NMR
techniques. The IR spectra of 6aem exhibited in all cases NeH
bands in the range 3359e3397 cm1. The strong absorption bands
at 1698e1728 cm1 were due to the C]O stretch vibrations of the
methyl ester moiety. The ESIeMS of compounds 6aem displayed,
in all cases, peaks corresponding to quasimolecular ions which
confirmed their molecular weights. The 1H NMR spectra of 6aem
were similar except for the aromatic protons. In a typical example,
1
H NMR spectra of 6b showed two doublets at d 1.30 and
1.31 ppm, each corresponding to three protons, due to the two
diastereotopic methyl protons of the isopropyl group, together
4693
N 2 +Cl−
SnCl2, HCl
17
16
5 7
15 18
4
8
5
R 9
2
HCl, EtOH
1 NH
O reflux, 4 h MeO2 C 14
CO 2Me 13 10
12 R
3 6a-m
(6b) 10-CH3 (6c)
(6e) 12-Cl (6f )
(6h) 10-Br (6i)
( 6k ) 12-OC 2H 5 (6l)
with a multiplet at d 2.94 ppm due to the vicinal CH proton. Four
singlets at d 1.11, 1.78, 2.42 and 3.64 ppm could be observed
attributed to methyl protons at C-14, C-15, Ar-CH3 and the ester
group, respectively. A singlet at d 3.85 ppm could be assigned to
H-13c. Six aromatic protons in the two benzene moiety appeared
in the range d 6.96e7.30 ppm while the NH proton resonated as
a broad singlet at d 8.31 ppm. The signals of other carbazole
derivatives were assigned by comparing with those of 6b. In the
12-fluoro compound 6d, three signals attributable to H-10, H-11
and H-13 splitted as a doublet of doublet at d 7.32 (JH-F meta ¼ 5.0),
a doublet of triplet at d 6.89 (JH-F ortho ¼ 9.0), and a doublet of
doublet at d 7.02 (JH-F ortho ¼ 10.5), respectively, due to coupling
with 19F.
4.2. Antimicrobial activity
All the synthesized compounds (2, 3 and 6aem) were screened
for their antimicrobial activities against four bacteria and three
fungi. The minimal inhibitory concentration (MIC) values of test
compounds against the test microbes are listed in Table 1. Also
included are the MICs of reference compounds amikacin (for
bacteria) and ketoconazole (for fungi). The results revealed that the
majority of the synthesized compounds showed varying degrees of
inhibition against the test microorganisms. It was found that
compounds 6def and 6m showed strong activities (1.9e7.8 mg/ml)
against the gram-positive bacteria (B. subtilis and S. aureus). Among
them compound 6d exhibited significant activity against B. subtilis
with the MIC value (1.9 mg/ml) comparable to that of positive
control. Compound 6d also showed strong activity (7.8 mg/ml)
against Gram-negative bacteria P. fluorescens, while 6e, 6f, 6h, 6l
and 6m showed moderate activities (15.6e31.2 mg/ml) against
E. coli and P. fluorescens. As for antifungal activities, most com-
pounds showed low inhibition against the three fungal strains.
Among them, only 6e and 6m exhibited moderate inhibition
(31.2 mg/ml) against C. albicans. Notably, compound 6e with a broad
antimicrobial spectrum was the only compound exhibiting activi-
ties against all test microbes. In addition, 6b, 6d, 6j and 6l also
showed mild inhibitory activities (62.5 mg/ml) against T. rubrum
and C. albicans while most compounds were inactive to A. niger.
From structureeactivity relationship (SAR) studies, it was indicated
that the incorporation of carbazole moiety to methyl dehydroabietate
caused enhanced activities against most test microorganisms. The
results also suggested that the antimicrobial activities of the carbazole
4694 W. Gu, S. Wang / European Journal of Medicinal Chemistry 45 (2010) 4692e4696

Table 1
Antimicrobial activities of compounds 2, 3 and 6aem.

Test compounds Minimum inhibitory concentrations (mg/ml)

Bs Sa Ec Pf Tr Ca An
2 >100 62.5 >100 >100 >100 >100 >100
3 31.2 31.2 >100 62.5 >100 >100 >100
6a 31.2 62.5 >100 62.5 >100 >100 >100
6b 31.2 62.5 >100 31.2 62.5 >100 >100
6c >100 >100 >100 >100 >100 >100 >100
6d 1.9 3.9 15.6 7.8 >100 62.5 >100
6e 7.8 31.2 31.2 15.6 62.5 31.2 62.5
6f 3.9 3.9 15.6 31.2 >100 >100 >100
6g 31.2 31.2 >100 >100 >100 >100 >100
6h 15.6 31.2 31.2 15.6 >100 >100 >100
6i 62.5 >100 >100 62.5 >100 >100 >100
6j 62.5 31.2 >100 >100 >100 62.5 >100
6k >100 62.5 >100 >100 >100 >100 >100
6l 62.5 >100 62.5 31.2 62.5 62.5 >100
6m 7.8 7.8 15.6 15.6 62.5 31.2 >100
Amikacin 0.9 0.9 1.9 0.9 e e e
Ketoconazole e e e e 3.9 3.9 7.8

derivatives were markedly influenced by the aromatic substituents.
Compounds 6d, 6e, 6f and 6m with electron-withdrawing substitu-
ents (F, Cl and NO2) in the aromatic ring were more active against all
test bacteria than compounds with electron-donating ones. In addi-
tion, carbazole derivatives containing 12-halogen and 12-OCH3
generally showed greater antibacterial activities than their analogs
with same substituents at C-10. As for antifungal activities, compounds
6e and 6m with 10-F and 12-NO2, respectively, also exhibited stronger
activities against C. albicans than other compounds. Notably, the 12-F
compound 6d was found to be the most potent antimicrobial agent
indicated that the incorporation of fluorine atom played an important
role in the antimicrobial activity possibly due to its ability to provide
the compound with increased oxidative and thermal stability and
increased lipid solubility [28].
5. Conclusions
A series of novel 1H-dibenzo[a,c]carbazole derivatives (6aem)
were synthesized from dehydroabietic acid in approach of new
antimicrobial agents. All compounds were examined for their in
vitro antimicrobial activities against four bacteria and three fungi.
Among them, compounds with 12-F, 10-F, 10-Cl, and 10-NO2
showed pronounced antimicrobial activities. The results open the
way for investigation of new potential lead compounds in the study
of antimicrobial agents. Further derivatization of the active scaf-
folds and the in-depth SAR study are also required.
6. Experimental protocols
6.1. General
Melting points were measured on an XT-4 apparatus (Taike
Corp., Beijing, China) and were uncorrected. The ESIeMS spectra
were recorded on a Mariner System 5304 mass spectrometer. 1H
NMR spectra were accomplished in CDCl3 on a Bruker DRX-500
NMR spectrometer using TMS as internal standard. Reactions and
the resulted products were monitored by TLC which was carried
out on silica gel IB-F flexible sheets from Mallinckrodt Baker Inc.,
Germany and visualized in UV light (254 nm). Silica gel (300e400
mesh) for column chromatography was purchased from Qingdao
Marine Chemical Factory, China. The reagents (chemicals), all being
of A.R. grade, were purchased from Shanghai Chemical Reagent
Company (Shanghai, China). The substituted anilines were
purchased from Alfa Aesar Co. (Tianjing China). Disproportionated
rosin was provided by Zhongbang Chemicals Co., Ltd. (Zhaoqing,
China), from which dehydroabietic acid (1, 97%) was isolated
according to the published method [29].
6.2. Chemistry
6.2.1. General procedures for the preparation of substituted
phenylhydrazine hydrochlorides (5)
To a solution of substituted aniline (4, 50 mmol) in 50 ml of 20%
HCl was added dropwise the solution of NaNO2 (3.63 g, 52.5 mmol)
in 8 ml of H2O while cooling with an ice-water bath. The reaction
mixture was stirred at 0e5  C for 1 h to give a clear solution. Then
to the solution was added dropwise a solution of SnCl2 (0.1 mol) in
30 ml of 35% HCl at 0e5  C. Then the mixture was stirred at room
temperature for 1e2 h. The solid product was filtered, washed with
35% HCl for 3 times and dried in a vacuum desiccator containing
anhydrous CaCl2. The product could be used in subsequent reac-
tions without further purification.
6.2.2. Methyl dehydroabietate (2)
To a solution of dehydroabietic acid (30 g, 0.1 mol) in 100 ml of
benzene was added slowly 10.9 ml of SOCl2 (17.85 g, 0.15 mol). The
mixture was then refluxed for 3 h. After cooling, the solvent and
excess SOCl2 were removed in vacuo to yield a yellow oily product,
which was then treated with 60 ml of MeOH through refluxing for
2 h. The mixture was then cooled and concentrated in vacuo to yield
a white solid, which was recrystallized in EtOH to afford compound
2 as colorless needles (28.9 g, 92% yield), m.p. 62.3e63.9  C, IR (KBr,
cm1): n 3052, 2994, 2930, 2868, 1721, 1381, 1250, 1082, 825. 1H
NMR (CDCl3, 300 MHz): d 1.23 (d, J ¼ 7.1 Hz, 6H, 13-CH(CH3)2), 1.27
(s, 3H, CH3), 1.42 (m, 1H), 1.50 (m, 1H), 1.57 (s, 3H, CH3), 1.61e1.70
(m, 5H), 2.24 (dd, J ¼ 12.5, 2.1 Hz, 1H), 2.30 (d, J ¼ 12.3 Hz, 1H),
2.80e2.90 (m, 3H), 3.66 (s, 3H, COOCH3), 6.88 (d, J ¼ 1.5 Hz, 1H,
H-14), 6.99 (dd, J ¼ 8.1, 1.5 Hz, 1H, H-12), 7.16 (d, J ¼ 8.1 Hz, 1H,
H-11). MS (EI) m/z 314 (Mþ), 299 ([MeCH3]þ). Anal. Calcd for
C21H30O2: C, 80.21; H, 9.62; found C, 80.38; H, 9.51.
6.2.3. Methyl 7-oxo-dehydroabietate (3)
To a solution of compound 2 (8.0 g, 25.5 mmol) in 30 ml of AcOH
was added dropwise a solution of CrO3 (2.64 g, 26.4 mmol) in 18 ml
of AcOHeAc2O (1:2, v/v) at 0  C and the reaction mixture was
stirred at room temperature overnight. Then the mixture was
poured onto 200 ml of ice-cold water and extracted with CH2Cl2
(3  100 ml). The organic layer was combined, washed with
 W. Gu, S. Wang / European Journal of Medicinal Chemistry 45 (2010) 4692e4696
saturated NaHCO3 solution, water and brine, dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was chromato-
graphed on a silica gel column (petroleum ethereacetone 100:1, v/
v) to give compound 3 as yellow oil (5.36 g, 64% yield). 1H NMR
(CDCl3, 300 MHz): d 1.25 (d, J ¼ 7.0 Hz, 6H, 13-CH(CH3)2), 1.26 (s, 3H,
H-17), 1.35 (s, 3H, H-16), 1.60e1.84 (m, 5H), 2.27e2.40 (m, 2H), 2.76
(m, 2H), 2.91 (m, 1H), 3.65 (s, 3H, COOCH3), 7.29 (d, J ¼ 8.1 Hz, 1H,
H-11), 7.40 (dd, J ¼ 8.1, 2.1 Hz, 1H, H-12), 7.87 (d, J ¼ 2.0 Hz, 1H,
H-14). MS (ESI) m/z 329 ([M þ H]þ). Anal. Calcd for C21H28O3: C,
76.79; H, 8.59; found C, 76.58; H, 8.75.
6.2.4. General procedures for the syntheses of 1H-dibenzo[a,c]
carbazole derivatives (6ae6m)
To a solution of compound 3 (1.8 g, 5.5 mmol) in 20 ml of EtOH
was added 12 mmol of substituted phenylhydrazine hydrochloride
(5) and 2 ml of concentrated HCl. The mixture was refluxed for 3 h.
After cooling, the mixture was poured onto 100 ml of ice-cold water
and extracted with CH2Cl2 (3  80 ml). The organic layer was
combined, washed with saturated NaHCO3 solution and brine,
dried over anhydrous Na2SO4 and concentrated to give a crude
product, which was subject to a silica gel column chromatography
(petroleum ethereacetone 50:1, v/v) to afford compound 6.
6.2.4.1. 2,3,4,4a,9,13c-Hexahydro-7-isopropyl-1,4a-dimethyl-1H-dibenzo
[a,c]carbazole-1-carboxylic acid methyl ester (6a). White powder; yield
61%; mp 170e172  C; IR (KBr, n, cm1): 3370, 2958, 2930, 2868,
1700, 1460, 1441, 1263. 1H NMR (CDCl3): 1.10 (s, 3H, H-14), 1.31 (d,
3H, J ¼ 7 Hz, H-17 or H-18), 1.32 (d, 3H, J ¼ 7 Hz, H-18 or H-17), 1.69
(m, 1H), 1.77 (s, 3H, H-15), 1.80e2.00 (m, 4H), 2.30 (m, 1H), 2.91 (m,
1H, H-16), 3.68 (s, 3H, COOCH3), 3.84 (s, 1H, H-13c), 7.06e7.20 (m,
3H), 7.25 (d, 1H, J ¼ 1.5 Hz), 7.28 (d, 1H, J ¼ 8.0 Hz), 7.32 (d, 1H,
J ¼ 8.0 Hz), 7.52 (d, 1H, J ¼ 7.5 Hz), 8.35 (brs, 1H, NeH). MS (ESI) m/z
402 ([M þ H]þ), 424 ([M þ Na]þ). Anal. Calcd for C27H31NO2: C,
80.76; H, 7.78; N, 3.49; found C, 80.56; H, 7.92; N, 3.58.
6.2.4.2. 2,3,4,4a,9,13c-Hexahydro-7-isopropyl-1,4a,12-trimethyl-1H-
dibenzo[a,c]carbazole-1-carboxylic acid methyl ester (6b). White
powder; yield 70%; mp 175e177  C; IR (KBr, n, cm1): 3366, 2956,
2929, 2852, 1698, 1450, 1382, 1248, 793. 1H NMR (CDCl3): 1.11 (s, 3H,
H-14), 1.30 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.31 (d, 3H, J ¼ 7 Hz, H-18
or H-17), 1.68 (m, 1H), 1.78 (s, 3H, H-15), 1.80e2.00 (m, 4H), 2.30 (m,
1H), 2.42 (s, 3H, Ar-CH3), 2.94 (m, 1H, H-16), 3.64 (s, 3H, COOCH3),
3.85 (s, 1H, H-13c), 6.96 (d, 1H, J ¼ 8 Hz), 7.12 (s, 1H), 7.13 (dd, 1H,
J ¼ 8, 1.5 Hz), 7.24 (d, 1H, J ¼ 1.5 Hz), 7.26 (d, 1H, J ¼ 8 Hz), 7.29
(d, 1H, J ¼ 8 Hz), 8.31 (brs, 1H, NeH). MS (ESI) m/z 416 ([M þ H]þ).
Anal. Calcd for C28H33NO2: C, 80.93; H, 8.00; N, 3.37; found C, 81.08;
H, 7.89; N, 3.47.
6.2.4.3. 2,3,4,4a,9,13c-Hexahydro-7-isopropyl-1,4a,10-trimethyl-1H-
dibenzo[a,c]carbazole-1-carboxylic acid methyl ester (6c). White
powder; yield 56%; mp 147e149  C; IR (KBr, n, cm1): 3384, 2957,
2929, 2868, 1702, 1457, 1259, 1128, 826, 746. 1H NMR (CDCl3): 1.10
(s, 3H, H-14), 1.35 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.36 (d, 3H,
J ¼ 7 Hz, H-18 or H-17), 1.70 (m, 1H), 1.79 (s, 3H, H-15), 1.82e2.02
(m, 4H), 2.33 (m, 1H), 2.60 (s, 3H, Ar-CH3), 3.00 (m, 1H, H-16), 3.62
(s, 3H, COOCH3), 3.89 (s, 1H, H-13c), 6.97 (d, 1H, J ¼ 7 Hz), 7.00 (t, 1H,
J ¼ 7 Hz), 7.17 (d, 1H, J ¼ 8 Hz), 7.22 (d, 1H, J ¼ 7.5 Hz), 7.28 (s, 1H),
7.30 (d, 1H, J ¼ 8 Hz), 8.24 (brs, 1H, NeH). MS (ESI) m/z 416
([M þ H]þ). Anal. Calcd for C28H33NO2: C, 80.93; H, 8.00; N, 3.37;
found C, 80.82; H, 8.11; N, 3.58.
6.2.4.4. 12-Fluoro-2,3,4,4a,9,13c-hexahydro-7-isopropyl-1,4a-dimethyl-
1H-dibenzo[a,c]carbazole-1-carboxylic acid methyl ester (6d). Brown
powder; yield 58%; mp 178e180  C; IR (KBr, n, cm1): 3390, 2957,
2933, 2869, 1714, 1574, 1453, 1245, 1182. 1H NMR (CDCl3): 1.11 (s,
4695
3H, H-14), 1.32 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.33 (d, 3H, J ¼ 7 Hz,
H-17 or H-18), 1.70 (m, 1H), 1.77 (s, 3H, H-15), 1.84e2.02 (m, 4H),
2.33 (m, 1H), 2.97 (m, 1H, H-16), 3.69 (s, 3H, COOCH3), 3.86 (s, 1H, H-
13c), 6.89 (dt, 1H, J ¼ 9.0, 2.0 Hz, H-11), 7.02 (dd, 1H, J ¼ 10.5, 2 Hz,
H-13), 7.18 (dd, 1H, J ¼ 8.0, 1.5 Hz), 7.26 (d, 1H, J ¼ 1.5 Hz), 7.30 (d,
1H, J ¼ 8.0 Hz), 7.32 (dd, 1H, J ¼ 8.5, 5.0 Hz, H-10), 8.41 (brs, 1H,
NeH). MS (ESI) m/z 420 ([M þ H]þ). Anal. Calcd for C27H30FNO2: C,
77.30; H, 7.21; N, 3.34; found C, 77.47; H, 7.32; N, 3.12.
6.2.4.5. 10-Fluoro-2,3,4,4a,9,13c-hexahydro-7-isopropyl-1,4a-dimethyl-
1H-dibenzo[a,c]carbazole-1-carboxylic acid methyl ester (6e). Yellow
powder; yield 49%; mp 140e142  C; IR (KBr, n, cm1): 3398, 2958,
2931, 2868, 1719, 1570, 1463, 1241, 1180. 1H NMR (CDCl3): 1.11 (s, 3H,
H-14), 1.34 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.35 (d, 3H, J ¼ 7 Hz, H-17
or H-18), 1.69 (m, 1H), 1.79 (s, 3H, H-15), 1.82e2.00 (m, 4H), 2.33 (m,
1H), 2.93 (m, 1H, H-16), 3.68 (s, 3H, COOCH3), 3.88 (s, 1H, H-13c),
6.98 (dt, 1H, J ¼ 8.5, 5.2 Hz, H-12), 7.12 (t, 1H, J ¼ 8.6 Hz), 7.18 (dd,
1H, J ¼ 8.0, 1.5 Hz), 7.26e7.34 (m, 3H), 8.48 (brs, 1H, NeH). MS (ESI)
m/z 420 ([M þ H]þ). Anal. Calcd for C27H30FNO2: C, 77.30; H, 7.21; N,
3.34; found C, 77.56; H, 7.55; N, 3.03.
6.2.4.6. 12-Chloro-2,3,4,4a,9,13c-hexahydro-7-isopropyl-1,4a-dimethyl-
1H-dibenzo[a,c]carbazole-1-carboxylic acid methyl ester (6f). Brown
powder; yield 57%; mp 110e112  C; IR (KBr, n, cm1): 3360, 2957,
2930, 2868, 1699, 1561, 1472, 1245, 964, 796. 1H NMR (CDCl3): 1.11
(s, 3H, H-14), 1.31 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.32 (d, 3H,
J ¼ 7 Hz, H-17 or H-18), 1.68 (m, 1H), 1.79 (s, 3H, H-15), 1.77e2.05
(m, 4H), 2.32 (m, 1H), 2.95 (m, 1H, H-16), 3.70 (s, 3H, COOCH3), 3.83
(s, 1H, H-13c), 7.05 (d, 1H, J ¼ 8 Hz), 7.15 (d, 1H, J ¼ 8 Hz), 7.23e7.30
(m, 3H), 7.40 (s, 1H), 8.42 (brs, 1H, NeH). MS (ESI) m/z 436
([M þ H]þ). Anal. Calcd for C27H30ClNO2: C, 74.38; H, 6.94; N, 3.21;
found C, 74.22; H, 6.99; N, 3.09.
6.2.4.7. 10-Chloro-2,3,4,4a,9,13c-hexahydro-7-isopropyl-1,4a-dimethyl-
1H-dibenzo[a,c]carbazole-1-carboxylic acid methyl ester (6g). Yellow
powder; yield 48%; mp 76e78  C; IR (KBr, n, cm1): 3367, 2956,
2932, 2867, 1696, 1558, 1465, 1242, 736. 1H NMR (CDCl3): 1.11 (s, 3H,
H-14), 1.32 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.33 (d, 3H, J ¼ 7 Hz, H-17
or H-18), 1.69 (m, 1H), 1.80 (s, 3H, H-15), 1.80e2.05 (m, 4H), 2.33 (m,
1H), 2.98 (m, 1H, H-16), 3.68 (s, 3H, COOCH3), 3.85 (s, 1H, H-13c),
7.06e7.10 (m, 2H), 7.15 (d, 1H, J ¼ 8 Hz), 7.24 (d, 1H, J ¼ 7.5 Hz),
7.28e7.36 (m, 2H), 8.35 (brs, 1H, NeH). MS (ESI) m/z 436 ([M þ H]þ).
Anal. Calcd for C27H30ClNO2: C, 74.38; H, 6.94; N, 3.21; found C,
74.51; H, 7.06; N, 3.05.
6.2.4.8. 12-Bromo-2,3,4,4a,9,13c-hexahydro-7-isopropyl-1,4a-dimethyl-
1H-dibenzo[a,c]carbazole-1-carboxylic acid methyl ester (6h). Brown
powder; yield 58%; mp 120e122  C; IR (KBr, n, cm1): 3357, 2956,
2930, 2868, 1698, 1508, 1470, 1245, 960, 794. 1H NMR (CDCl3): 1.10
(s, 3H, H-14), 1.32 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.33 (d, 3H,
J ¼ 7 Hz, H-17 or H-18), 1.70 (m, 1H), 1.78 (s, 3H, H-15), 1.80e2.00
(m, 4H), 2.33 (m, 1H), 2.95 (m, 1H, H-16), 3.74 (s, 3H, COOCH3), 3.84
(s, 1H, H-13c), 7.18 (d, 1H, J ¼ 8.5 Hz), 7.21 (d, 1H, J ¼ 8 Hz), 7.25e7.30
(m, 3H), 7.46 (s, 1H, H-13), 8.48 (brs, 1H, NeH). MS (ESI) m/z 480,
482 ([M þ H]þ). Anal. Calcd for C27H30BrNO2: C, 67.50; H, 6.29; N,
2.92; found C, 67.38; H, 6.21; N, 2.98.
6.2.4.9. 10-Bromo-2,3,4,4a,9,13c-hexahydro-7-isopropyl-1,4a-dimethyl-
1H-dibenzo[a,c]carbazole-1-carboxylic acid methyl ester (6i). Brown
powder; yield 40%; mp 107e110  C; IR (KBr, n, cm1): 3365, 2953,
2932, 2866, 1702, 1523, 1467, 1242, 742. 1H NMR (CDCl3): 1.11 (s, 3H,
H-14), 1.32 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.33 (d, 3H, J ¼ 7 Hz, H-17
or H-18), 1.69 (m, 1H), 1.80 (s, 3H, H-15), 1.80e2.00 (m, 4H), 2.35 (m,
1H), 2.97 (m, 1H, H-16), 3.69 (s, 3H, COOCH3), 3.87 (s, 1H, H-13c),
6.97 (t, 1H, J ¼ 8.0 Hz), 7.16 (d, 1H, J ¼ 8.5 Hz), 7.26e7.33 (m, 2H),
4696 W. Gu, S. Wang / European Journal of Medicinal Chemistry 45 (2010) 4692e4696
7.41 (d, 1H, J ¼ 8.0 Hz), 7.62 (d, 1H, J ¼ 8.0 Hz), 8.38 (brs, 1H, NeH).
MS (ESI) m/z 480, 482 ([M þ H]þ). Anal. Calcd for C27H30BrNO2: C,
67.50; H, 6.29; N, 2.92; found C, 67.83; H, 6.49; N, 2.56.
6.2.4.10. 2,3,4,4a,9,13c-Hexahydro-7-isopropyl-12-methoxy-1,4a-
dimethyl-1H-dibenzo[a,c] carbazole-1-carboxylic acid methyl
ester (6j). White powder; yield 71%; mp 95e97  C; IR (KBr, n,
cm1): 3396, 2956, 2930, 2862, 1717, 1620, 1454, 1245, 1219. 1H
NMR (CDCl3): 1.11 (s, 3H, H-14), 1.32 (d, 3H, J ¼ 7 Hz, H-17 or H-18),
1.33 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.72 (m, 1H), 1.80 (s, 3H, H-15),
1.82e2.02 (m, 4H), 2.33 (m, 1H), 2.96 (m, 1H, H-16), 3.63 (s, 3H,
COOCH3), 3.84 (s, 3H, Ar-OCH3), 3.88 (s, 1H, H-13c), 6.82 (dd, 1H,
J ¼ 8.5, 2 Hz), 6.87 (s, 1H), 7.16 (d, 1H, J ¼ 8 Hz), 7.26e7.32 (m, 3H),
8.31 (brs, 1H, NeH). MS (ESI) m/z 432 ([M þ H]þ). Anal. Calcd for
C28H33NO3: C, 77.92; H, 7.71; N, 3.24; found C, 78.13; H, 7.82;
N, 3.09.
6.2.4.11. 2,3,4,4a,9,13c-Hexahydro-7-isopropyl-10-methoxy-1,4a-
dimethyl-1H-dibenzo[a,c] carbazole-1-carboxylic acid methyl
ester (6k). White powder; yield 64%; mp 169e170  C; IR (KBr, n,
cm1): 3364, 2955, 2934, 2869, 1728, 1670, 1572, 1460, 1240, 730. 1H
NMR (CDCl3): 1.11 (s, 3H, H-14), 1.33 (d, 3H, J ¼ 7 Hz, H-17 or H-18),
1.34 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.70 (m, 1H), 1.78 (s, 3H, H-15),
1.82e2.02 (m, 4H), 2.33 (m, 1H), 2.97 (m, 1H, H-16), 3.62 (s, 3H,
COOCH3), 3.88 (s, 1H, H-13c), 4.03 (s, 3H, Ar-OCH3), 6.64 (dd, 1H,
J ¼ 6.5, 1.5 Hz), 6.96e7.01 (m, 2H), 7.16 (d, 1H, J ¼ 7.5 Hz), 7.29 (d, 1H,
J ¼ 7.5 Hz), 7.31 (s, 1H), 8.63 (brs, 1H, NeH). MS (ESI) m/z 432
([M þ H]þ). Anal. Calcd for C28H33NO3: C, 77.92; H, 7.71; N, 3.24;
found C, 78.06; H, 7.65; N, 3.32.
6.2.4.12. 12-Ethoxy-2,3,4,4a,9,13c-hexahydro-7-isopropyl-1,4a-dimethyl-
1H-dibenzo[a,c] carbazole-1-carboxylic acid methyl ester (6l). Brown
powder; yield 61%; mp 73e76  C; IR (KBr, n, cm1): 3380, 2956,
2930, 2868, 1718, 1623, 1510, 1474, 1244, 1216, 816. 1H NMR (CDCl3):
1.10 (s, 3H, H-14), 1.32 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.33 (d, 3H,
J ¼ 7 Hz, H-17 or H-18), 1.36 (t, 3H, J ¼ 7 Hz, Ar-OCH2CH3), 1.70 (m,
1H), 1.79 (s, 3H, H-15), 1.81e2.02 (m, 4H), 2.33 (m, 1H), 2.95 (m, 1H,
H-16), 3.62 (s, 3H, COOCH3), 3.88 (s, 1H, H-13c), 4.09 (q, 2H, Ar-
OCH2CH3), 6.80 (dd, 1H, J ¼ 8.5, 1.5 Hz), 6.88 (s, 1H), 7.14 (d, 1H,
J ¼ 8 Hz), 7.23e7.30 (m, 3H), 8.43 (brs, 1H, NeH). MS (ESI) m/z 446
([M þ H]þ). Anal. Calcd for C29H35NO3: C, 78.17; H, 7.92; N, 3.14;
found C, 78.32; H, 7.80; N, 3.01.
6.2.4.13. 2,3,4,4a,9,13c-Hexahydro-7-isopropyl-1,4a-dimethyl-12-nitro-
1H-dibenzo[a,c]carbazole-1-carboxylic acid methyl ester (6m). Brown
powder; yield 36%; mp 137e140  C; IR (KBr, n, cm1): 3356, 2955,
2932, 2868, 1713, 1612, 1506, 1467, 1351, 1242. 1H NMR (CDCl3): 1.11
(s, 3H, H-14), 1.33 (d, 3H, J ¼ 7 Hz, H-17 or H-18), 1.34 (d, 3H,
J ¼ 7 Hz, H-17 or H-18), 1.72 (m, 1H), 1.80 (s, 3H, H-15), 1.83e2.02
(m, 4H), 2.33 (m, 1H), 2.98 (m, 1H, H-16), 3.69 (s, 3H, COOCH3), 3.87
(s, 1H, H-13c), 7.16 (dd, 1H, J ¼ 8.0, 1.5 Hz), 7.28 (d, 1H, J ¼ 1.5 Hz),
7.33 (d, 1H, J ¼ 8.0 Hz), 7.63 (dd, 1H, J ¼ 8.5, 1.0 Hz), 7.88 (d, 1H,
J ¼ 8.5 Hz), 8.48 (brs, 1H, NeH), 8.59 (d, 1H, J ¼ 1.0 Hz). MS (ESI) m/z
447 ([M þ H]þ). Anal. Calcd for C27H30N2O4: C, 72.62; H, 6.77; N,
6.27; found C, 72.39; H, 6.58; N, 6.09.
Acknowledgements
The authors are grateful to Professor Hang, School of Chemistry
and Chemical Engineering, Nanjing University, for recording all the
NMR data. The work was supported by the National Natural Science
Foundation of China (Project: 30972316).
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