Synthesis, antibacterial and antifungal activities of some carbazole derivatives

Article abstract of DOI:10.1016/j.bmcl.2010.01.159

A series of N-substituted carbazole derivatives were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, Escherichia coli, Pseudomonas

Full text of DOI:10.1016/j.bmcl.2010.01.159

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1881–1884
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, antibacterial and antifungal activities of some carbazole derivatives
Fei-Fei Zhang a, Lin-Ling Gan b, Cheng-He Zhou a,
*
a School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
b School of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2009
Revised 22 December 2009
Accepted 29 January 2010
Available online 4 February 2010
A series of N-substituted carbazole derivatives were synthesized and evaluated for antibacterial and anti-
fungal activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Bacil-
lus subtilis, Escherichia coli, Pseudomonas aeruginosa, Bacillus proteus, Candida albicans and Aspergillus
fumigatus by two fold serial dilution technique. Some of the synthesized compounds displayed compara-
ble or even better antibacterial and antifungal activities than reference drugs fluconazole, chloramphen-
icol and norfloxacin against tested strains.
Keywords:
Carbazole
Ó 2010 Elsevier Ltd. All rights reserved.
Imidazole
1,2,4-Triazole
Triazolium
Antibacterial
Antifungal
Disease-causing microbes that have become resistant to drug
therapy are an increasing public health problem particularly dur-
ing the last decade. The hospital-acquired infections are resistant
to the most powerful antibiotics available methicillin and vanco-
mycin. These drugs are reserved to treat only the most intractable
infections in order to retard the development of resistance to
them.1 Therefore it is imperative to design and develop new anti-
microbial agents with novel chemical structures possibly having
modes of action rather than analogues of the existing ones.
Carbazole and its derivatives are an important type of nitrogen-
containing aromatic heterocyclic compounds, possess desirable
num at the dose of 12.5 lg, which was isolated from Murraya euch-
restifolia Hayata collected in Taiwan.7
Numerous researches have focused on the isolation, purification
and biological activity of natural carbazole compounds as well as
the total synthesis of biologically active carbazole alkaloids and
their analogues. Recently, the novel artificial synthetic carbazole
derivatives as antibiotics have attracted special attention, when
it was found that carbazole-based macrocyclic carbazolophanes
exhibited significant antibacterial and antifungal activities.8 Some
carbazole derivatives combined via spacers gave good antibacterial
activities against tested human pathogens compared to commer-
cial antibiotics (benzalkonium chloride, cetylpyridinium chloride
and tetracycline).9 However, to the best of our knowledge, imidaz-
ole or 1,2,4-triazole-based N-substituted carbazole derivatives
have not been reported. Herein, we wish to report the synthesis,
antibacterial and antifungal activities of a series of N-substituted
carbazole derivatives including carbazole-based halides 1a–c, imi-
dazoles 2a–c, triazoles 3a–c, triazolium 4 and bis-carbazoles 5a–c.
It is well-known that azole moieties such as imidazole and tri-
azole nucleus as important pharmacophore appear extensively in
electronic and charge-transport properties, as well as large p-conju-
gated system, and the various functional groups are easily intro-
duced into the structurally rigid carbazolyl ring. These
characteristics result in the extensive potential applications of car-
bazole-based derivatives in the field of chemistry (photoelectrical
materials,2 dyes,3 supramolecular recognition4 etc.) and medicinal
chemistry5 (antitumor, antimicrobial, antihistaminic, antioxidative,
anti-inflammatory, psychotropic agents etc.). Carbazole rings are
present in a variety of naturally occurring medicinally active sub-
stances.5 For example, the carbazomycins are an unprecedented
class of antibiotics with a carbazole framework.6 Carbazomycins A
and B (Fig. 1) inhibit the growth of phytopathogenic fungi and have
antibacterial and anti-yeast activities. However, Murrayafoline A
exhibited strong fungicidal activity against Cladosporium cucumeri-
RO
Me
OMe
Me
N
H
N
OMe
Me
H
Carbazomycin A, R = Me
Carbazomycin B, R = H
Murrayafoline A
* Corresponding author. Tel./fax: +86 23 68254165.
E-mail addresses: zhouch@swu.edu.cn, zfeifei@swu.edu.cn (C.-H. Zhou).
Figure 1. Structures of some biologically active carbazole compounds.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.159

1882
F.-F. Zhang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1881–1884
various types of pharmaceutical agents, widely implicate in bio-
chemical processes and display diversity of pharmacological activ-
with petroleum ether (30–60 °C). Bis-carbazoles 5a–c were conve-
niently prepared by the reaction of carbazole with corresponding
alkyl or aryl dibromides. Some synthetic data were given in Table
1. These new compounds were confirmed by MS, HRMS, IR and
ities.10
A large number of azole compounds are used as
antimicrobial drugs in clinic, for example, miconazole, clotrimazole
and econazole are administered topically, while ketoconazole, itr-
aconazole and fluconazole are useful in the treatment of systemic
infections. Furthermore, it has been found that some azoles such
as miconazole gave remarkable antibacterial activity against
MRSA.11 The widespread use of azole antimicrobial drugs led
numerous efforts to develop some azole derivatives as new antimi-
crobial agents.
1H, 13C, 1H–1H COSY, 1H–13
spectra.13
C HETCOR, APT and DEPT NMR
All of the synthesized compounds were screened in vitro for
antibacterial activities against Gram-positive S. aureus, MRSA and
B. subtilis, Gram-negative E. coli, P. aeruginosa and B. proteus as well
as antifungal activities against C. albicans and A. fumigatus by two-
fold serial dilution technique.14 All compounds were evaluated at
the concentrations of the antimicrobial agents ranging from
In this connection, a series of carbazole-based azole derivatives
such as imidazole, 1,2,4-triazole ones and so on were designed and
synthesized for the first time, and their antibacterial and antifungal
activities were evaluated against Staphylococcus aureus, MRSA,
Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Bacillus
proteus, Candida albicans and Aspergillus fumigatus. Recent studies
found that the linkers have an important effect on the antimicro-
bial activities, particularly the six-carbon chain spacer gave better
biological activities.12 Therefore various functional groups includ-
ing aryl and alkyl bridged types as well as different lengths of alkyl
chains were introduced into the target compounds in order to
investigate their structure–activity relationships. Some works have
shown that introduction of electropositive groups in triazole deriv-
atives is useful to increase the water solubility and membrane per-
meability, and thereby improve their biological activities.12 In view
of this, 1,2,4-triazolium derivative 4 was designed and synthesized
by the use of 2,4-dichlorobenzyl chloride, because halobenzyl moi-
ety was found to be biologically important and could improve the
antimicrobial activities. In addition, bis-carbazole compounds 5a–c
were prepared by the replacement of triazolyl group with carbaz-
olyl ring in target molecules 3a–c in order to further investigate
the effect of carbazolyl group on the antimicrobial activities, as a
comparison with triazole nucleus.
The synthetic route of N-substituted carbazole derivatives is
shown in Scheme 1. The target carbazole-based azole derivatives
were synthesized by using commercially available carbazole as
starting materials. The reaction of carbazole with alkyl or aryl
dibromides at room temperature produced the halides 1a–c with
the yields of 41–77.5% in the presence of sodium hydride under a
stream of nitrogen. Carbazole halides 1a–c reacted with imidazole
using NaH as the base to afford the imidazole derivatives 2a–c with
yields ranging from 83.5% to 89.2%. Triazole compounds 3a–c were
successfully synthesized in good yields (76.4–91.1%) by mixing
intermediates 1a–c, 1,2,4-triazole and potassium carbonate in ace-
tonitrile at 45 °C. The quaternization of compound 3a with com-
mercially available 2,4-dichlorobenzyl chloride gave desired
triazolium derivative 4 in good yield after purification via washing
0.5 lg/mL to 512 lg/mL and scored for MIC50 as the level of growth
inhibition of the microorganisms compared with that of the cur-
rent antimicrobial drugs fluconazole, chloramphenicol and nor-
floxacin in clinic. The data of antibacterial and antifungal tests
are depicted in Table 1.
The obtained results showed that the synthesized compounds
1–5 exhibited poor to good activities against all tested strains. As
noted in Table 1, all carbazole derivatives, except for bis-carbazole
5b bridged by (CH2)4 linker, could effectively inhibit the growth of
S. aureus. Imidazole-derived carbazole compounds 2a–c showed
good antibacterial activities against bacteria with MIC values of
1–8 lg/mL and moderate antifungal activity (MIC = 16 lg/mL)
against C. albicans, and exhibited better antibacterial activity than
chloramphenicol or almost equipotent to norfloxacin. In addition,
compounds 2a–c showed potent activity against MRSA with MIC
values of 4–8
activities against C. albicans (MIC = 2–4
reference drug fluconazole (MIC = 0.5
l
g/mL. Triazole compounds 3a–c gave comparable
g/mL) with corresponding
g/mL). The triazole deriva-
l
l
tive 3c containing a (CH2)6 spacer also showed moderate potency
against MRSA, E. coli and P. aeruginosa.
Compared to imidazoles 2a–c and triazoles 3a–c, carbazole N-
substituted bromides 1a–c and bis-carbazole compounds 5a–c
showed poor antimicrobial activities. Unexpectedly, the introduc-
tion of 1,2,4-triazole moiety in carbazole compounds 3a–c instead
of imidazole ring decreased their antibacterial activities, and in-
creased their antifungal activities against C. albicans, in comparison
with imidazoles 2a–c and triazoles 3a–c. These facts suggested
that the azole (imidazole or 1,2,4-triazole) residue should be spe-
cially helpful for biological activity, imidazole moiety seems to
be favourable for antibacterial efficacy against tested bacteria,
while 1,2,4-triazole group is conducive to antifungal activities such
as C. albicans. Moreover, the structural factors of linker including
the type of the bridged groups such as aryl and alkyl ones, as well
as the length of the bridged alkyl chain could efficiently affect their
antimicrobial activities. Here an effect of the bridged linkers on the
antibacterial and antifungal activities was not obvious, and further
2
3
4
4'
5'
1
Br
Br
R
6a-c
N
NH
a, R =
1-3, 5, 6:
1'
NH
8'
N
R
Br
N
R
N
N
NaH, THF
b, R = (CH2)2
NaH, THF
5
2a-c
1a-c
8
c, R =
(CH2)4
6
7
N
NH
N
Br
Br
R
K2CO3, CH3CN
NaH, THF
Cl
Cl
N
N
Cl
Cl
N
N
R
N
N
N
N
R
N
N
CH3CN
Cl
4
3a-c
Cl
5a-c
Scheme 1. Synthetic route of N-substituted carbazole derivatives.

F.-F. Zhang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1881–1884
1883
Table 1
Some characteristic, in vitro antibacterial and antifungal activities as MIC50
(lg/mL) for synthetic N-substituted carbazole derivatives 1–5
Compd
Mp (°C)
Yield (%)
S. aureus
MRSA
B. subtilis
E. coli
P. aeruginosa
B. proteus
C. albicans
A. fumigatus
1a
1b
1c
2a
2b
2c
3a
3b
3c
4
5a
5b
143–144
123ꢁ124
58ꢁ59
97ꢁ99
73ꢁ74
Oil
121ꢁ123
79ꢁ80
78ꢁ79
229ꢁ230
246ꢁ248
228ꢁ229
118ꢁ119
—
41.0
77.5
60.0
89.2
84.9
83.5
91.1
86.6
76.4
82.4
78.2
86.4
84.7
—
128
256
128
1
2
8
256
256
32
>512
>512
>512
8
4
8
>512
>512
64
256
>512
>512
4
4
8
>512
>512
>512
2
>512
>512
>512
—
256
>512
>512
8
8
4
32
32
16
2
>512
>512
>512
—
64
0.5
256
128
>512
1
1
1
>512
128
32
512
>512
>512
4
1
1
>512
>512
>512
8
>512
64
>512
—
16
>512
512
>512
16
16
16
4
2
2
32
>512
>512
>512
0.5
—
>512
>512
512
>512
64
128
>512
>512
>512
64
>512
>512
256
512
—
2
8
4
256
>512
128
—
64
8
>512
>512
>512
—
8
1
>512
>512
>512
—
>512
2
5c
Fluconazole
Chloramphenicol
Norfloxacin
—
—
—
—
>512
1
1
—
—
study is necessary in order to deduce the structure–activity
relationships.
The carbazole triazolium compound 4, a quaternization product
of triazole 3a, displayed comparable or even better efficacy than
the standard drugs chloramphenicol or norfloxacin against all
rial agents against MRSA strain. Further in vivo and cytotoxicity
studies of these potential compounds are necessary. Compound 4
as artificial anion receptor is expected to play important roles in
supramolecular recognition to various anions via non-covalent
interactions by the use of the desirable electronic and charge-
tested strains with MIC values ranging from 1 to 64
lg/mL. In com-
transport properties, as well as large p-conjugated system, electro-
parison with triazole 3a, its corresponding triazolium 4 gave excel-
lent antibacterial and antifungal activities except for C. albicans
(see Table 1). It was also noteworthy that anti-MRSA activity of
compound 4 was comparable to that of chloramphenicol. This
means the halobenzyl triazolium electropositive moiety plays an
important role in antimicrobial activity, which could not only
broaden the antimicrobial spectrum of activity, but also greatly in-
crease potency. On the other hand, amphiphilic quaternary ammo-
nium compounds especially imidazoliums are generally known to
be utilized for the recognition to anions such as halides, dihydro-
gen phosphate and dicarboxylates by the strong (C–H)+ꢀ ꢀ ꢀXꢁ
hydrogen binding between imidazolium moieties and these an-
ions.15 However, the studies about anion receptors dealing with
the triazolium which is the analogue of imidazolium are seldom
observed. Carbazole-based derivatives, having desirable electronic
positive triazolium moiety in carbazole triazolium 4. Synthesis of
other similar carbazole derivatives and their antibacterial and anti-
fungal activities including the effects of anions on antimicrobial
efficacy as well as the mode of action of the prepared compounds
and anion recognition towards various biologically important an-
ions are under active investigation, which will be discussed in de-
tail in the future paper.
Acknowledgments
This work was partially supported by Natural Science Founda-
tion of Chongqing (CSCT: 2007BB5369) and Southwest University
(SWUB2006018, XSGX0602).
References and notes
and charge-transport properties as well as large p-conjugated sys-
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tem, as good fluorophoric receptors were found to be able to be
used as phosphate and fluoride ion sensors and as fluorescence
markers for cancer cells.16 Our preliminary researches have re-
vealed that compound 4 containing triazolium group and carbazole
moiety showed high binding affinity with anions by virtue of form-
ing strong [CꢁH]+ꢀ ꢀ ꢀanion hydrogen bonds. Further study on anion
recognition towards various biologically important anions and the
effects of anions on antimicrobial activities is in progress.
In conclusion, a series of carbazole-based azole derivatives were
designed and synthesized for the first time via an easy, convenient
and efficient synthetic route. The antimicrobial results showed that
carbazoles in combination with imidazole derivatives 2a–c were
the most active compounds against S. aureus, MRSA, B. subtilis,
E. coli, P. aeruginosa and B. proteus (MIC values of 1–8 lg/mL),
and carbazole-triazole compounds 3a–c possessed significant anti-
fungal activities against C. albicans. Meanwhile, carbazole triazoli-
um compound 4 exhibited good activity against both bacteria and
fungi. Introduction of azole moiety (imidazole or 1,2,4-triazole)
and electropositive group in carbazole derivatives could improve
the antimicrobial activities. The minimum inhibition concentra-
11. Güven, Ö. Ö.; Erdog˘an, T.; Göker, H.; Yıldız, S. Bioorg. Med. Chem. Lett. 2007, 17,
2233.
12. (a) Luo, Y.; Lu, Y. H.; Gan, L. L.; Zhou, C. H.; Wu, J.; Geng, R. X.; Zhang, Y. Y. Arch.
Pharm. Chem. Life Sci. 2009, 342, 386; (b) Muroi, H.; Nihei, K. I.; Tsujimoto, K.;
Kubo, I. Bioorg. Med. Chem. 2004, 12, 583.
13. Experimental: Melting points are uncorrected and were recorded on X-6
melting point apparatus. TLC analyses were done using pre-coated silica gel
plates and visualization was done using UV lamp at 254 nm. IR spectra were
recorded on a Bio-Rad FTS-185. 1H NMR and 13C NMR spectra were recorded on
a Bruker AV 300 or Varian 400 spectrometer using TMS as an internal standard.
Chemical shifts were given in d ppm and signals are described as singlet (s),
tions of several compounds were 64 lg/mL, which should be a
good starting point for us to optimize the structure and obtain
more potent antibacterial and antifungal agents with these scaf-
folds. Moreover, compounds 2a–c and 4 should also be worthy to
further investigate as potential lead compounds for new antibacte-

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F.-F. Zhang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1881–1884
doublet (d), triplet (t), quartet (q), broad (br) and multiplet (m). All the solvents
used were analytical grade only. The mass spectra were recorded on FINIGAN
TRACE GC/MS and HRMS.
1-H), 8.16 (s, 1H, carbazole 4-H), 8.18 (s, 1H, carbazole 5-H), 9.23 (s, 1H,
triazole 3-H) ppm; MS(m/z): 497 [MꢁCl]+; HRMS (TOF) calcd for C29H24Cl3N4
[M+H]+, 533.1067; found, 533.1068.
Synthesis of 9-(4-(-imidazol-1-yl)butyl)-9H-carbazole (2b): To a 100 ml round
flask, 9-(4-bromobutyl)-9H-carbazole (1.76 g, 6 mmol), imidazole (0.49 g,
7 mmol) NaH (0.2 g, 8 mmol) and THF (10 mL) solution were added. The
mixture was stirred at room temperature for 48 h under a stream of nitrogen.
After the reaction came to the end (monitored by TLC, eluent, chloroform/
methanol, 10/1, V/V), THF was removed by a rotary evaporator and then the
mixture was cooled. Water (30 mL) was added. The resulting solution was
extracted with CH2Cl2 (3 ꢂ 30 mL). All the combined CH2Cl2 solutions were
dried with anhydrous Na2SO4 and then evaporated under reduced pressure.
The residue was purified via silica gel column chromatography (chloroform/
methanol, 10/1, V/V) to give compound 2b (1.43 g) as white solid. Yield 84.9%;
Synthesis of 1,4-bis((9H-carbazol-9-yl)methyl) benzene (5a): To a 100 ml round
flask, carbazole (2.17 g, 8 mmol), 1,4-bis(bromomethyl)benzene (1.08 g,
4 mmol), NaH (0.24 g, 10 mmol) and THF (10 mL) solution were added. The
mixture was stirred at room temperature for 48 h under a stream of nitrogen.
After the reaction came to the end (monitored by TLC, eluent, petroleum ether/
chloroform, 2/1, V/V), THF was removed by a rotary evaporator. The residue
was cooled and water (30 mL) was added. The resulting solution was extracted
with CH2Cl2 (3 ꢂ 30 mL). All the combined CH2Cl2 solutions were dried with
anhydrous Na2SO4 and then evaporated under reduced pressure. The resulting
residue was purified via silica gel column chromatography (petroleum ether/
chloroform, 2/1, V/V) to give compound 5a (1.36 g) as white solid. Yield 78.2%;
mp 73ꢁ74 °C; IR (KBr)
m
: 3050 (Ar-H), 2931, 2863 (CH2), 1594, 1484, 1452
mp 246ꢁ248 °C; IR (KBr)
1511, 1484, 1459, 1436 (aromatic frame), 1327, 1209, 1152, 1116, 848, 748,
716 cmꢁ1 1H NMR (400 MHz, CDCl3) d: 5.45 (s, 4H, N–CH2), 7.02 (s, 4H, Ph-H),
7.21ꢁ7.26 (m, 4H, carbazole 3,6-H), 7.30ꢁ7.32 (m, 4H, carbazole 2,7-H),
7.38ꢁ7.40 (d, 2H, J = 4 Hz, carbazole 1-H), 7.40ꢁ7.41 (d, 2H, J = 4 Hz, carbazole
8-H), 8.10ꢁ8.12 (m, 4H, carbazole 4,5-H) ppm; 13C NMR (400 MHz, CDCl3) d:
136.6 (carbazole 10,80-C), 126.8 (Ph 1-C), 125.8 (Ph 2-C), 122.5 (carbazole 40,50-
C), 120.4 (carbazole 2,7-C), 119.2 (carbazole 4,5-C), 116.3 (carbazole 3,6-C),
108.8 (carbazole 1,8-C), 46.2 (N-CH2) ppm; MS (m/z): 459 [M+Na]+, 436 [M]+;
HRMS (TOF) calcd for C32H25N2 [M+H]+, 437.2018; found, 437.2015.
m: 3046, 3026 (Ar-H), 2913, 2853 (CH2), 1628, 1595,
(aromatic frame), 1325, 1230, 1152, 1076, 815, 751, 724, 664 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) d: 1.76ꢁ1.84 (m, 2H, imidazole-CH2CH2), 1.88ꢁ1.92 (m, 2H,
carbazole-CH2CH2), 3.79ꢁ3.82 (t, 2H, J = 6.8 Hz, imidazole-CH2), 4.32ꢁ4.36 (t,
2H, J = 6.4 Hz, carbazole-CH2), 6.76 (s, 1H, imidazole 4-H), 7.01 (s, 1H,
imidazole 5-H), 7.23ꢁ7.27 (m, 2H, carbazole 3,6-H), 7.35 (m, 2H, carbazole
2,7-H), 7.37 (s, 1H, imidazole 2-H), 7.45ꢁ7.49 (m, 2H, carbazole 1,8-H),
8.09ꢁ8.12 (m, 2H, carbazole 4,5-H) ppm; MS (m/z): 312 [M+Na]+, 290 [M]+,
222 [Mꢁimidazole]+; HRMS (TOF) calcd for C19H20N3 [M+H]+, 290.1657; found,
290.1652.
;
Synthesis of 9-(6-(1H-1,2,4-triazol-1-yl)hexyl)-9H-carbazole (3c): A mixture of
1H-1,2,4-triazole (0.50 g, 7 mmol), 9-(6-bromohexyl)-9H-carbazole (1.44 g,
5 mmol), potassium carbonate (1.43 g, 10 mmol) and TBAB (tetrabutyl
ammonium bromide, 5 mg) in acetonitrile (30 mL) was stirred at 45 °C. After
the reaction came to the end (monitored by TLC, eluent, chloroform/methanol,
8/1, V/V), the solvent was evaporated and then water (30 mL) was added. The
resulting mixture was extracted with CH2Cl2 (3 ꢂ 30 mL), the combined
organic phase was dried over anhydrous Na2SO4 and then evaporated under
reduced pressure. The resulting residue was purified via silica gel column
chromatography (chloroform/methanol, 8/1, V/V) to give compound 3c (1.06 g)
14. (a) Kadi, A. A.; El-Brollosy, N. R.; Al-Deeb, O. A.; Habib, E. E.; Ibrahim, T. M.; El-
Emam, A. A. Eur. J. Med. Chem. 2007, 42, 235; (b) Özbek, N.; Katırcıog˘lu, H.;
Karacan, N.; Baykal, T. Bioorg. Med. Chem. 2007, 15, 5105. Experimental
determination of antibacterial and antifungal activities. The minimal inhibitory
concentrations (MICs) of the title compounds were determined in vitro by the
modified microbroth dilution method according to the methods defined by the
National Committee for Clinical Laboratory Standards. The test strains were
provided by the School of Pharmaceutical Sciences, Southwest University.
Fluconazole and chloramphenicol obtained from their respective
manufacturers served as controls. The prepared compounds 1–5 were
evaluated for their antibacterial activity against S. aureus ATCC 29213, MRSA
N 315 and B. subtilis ATCC 21216 as Gram-positive, E. coli ATCC 25922, P.
aeruginosa ATCC 27853 and B. proteus ATCC 49027 as Gram-negative bacteria.
The bacterial suspension was adjusted with sterile saline to a concentration of
1 ꢂ 105 CFU. The test compounds were dissolved in dimethyl sulfoxide (DMSO)
to prepare the stock solutions. The test compounds and reference drugs were
prepared in Mueller–Hinton broth (Guangdong huaikai microbial sci. & tech
co., Ltd, Guangzhou, Guangdong, China) by twofold serial dilution to obtain the
as white solid. Yield 76.4%; mp 79ꢁ80 °C; IR (KBr)
2857 (CH2), 1595, 1511, 1485, 1454 (aromatic frame), 1274, 1235 (triazole
frame), 1136, 1016, 885, 754, 725, 683 cmꢁ1 1H NMR (400 MHz, CDCl3) d:
m: 3100, 3052 (Ar-H), 2928,
;
1.26ꢁ1.35 (m, 2H, carbazole-CH2CH2CH2), 1.36ꢁ1.42 (m, 2H, triazole-
CH2CH2CH2), 1.78ꢁ1.84 (m, 2H, carbazole-CH2CH2), 1.85ꢁ1.91 (m, 2H,
triazole-CH2CH2), 4.05ꢁ4.08 (t, 2H, J = 7 Hz, carbazole-CH2), 4.28ꢁ4.31 (t, 2H,
J = 7 Hz, triazole-CH2), 7.21ꢁ7.23 (d, 1H, J = 6.8 Hz, carbazole 3-H), 7.24ꢁ7.25
(d, 1H, J = 4 Hz, carbazole 6-H), 7.36 (s, 1H, carbazole 2-H), 7.38 (s, 1H,
carbazole 7-H), 7.44ꢁ7.48 (m, 2H, carbazole 1,8-H), 7.91 (s, 1H, carbazole 4-H),
7.95 (s, 1H, triazole 5-H), 8.09 (s, 1H, carbazole 5-H), 8.11 (s, 1H, triazole 3-H)
ppm; MS (m/z): 341 [M+Na]+, 319 [M]+; HRMS (TOF) calcd for C20H23N4
[M+H]+, 319.1923; found, 319.1928.
required concentrations of 512, 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5 lg/mL. These
dilutions were inoculated and incubated at 37 °C for 24 h. To ensure that the
solvent had no effect on bacterial growth, a control test was performed with
test medium supplemented with DMSO at the same dilutions as used in the
experiment. The new compounds were evaluated for their antifungal activity
Synthesis of 1-(4-((9H-carbazol-9-yl) methyl) benzyl-4- (2,4-dichlorobenzyl)-1H-
1,2,4-triazolium chloride (4):
A
mixture of 9-(4-((1H-1,2,4-triazol-1-
against C. albicans ATCC 76615 and A. fumigatus ATCC 96918. A spore
yl)methyl)benzyl)-9H-carbazole (0.74 g, 2.2 mmol) and 2,4-dichlorobenzyl
chloride (0.49 g, 2.5 mmol) in acetonitrile (15 mL) was stirred at 80 °C. After
the reaction came to the end, the solvent was evaporated under reduced
pressure. The residue was washed three times with petroleum ether
suspension in sterile distilled water was prepared from 1-day old culture of
the fungi growing on Sabouraud agar (SA) media. The final spore concentration
was 1ꢁ5 ꢂ 103 spore mLꢁ1. From the stock solutions of the tested compounds
and reference antifungal fluconazole, dilutions in sterile RPMI 1640 medium
(Neuronbc Laboraton Technology CO., Ltd, Beijing, China) were made resulting
(30ꢁ60 °C) and dried to give compound
82.4%; mp 229ꢁ230 °C; IR (KBr) : 3093, 3009 (Ar-H), 2940, 2817 (CH2), 1630,
1594, 1573, 1528, 1483, 1459 (aromatic frame), 1347, 1329, 1183, 928, 775,
740, 559 cmꢁ1 1H NMR (400 MHz, DMSO-d6) d: 5.52 (s, 2H, carbazole-CH2),
4 (0.97 g) as white solid. Yield
m
in eleven wanted concentrations (0.5–512 lg/mL) of each tested compound.
These dilutions were inoculated and incubated at 35 °C for 24 h. The drug
MIC50 was defined as the first well with an approximate 50% reduction in
growth compared to the growth of the drug-free well. The minimum inhibitory
;
5.55 (s, 2H, PhCH2-triazole), 5.67 (s, 2H, triazole-CH2-(2,4-dichlorobenzyl)),
7.18ꢁ7.19 (d, 2H, J = 3.2 Hz, Ph-H), 7.20ꢁ7.21 (d, 2H, J = 3 Hz, 2,4-
dichlorobenzyl 5,6-H), 7.23 (s, 1H, 2,4-dichlorobenzyl 3-H), 7.30ꢁ7.32 (d, 2H,
J = 8 Hz, Ph-H), 7.40ꢁ7.44 (m, 2H, carbazole 3,6-H), 7.51ꢁ7.54 (m, 1H,
carbazole 2-H), 7.58 (s, 1H, carbazole 7-H), 7.59ꢁ7.60 (d, 1H, J = 3.6 Hz,
carbazole 8-H), 7.61 (s, 1H, triazole 5-H), 7.74ꢁ7.75 (d, 1H, J = 2.4 Hz, carbazole
concentration (MIC50) values (in lg/mL) were summarized in Table 1.
15. Yun, S.; Ihm, H.; Kim, H. G.; Kim, J. K.; Kim, K. S. J. Org. Chem. 2003, 68, 2467.
16. Chang, C. C.; Kuo, I. C.; Ling, I. F.; Chen, C. T.; Chen, H. C.; Lou, P. J.; Lin, J. J.;
Chang, T. C. Anal. Chem. 2004, 76, 4490.