Synthesis, characterization and biological evaluation of some newer carbazole derivatives

Article abstract of DOI:10.2298/JSC130123069S

A series of novel 5-[(9H-carbazol-9-yl)methyl]-N-[(substituted phenyl)( piperazin-1-yl)methyl]-1,3,4-oxadiazol-2-amines (4a-o) derivatives was synthesized by starting with carbazole, which on reaction with ethyl chloroacetate yielded ethyl 2-(9H-carbazole

Full text of DOI:10.2298/JSC130123069S

J. Serb. Chem. Soc. 79 (2) 125–132 (2014)
JSCS–4570
UDC 547.759.32+547.233+547.251.1+
542.913+543.42:615.281/.282
Original scientific paper
Synthesis, characterization and biological evaluation of some
newer carbazole derivatives
*
DIVYANSHU SHARMA, NITIN KUMAR and DEVENDER PATHAK
Rajiv Academy for Pharmacy, Delhi-Mathura Highway, Chhattikara, Mathura - 281001, India
(Received 23 January, revised 16 June 2013)
Abstract: A series of novel 5-[(9H-carbazol-9-yl)methyl]-N-[(substituted phe-
nyl)(piperazin-1-yl)methyl]-1,3,4-oxadiazol-2-amines (4a–o) derivatives was
synthesized by starting with carbazole, which on reaction with ethyl chlo-
roacetate yielded ethyl 2-(9H-carbazole-9-yl)acetate (1). Compound 1 on
reaction with semicarbazide followed by cyclisation with sulphuric acid gave
5-((9H-carbazole-9-yl)-1,3,4-oxadiazol-2-amine (3), which through Mannich
reaction with piperazine and a variety of aromatic aldehydes in the presence of
acetic acid yielded the titled compounds (4a–o). The structures of compounds
1
were characterized by UV, FT-IR, H-NMR and MS spectral studies, and by
elemental analysis. All the derivatives were evaluated for their antibacterial,
antifungal and anticancer activities. Among the tested compounds, 4a, 4d, 4e
and 4n exhibited significant antibacterial and antifungal activity, while the
compounds 4a, 4d, 4k and 4n were found to be active on the human breast
cancer cell line MCF7.
Keywords: Mannich reaction; antibacterial activity; antifungal activity; MCF7;
synthesis; spectroscopy.
INTRODUCTION
Carbazole derivatives are well known for their pharmacological activities. It
is evident from the literature that the derivatives of carbazole moiety possess a
1–3
wide spectrum of pharmacological activities, such as antibacterial,
anti-
4,5
6–10
11
12
fungal, antitumour, antineoplastic,
anticonvulsant, antioxidant, antidia-
13
14
15
betic, antipsychotic and larvicidal activity.
Various heteroannulated carbazole derivatives have drawn attention because
of their natural occurrence and the broad spectrum of biological activity asso-
ciated with these compounds. The carbazole moiety is a frequent moiety of
numerous drugs, such as olivacine, ondansetron, rimcazole, stauroapirone, carba-
zolol, carvedilol, carprofen, cacotheline, rebaccamycin, ellipticine and various
*Corresponding author. E-mail: dev_15@rediffmail.com
doi: 10.2298/JSC130123069S
125
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SHARMA, KUMAR and PATHAK
16
naturally occurring carbazole alkaloids. Carbazole derivatives have docu-
mented consistent advances in the design of novel antipsychotic, neuroleptic and
17
anticonvulsant agents. Furthermore, various congeners of oxadiazole, thiadia-
zole, azetidinone and thiazolidinone have also been reported to exhibit potential
antimicrobial, anticancer, antipsychotic, antidepressant and anticonvulsant acti-
18–21
vity.
In view of broad biological activity of carbazole derivatives, in this
study it was planned to synthesize new carbazole derivatives and by incorpor-
ation of new pharmacophores, such as oxadiazole at position 9 of carbazole
nucleus, with the hope of obtaining better pharmacologically active drugs as anti-
cancer and antimicrobial agents. In the same direction, a one pot method was
developed to synthesize a series of 5-[(9H-carbazol-9-yl)methyl]-N-[(substituted-
-phenyl)(piperazin-1-yl)methyl]-1,3,4-oxadiazol-2-amine derivatives (4a–o) as
Mannich bases.
EXPERIMENTAL
The purity of all the newly synthesized compounds were checked by TLC on silica gel-
-protected aluminium sheets (type 60 F254, Merck) and the spots were detected by exposure to
iodine vapour and a UV-lamp at λ 254 nm. The melting points were determined in open
capillary tubes and are uncorrected. The infrared (FT-IR) spectra were recorded on a 470-
-Shimadzu infrared spectrophotometer using the KBr pressed pellet technique and the result
1
are expressed in cm-1. The H- and 13C-NMR spectra were recorded on a Bruker DRX-300
instrument using CDCl3 as a solvent. The chemical shifts, δ, are given in ppm downfield from
the internal standard tetramethylsilane (TMS). The splitting patterns are designated as follows;
s: singlet; d: doublet and m: multiplet. The mass spectra were obtained on a Shimadzu 2010A
LC-MS spectrometer. Elemental analyses were realised on an Elemental Vario EL III Carlo
Erba 1108 instrument and the obtained values were within ±0.04 % of the theoretical values.
Synthesis of ethyl 2-(9H-carbazol-9-yl)acetate (1)
To a solution of carbazole (2.01 g, 0.012 mol) in 18 mL of dry acetone, ethyl chloro-
acetate (1.472 g, 0.012 mol) was added dropwise in the presence of anhydrous potassium
carbonate (0.09 g) and the resultant mixture refluxed for 22 h. Then the mixture was cooled
and the thus obtained solid was filtered, dried and recrystallized from methanol to give com-
pound 1.17 Yield: 59.44 %; m.p.: 240–241 °C
Synthesis of 1-[2-(9H-carbazol-9-yl)acetyl]semicarbazide (2)
Compound 1 (2.53 g, 0.01 mol) was dissolved in 90 mL of acetone (solution A) and
semicarbazide (0.62 g, 0.01 mol) was dissolved in 20 mL of water (solution B). Solution B
was poured into solution A and the mixture was refluxed for 28 h. On cooling, the solid
product that separated out was filtered, dried and recrystallized from methanol to give com-
pound 2.17 Yield: 70.40 %; m.p.: 184–185 °C.
Synthesis of 5-[(9H-carbazol-9-yl)methyl]-1,3,4-oxadiazol-2-amine (3)
A solution of compound 2 (2.83 g, 0.01 mol) with 25 mL of conc. H2SO4 was kept
overnight at room temperature, then the reaction mixture was poured into ice-cold water,
neutralized with ammonia and extracted with ether. The ethereal solution was distilled off and
the product obtained was recrystallized from acetone to give compound 3.17 Yield: 65.9 %;
m.p.: 161–162 °C.
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SYNTHESIS AND BIOLOGICAL EVALUATION OF CARBAZOLE DERIVATIVES
127
General synthetic procedure for the synthesis of 5-[(9H-carbazol-9-yl)methyl]-N-[(substituted
phenyl)(piperazin-1-yl)methyl]-1,3,4-oxadiazol-2-amines (4a–o)
A mixture of equimolar quantity (0.01 mol) of compound (3), derivative of aromatic
aldehydes and piperazine along with few drops of glacial acetic acid was refluxed in 15 mL of
methanol for 8–13 h. The hot solution was poured onto crushed ice and the thus obtained solid
mass was filtered, dried and recrystallized from acetone to give compounds 4a–o.
Antibacterial activity
The antibacterial activities of the newly synthesized compounds were tested by the disc
diffusion method on nutrient agar medium against the bacterial strains Staphylococcus aureus
ATCC 6538 and Bacillus subtilis ATCC 6633 (Gram-positive), and Escherichia coli ATCC
35210 and Pseudomonas aeruginosa ATCC 27853 (Gram-negative).
In the disc diffusion method, a paper disc (6 mm in diameter) was impregnated with the
test compounds dissolved in DMSO at concentrations of 25, 50 and 100 μg mL-1. A disc
impregnated with DMSO was used as the solvent control because of the free solubility of the
test compounds. The nutrient agar medium in Petri dishes was inoculated with bacterial strains
and the discs impregnated with the solutions of different concentrations of the compounds
were placed over it. The plates were incubated at 35 °C for 24 h. The zone of inhibition
indicating the inhibited growth of microorganism around the discs was observed.
Ciprofloxacin was used as the standard (50 μg mL-1) to compare the efficacy of tested
compounds. Each testing was performed in triplicate. The results were interpreted in terms of
diameter (mm) of the zone of inhibition.
Antifungal activity
The antifungal activity of the newly synthesized compounds was tested on the fungal
strains Candida albicans ATCC 10261 and Aspergillus niger ATCC 9643 using the paper disc
diffusion method by using agar medium.
The procedure for the activity testing was similar to that described above for the anti-
bacterial testing and the same concentrations of the tested compounds were employed. The
results were recorded and reported after incubation for 48 h at 25 °C for the fungal strains and
fluconazole was used as the standard (50 μg mL-1). The zones of inhibition indicating the
inhibited growth of microorganism by the prepared compounds around the discs was observed
and reported. Each experiment was performed in triplicate.
Anticancer activity
The newly synthesized compounds were evaluated for their anticancer activity by deter-
mining the percentage control growth of human breast cancer cell lines MCF7 by the in vitro
sulforhodamine B assay (SRB assay) method.22 The cell lines were grown in Roswell Park
Memorial Institute (RPMI) 1640 medium containing 10 % foetal bovine serum and 2 mM
L-glutamine. The tested compounds were solubilised in appropriate solvent at 400-fold the
desired final maximum test concentration and stored frozen prior to use. At the time of drug
addition, an aliquot of frozen concentrate was thawed and diluted to 10 times the desired final
maximum test concentration with complete medium containing the test article at a concentra-
tion of 10-3 µg ml-1. Additional three 10-fold serial dilutions were made to provide a total of
four drug concentrations plus control. Aliquots of 10 μL of these different drug dilutions were
added to the appropriate microtitre wells already containing 90 μL of medium, resulting in the
required final drug concentrations, i.e., 10, 20, 40 and 80 μg mL-1. The absorbance was read
on a plate reader at a wavelength of 540 nm with 690 nm reference wavelength. The percent
growth was calculated on a plate-by-plate basis for the test wells relative to the control wells.
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SHARMA, KUMAR and PATHAK
The percent growth was expressed as the ratio of the average absorbance of the test well to the
average absorbance of the control wells×100. Using the six absorbance measurements (time
zero (Tz), control growth (C), and test growth in the presence of drug at the four concentration
levels (Ti)), the percentage growth was calculated at each of the drug concentration levels.
Percentage growth inhibition was calculated as: ((Ti – Tz)/(C – Tz))×100 for concentrations for
which Ti ≥ Tz (Ti – Tz is positive or zero) or ((Ti – Tz)/Tz)×100 for concentrations for which Ti
< Tz (Ti – Tz is negative). The dose response parameters, i.e., growth inhibition of 50 %
(GI50), total growth inhibition (TGI) and killing of 50 % of the cells (LC50), were calculated
for each test substance.
RESULTS AND DISCUSSION
The reaction sequences leading to different carbazole derivatives are out-
lined in Scheme 1. The carbazole derivatives were synthesized by incorporating
new pharmacophores, such as oxadiazole, at position 9 of the carbazole nucleus
by a conventional method in which carbazole was taken as a starting material to
produce the corresponding 5-[(9H-carbazol-9-yl)methyl]-N-[(substituted-phe-
nyl)(piperazin-1-yl)methyl]-1,3,4-oxadiazol-2-amines (4a–o). Synthesized com-
pounds were identified based on their physical parameters, i.e., solubility, melt-
ing point, chromatographic methods (TLC). The data is given in Table I and
1
spectroscopic methods (UV, IR, H-NMR, MS and elemental analysis are given
1
in the Supplementary material to this paper. The H-NMR spectra showed a peak
between δ 6.00–7.00 ppm, which was assigned to the N–H (aliphatic) proton. A
peak characteristic of –CH– appeared between δ 4.00–5.00 ppm. The peaks at δ
6.00–8.00 ppm showed the presence of aromatic protons. In the FT-IR spectra, a
–1
peak characteristic of N–H (aliphatic) appeared at 3200–3450 cm and a peak
–1
for C=N was observed at 1500–1600 cm .
Pharmacological screening
All the newly synthesized compounds 4a–o were screened for their anti-
bacterial and antifungal activity (Table II). The results revealed that among the
synthesized compounds tested, 4a, 4d and 4n were found to be more potent
–1
against all the bacterial and fungal strains at a concentration 50 μg mL
Anticancer screening. All the synthesized compounds 4a–o were evaluated
for their anticancer activity against the human breast cancer cell line MCF7 by
the SRB assay The in vitro anticancer study was realised at the Tata Memorial
Centre, Advanced Centre for Treatment Research and Education in Cancer
(ACTREC), Navi Mumbai, India. The obtained data are given in Table III.
Among all the synthesized compounds tested, 4a, 4d, 4k, 4m and 4n were found
to be most active against human breast cancer cell lines. It was found that for a
large variety of polycyclic compounds, basic moieties attached to the ring system
not only improve the solubility under physiological conditions, but also lead to
1
an increase in anticancer activity. In the present study, it was established that
presence of an electronegative atom on the benzene ring makes MCF7 cell lines
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SYNTHESIS AND BIOLOGICAL EVALUATION OF CARBAZOLE DERIVATIVES
129
Scheme 1. Synthesis of carbazole derivatives 4a–o.
TABLE I. Physical data of the synthesized compounds 4a–o
Compound
R
Yield, % Reaction time, h M.p. range, °C Rf valuea
4a
4b
4c
4d
4e
4f
p-Nitro
p-Hydroxy
3,4,5-Trimethoxy
p-Chloro
p-(Dimethylamino)
o-Nitro
82.55
79.69
61.5
73.22
53.78
63.96
72.71
4.0
5.0
4.3
6.0
5.5
4.4
5.2
236–237
208–209
184–185
221–222
202–203
225–226
213–214
0.73
0.62
0.69
0.75
0.59
0.65
0.56
4g
m-Hydroxy
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SHARMA, KUMAR and PATHAK
TABLE I. Continued
Compound
R
Yield, %
Reaction time, h M.p. range, °C Rf valuea
4h
4i
4j
4k
4l
4m
4n
m-Nitro
o-Hydroxy
m-Chloro
o-Chloro
m-Methoxy
p-Methoxy
p-Fluoro
H
69.98
59.33
67.07
56.45
52.54
58.75
55.0
6.8
5.0
4.4
6.2
4.5
7.0
6.0
5.2
229–230
218–219
231–232
237–238
192–193
189–190
234–235
176–177
0.71
0.60
0.67
0.66
0.77
0.79
0.54
0.63
4o
51.23
a
Solvent system: benzene:chloroform:methanol (4:3:2)
TABLE II. Antibacterial and antifungal activity of compounds 4a–o; diameter of zone of
inhibition at 50 μg mL-1, mm (mean SD (n = 3))
Bacteria
Fungi
Compound
B. subtilis S. aureus E. coli P. aeruginosa C. albicans A. niger
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
16.2±0.3
12.6±0.1
10.1±0.3
15.6±0.1
14.1±0.3
13.6±0.2
11.3±0.1
15.4±0.1
10.8±0.2
14.3±0.3
13.5±0.1
10.1±0.4
9.9±0.1
16.8±0.2
8.2±0.1
15.5±0.2
–
16.1±0.3
14.6±0.1
12.8±0.3
16.2±0.1
15.9±0.1
14.8±0.2
13.6±0.2
15.2±0.1
11.4±0.1
13.7±0.2
12.4±0.3
8.8±0.1
10.3±0.1
16.5±0.1
9.9±0.3
17.8±0.6
–
22.0±0.2
20.2±0.1
17.1±0.1
21.8±0.1
22.3±0.5
21.6±0.2
19.4±0.2
21.9±0.2
18.6±0.1
20.8±0.1
21.0±0.3
15.8±0.1
16.7±0.3
22.6±0.1
14.5±0.1
22.2±0.4
24.0±0.1
19.5±0.2
17.1±0.2
24.1±0.1
22.7±0.3
23.0±0.4
18.0±0.1
22.4±0.1
19.1±0.4
23.7±0.2
21.5±0.3
15.6±0.1
17.2±0.2
23.6±0.1
15.9±0.2
26.5±0.5
–
16.3±0.3 11.1±0.2
13.1±0.1
10.1±0.4
9.9±0.1
8.1±0.5
16.1±0.1 11.7±0.2
15.3±0.2 10.5±0.2
14.9±0.1 10.2±0.1
12.2±0.3
9.5±0.4
15.1±0.4 10.9±0.1
14.9±0.2 10.3±0.3
15.6±0.3 10.8±0.4
15.1±0.1 10.4±0.3
8.9±0.4
9.5±0.1
7.1±0.2
8.3±0.1
15.9±0.3 11.4±0.4
4o
8.1±0.2
–
5.8±0.1
–
Ciprofloxacina
Fluconazolea
–
-1
16.9±0.5 11.8±0.3
a
Standards – ciprofloxacin and fluconazole at 50 μg mL concentrations. Statistical analysis of the data was
performed by one way ANOVA
TABLE III. Anticancer activity of compounds 4a–o against human breast cancer cell line
MCF7
Drug concentration, µg mL-1
Control growth Drug concentration
%
µg mL-1
Compound
a
GI50
TGI
LC50
10
20
40
80
4a
4b
4c
4d
4e
40.4
58.5
52.4
43.7
59.6
27.4
45.3
40.9
19.1
41.5
10.3 2.1
38.2 30.8
34.7 29.2
10.0 2.8
30.2 22.6
<10
<20
<20
<10
<20
34.4
>80
>80
35.2
>80
60.6
>80
>80
60.2
>80
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SYNTHESIS AND BIOLOGICAL EVALUATION OF CARBAZOLE DERIVATIVES
131
TABLE III. Continued
Drug concentration, µg mL-1
Control growth Drug concentration
%
µg mL-1
Compound
a
GI50
TGI
LC50
10
20
40
80
4f
53.4
61.6
51.9
58.2
55.8
46.9
50.6
49.2
35.4
66.4
0.3
38.7
50.2
33.7
49.3
38.5
31.5
37.3
34.6
11.3
53.7
27.2 13.3
41.9 36.0
28.5 16.4
37.0 31.3
27.6 18.1
11.8 3.4
29.7 20.2
18.3 13.9
<20
<40
<20
<20
<20
<10
<20
<10
<10
<40
<10
>80
>80
68.4
>80
72.9
26.5
>80
60.3
16.5
>80
11.6
>80
>80
>80
>80
>80
53.6
>80
>80
35.6
>80
4g
4h
4i
4j
4k
4l
4m
4n
4o
8.4
1.2
45.2 39.4
ADRb
–10.7 –33.6 –59.7
23.2
a
b
-1
A GI value of < 10 µg mL is considered to demonstrate activity in the case of a pure compound; standard
50
– adriamycin (ADR), positive control compound
more susceptible towards the compound. The results revealed that the substi-
tution is more effective at position 4 than at position 2.
SUPPLEMENTARY MATERIAL
Analytic and spectral data for the prepared compounds are available electronically from
http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgements. The authors are thankful to the management of Rajiv Academy for
Pharmacy, Mathura for providing research facilities and the Tata Memorial Centre, Mumbai
for determining the anticancer activity of the synthesized compounds.
И З В О Д
СИНТЕЗА, КАРАКТЕРИЗАЦИЈА И ИСПИТИВАЊЕ БИОЛОШКЕ АКТИВНОСТИ НОВИХ
ДЕРИВАТА КАРБАЗОЛА
DIVYANSHU SHARMA, NITIN KUMAR и DEVENDER PATHAK
Rajiv Academy for Pharmacy, Delhi-Mathura Highway, Chhattikara, Mathura - 281001, India
Синтетисана је серија нових деривата 5-[(9H-карбазол-9-ил)метил]-N-[(супституи-
сани фенил)(пиперазин-1-ил)метил]-1,3,4-оксадиазол-2-амина (4a–o), полазећи од кар-
базола. У реакцији карбазола и етил-хлорацетата добијен је етил-2-(9H-карбазол-9-
ил)ацетат (1), који у реакцији са семикарбазолом и након циклизације у присуству
сумпорне киселине даје 5-(9H-карбазол-9-ил)-1,3,4-оксадиазол-2-амин (3). Амин 3 у
Маниковој реакцији са пиперазином и различитим ароматичним алдехидима, у при-
суству сирћетне киселине, даје циљане деривате 4a–o. Једињења су окарактерисана UV,
FT-IR, 1H-NMR, MS спектрима и елементалном анализом. Испитане су антибактеријске,
антифунгална и антиканцерска активност свих добијених дервата. Деривати 4a, 4d, 4e и
4n погазују значајну антибактеријску и антифунгалну активност, док деривати 4a, 4d, 4k
и 4n показују активност и према хуманим ћелијским линијама рака дојке MCF7.
(Примљено 23. јануара, ревидирано 16. јуна 2013)
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SHARMA, KUMAR and PATHAK
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