Molecules: Recent Developments and Biological Activities of N-Substituted Carbazole Derivatives: A Review
Molecules: Recent Developments and Biological Activities of N-Substituted Carbazole Derivatives: A Review
Molecules: Recent Developments and Biological Activities of N-Substituted Carbazole Derivatives: A Review
3390/molecules200813496
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Review
†
These authors contributed equally to this work.
1. Introduction
Heterocycles are inextricably woven into the life processes [1]. The importance of heterocycles
in drug discovery is one of the major areas in medicinal chemistry [2]. There are a vast number of
pharmacologically active heterocyclic compounds, many of which are being used clinically, such as
vincristine, morphine, chloroquine, meperidine, sulphadiazine, etc. Sulphur- and nitrogen- containing
Molecules 2015, 20 13497
heterocyclic compounds have maintained the interest of researchers through decades of historical
development of organic synthesis [3,4].
Carbazole is an aromatic heterocyclic organic compound. It has a tricyclic structure, consisting of two
six membered benzene ring fused on either side with a five membered nitrogen-containing ring. Carbazole
and its derivatives are an important type of nitrogen containing heterocyclic compounds that are widespread
in nature [5]. Various classes of carbazoles are given in Figure 1. The Carbazole ring is present in a variety
of naturally occurring medicinally active substances [6] e.g., carbazomycins [7,8] and murrayafoline
A [9]. Series of carbazole derivatives including oxazinocarbazoles, isoxazolocarbazolequinone,
pyrido-carbazolequinone [10], tetrahydrocarbazoles [11], benzocarbazoles [12], furo-carbazoles [13],
pyridocarbazoles [14], pyrrolo-carbazoles [15,16], indolocarbazoles [17], oxazolinyl carbazoles [18],
thienocarbazoles [19], imidazocarbazoles [20], thiazolocarbazoles [21], benzopyrano-carbazoles [22],
benzofurano-carbazoles [23] and N-substituted carbazoles have been synthesized and are well known for
their pharmacological activities [24] such as antioxidant [25], anti-inflammatory [26], antibacterial [27],
antitumor [28,29], anticonvulsant [30], antipsychotic [31], antidiabetic [32], larvicidal [33] properties,
etc. Keeping in view the so vast therapeutical potential of carbazoles, this review will summarize the
biological activities so far reported for the N-substituted carbazoles.
5 4
6 3 S N
4b 4a
C A 2
7 B S
8 8a 9a 1 N
N9
H N N
H H
R
N
H
N N
H O
N N
H H
Tetrahydro carbazoles
Oxazolinyl carbazoles Imidazocarbazoles Benzofurano carbazoles
N
H
Benzopyranocarbazoles
The Spread of drug resistant bacteria has badly affected the efficiency of many known antibacterial
agents [34], while the emergence of fungal infections in the immuno-compromised population has
also significantly increased over past few decades [35,36]. Carbazoles are considered to be one of the
important classes of antimicrobial agents [37,38].
Molecules 2015, 20 13498
Zhang et al. [39] reported the antibacterial and antifungal activities of series of N-substituted
carbazoles. It has been observed that introduction of 1,2,4-triazole moiety in carbazoles (compound 1)
resulted in an increase of antifungal activity against C. albicans, with a minimum inhibitory concentration
(MIC) of 2–4 µg/mL. The introduction of an imidazole moiety (compound 2) seems to be favourable
for antibacterial efficacy against S. aureus, B. subtilis, E. coli, methicillin resistant S. aureus (MRSA),
P. aeruginosa and B. proteus (MIC 1–8 µg/mL). The carbazole triazolium compound, a quaternization
product of triazole 3, displayed excellent antibacterial and antifungal activities against all strains with
MIC values ranging from 1.0 to 64 µg/mL (Figure 2).
N N N
N
N N
1 2
Cl
N
Cl N
N
N
CH3 CH3
CH3 CH3
H 3C CH3
H3 C
CH3 N
N N
N N
H3COOC CH3 H3COOC CH3 N
O2N
4 5
CH3
N
C N
H2C C CH2
R
O
O
7 H 2C CCl 3
CH 3
8 H 2C CH
CH 3
N
9 NO 2
O
OR
Figure 4. Cont.
Molecules 2015, 20 13500
R1
10 CF3
O
O
11 Br
12 Cl
N
NO2
O S 13 F
O
R1 Cl
Kumar et al. [43] reported the synthesis of 9N-(hydrazinoacetyl)-carbazoles which have been
evaluated for the potential antimicrobial activity. The carbazole derivatives containing imidazole
and indole-imidazole moieties such as 1-carbazole-9-yl-2-(4-nitro-phenyl)-4,5-diphenyl-1H-1-yl-amino)-
ethanone (14) and 1-carbazole-9-yl-2-(substituted phenyl)-1,4-dihydroimidazo[4,5-b] indol-1-yl-amino)-
ethanones 15 and 16 were found to be the most potent against B. subtilis, S. aureus, E. coli and
K. pneumoniae with zones of inhibition of 10.3–15.4 mm in diameter at MIC values ranging from
6.2 to 50 µg/mL (Figure 5).
R1
N
NO2
N N R2
N HN
HN N
O
O N
R1 R2
14 15 N(CH3)2 H
16 H Cl
disc diffusion method. The compounds 18 and 20 showed potent antibacterial activity against all
bacterial strains, with zones of inhibition of 16.82–26.08 mm in diameter at a concentration of 50 µg/mL,
whereas the compounds 17–21 showed significant antifungal activity against C. albicans and A. niger
with zones of inhibition of 7.91–16.8 mm in diameter at a concentration of 50 µg/mL (Figure 6).
R1
N R1 R2 R3
17 Cl H H
N R2
R3 18 F H H
N HN
H 19 H H Cl
N
O
20 H NO2 H
21 H OH H
Segall and coworkers [45] reported a potent antifungal activity of N-alkylated carbazoles namely
6,11-dihydro-2-methoxy-11-[2-(1-piperidinyl)]ethyl-5H-benzo[a]carbazole (22) and wiskostatin (23)
against C. albicans with MIC < 11 µM and 100 µM, respectively (Figure 7). Wiskostatin, an inhibitor
of neuronal Wiskott-Aldrich syndrome protein (N-WASP)-mediated actin polymerization in vitro in
relation to WASP, was identified as antifungal agent [46].
N CH3
N N N
OH H3C
22 23
CH3
CH3
N
N N HN
N N
HN N
H2C H 2C NH N
NH C O
C H3C N O
O O
24 25
They showed promising antifungal activity against C. albicans and A. fumigatus with MIC values
ranging from 8.7 to 10.8 µg/mL and antibacterial activity against S. aureus, B. subtilis, E. coli with MIC
values ranging from 1.1 to 10.3 µg/mL. The lipophilic character of these compounds may facilitate the
crossing through biological membranes of microorganism and thereby inhibit their growth.
A series of N-substituted-carbazoles, synthesized by Sharma et al. [48], have been screened for their
antimicrobial activities. The compounds 5-[(9H-carbazol-9-yl)methyl]-N-[(substituted phenyl)(piperazin-
1-yl)methyl]-1,3,4-oxadiazol-2-amines 26, 27 and 28 have displayed antimicrobial activity against
bacterial strains (S. aureus, B. subtilis, E. coli, P. aeruginosa) and fungal strains (C. albicans and A. niger)
with zones of inhibition of 11.1–24.0 mm in diameter at a concentration of 50 µg/mL (Figure 9).
N
R
N
N 26 NO 2
HN
H
C N NH
27 Cl
28 F
Cancer has emerged as one of the most alarming disease in the last few decades throughout the
world. It is a multifactorial disease contributing towards uncontrolled growth and invasion of abnormal
cells leading to the formation of tumors [49]. Pim-kinases control various proteins involved in significant
biological processes such as cell cycle progression and apoptosis. Over expression of pim-kinases have
been observed in human leukaemia and lymphoma, prostate, pancreatic and colon cancer contributed to
Molecules 2015, 20 13503
tumorigenesis. For these reasons, pim-kinases are considered as important targets for the development of
new anticancer drugs.
A series of N-substituted carbazoles synthesized by Akue-Gedu et al. [16] have been studied for
their antiproliferative activity. These N-substituted pyrrolocarbazoles 29, 30 and 31 were found to be
most potent inhibitors for pim-kinase activity with IC50 in the nanomolar range (46–75 nM) and
have demonstrated antiproliferative activities against three human cancer cell lines, PA1 (ovarian
carcinoma) PC3 and DU145 (prostatic carcinoma) with MIC values in the range of 8–20 µM (Figure 10).
CHO
CHO
N N
N N H
H
(CH2)4
(CH2)4
NC N(CH3)2
29 30
CHO
N N
H
(CH2)4
NHBOC
31
Figure 10. Structures of pyrrolo-carbazoles 29–31.
Giraud et al. [50] have synthesized N1-N10-bridged pyrrolo [2,3-a] carbazoles. The ability of these
compounds to inhibit pim-kinases has been evaluated. The compounds 5,6-dihydro-4H-indolo[1,2,3-ef]
pyrrolo[3,2,1-jk][1,5] benzodiazepine-1-carbaldehyde (32) and 5,6,7,8-tetrahydro-4H-indolo[1,2,3-gh]
pyrrolo[3,2,1-lm][1,5] benzodiazonine-1-carbaldehyde (33) showed potent activity with nanomolar
inhibitory potencies against the acute myeloid leukemia IPC-81 cell line, which is a good predictor of
leukaemia therapy (Figure 11).
CHO CHO
N N N
N
32 33
R1
N
N R2
R1 R2 R3
R3
N HN
34 H OCH3 H
N
O
35 H H OCH3
A study was carried out by Kaushik et al. [44] on A549 cell lines in order to explore the anti-tumor
potential of N-substituted carbazoles and the compounds 17, 18, 19 and 36 were found to be active
(Figure 13). A fluoro group at para-position in compound 18 makes its anticancer activity more significant.
N
HN
H
N
O
N
36
Cl
Zhu et al. [51] have documented the synthesis of N-annulated indolocarbazoles and further evaluated
their cyclin dependent kinases (CDKs) inhibitory activity. The compounds 37, 38 and 39 were found to
be potent inhibitors of cyclin D1/CDK4 and were effective antiproliferative agents against two human
carcinoma cell lines, HCT116 (colon) and NCI-460 (lung). The replacement of the indole moiety with
a naphthyl group (compound 40) also resulted in potent antiproliferative activity, with MIC values
ranging between 0.37 and 0.96 µM (Figure 14).
Molecules 2015, 20 13505
H
N
O
O R1 R2 R3
37 CH2OH H H
38 F CH2OH H
N
HN
R3 39 H H CH 2(OH)
R1
R2
H
N
O
OH
40
N-substituted carbazoles, synthesized by Sharma et al. [48], have been screened for their antitumor
activity. The compounds 5-[(9H-carbazol-9-yl)-methyl]-N-[(substituted phenyl)(piperazin-1-yl)methyl]-
1,3,4-oxadiazol-2-amines 41–45 were found to be effective against human breast cancer cell lines (MCF-7).
The LC50 values (µg/mL) of compounds 41-45 were 60.6, 60.2, 53.6, 80.0 and 35.6, respectively
(Figure 15).
R1 R2
N
41 NO2 H
N
N
42 Cl H
O
HN
H
C N NH 43 H Cl
R2
44 OCH 3 H
45 F H
R1
Ciftci et al. [52] have studied the apoptotic effects of N-ethyl-carbazole derivatives on A549 lung
carcinoma and C6 glioma cell lines. The compounds 46 (IC50 = 5.9 µg/mL) and 47 (IC50 = 25.7 µg/mL)
Molecules 2015, 20 13506
were found to be highly active against C6 and A549 cancer cell lines, respectively whereas compounds
48 and 49 showed moderate cytotoxic activity against both cell lines (Figure 16).
R
S
H 46 4-(2-dimethylaminoethyl)piperazin-1-yl
N
S R
47 Morpholin-4-yl
O
N
48 2-methylpiperidin-1-yl
C 2H 5
49 4-methylpiperazin-1-yl
Howorko et al. [53] have reported the cytotoxic potential of compounds 50–53 against three human
tumor cell lines, namely CCRF/CEM (T lymphoblast leukemia), A549, and MCF7 cell line. In another
study, carried out by Li et al. [54], the compound 54 was found to be cytotoxic against cell line A549
(IC50 = 0.07 µM) and colon cancer HT29 cells (IC50 = 0.11 µM). The structures of these compounds
are given in Figure 17.
R2
R1 R2
R1
N 50 OCH3 NHC(CH3)2CH2OH
51 OCH3 NHCCH2CH3(CH2OH)2
52 OH NHC(CH3)2CH2OH
53 OH OH
N
CH3
CH3
O
HN OH
C2H5
54
Roy et al. [55] have synthesized two indolocarbazoles and reported that compound 55 was found to
be a novel check point kinase (ChK1) inhibitor.
Molecules 2015, 20 13507
Nakamura et al. [56] have studied the antitumor activity of a novel N-substituted carbazole, namely
{[12,13-dihydro-5-[2-(dimethylamino)-ethyl]-4H-benzo[c]pyrimido[5,6,1-jk]carbazole-4,6,10-(5H,-11H)-
trione hydrochloride]} (56). It inhibited topoisomerase II activity at a concentration of 2.5 µM which is
a 10 times lower concentration than that of etoposide (standard).
Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors
that upon activation, results into the transduction of signals from the cell membrane to the nucleus.
The seven STATs namely STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 have so
far been identified in mammals. Among them, STAT3 is the most intimately linked to tumorigenesis.
Saturnino et al. [57] have synthesized a series of N-alkylcarbazole derivatives and evaluated their
activity on STAT3. Compounds 57–59 were revealed to inhibit the STAT3 activation by 50%, 90%
and 95%, respectively, at a concentration of 50 µM (Figure 18).
H
N
O
O O
N
N
N
N O
CH3 O
55
N
NH(CH 3)
H3 C CH3 56
H3C
O
H3C
N
O CH3
O (CH2)n
H3CO
57 n=5
58 n=6
H3CO O
59 n=7
Neuroprotection refers to the strategies and relative mechanisms able to defend the central
nervous system (CNS) against neuronal injury due to both acute (e.g., stroke or trauma) and chronic
neurodegenerative disorders [58,59]. Increased oxidative stress has been recognized as a common culprit
of many neurological disorders including Alzheimer’s disease, Parkinson’s disease and stroke [60,61].
Molecules 2015, 20 13508
The β-Amyloid (Aβ) deposition is one of the hallmarks of Alzheimer’s disease. Therefore inhibition of
Aβ peptide accumulation may be a preventive strategy for Alzheimer’s disease [62].
Zhu et al. [63] in 2013 have synthesized a series of N-substituted carbazoles and studied their
neuroprotective effects on neuronal cells HT22 against cell injury induced by glutamate or homocysteic
acid. The compound 2-phenyl-9-(p-tolyl)-9H-carbazole (60) displayed considerable neuroprotective
ability at the concentration as low as 3 µM which might result from its antioxidative activity with
GSH-independent mechanism. The compounds substituted with bulky groups such as methoxy-phenyl
(compound 61), t-butyl-phenyl (62), trifluoro-phenyl (63), and N,N-dimethyl-phenyl (64) at the
N-position of the carbazole also possessed significant neuroprotective activity at a concentration of 30 µM
(Figure 19). It was observed that the presence of a substituent at the N-position of carbazole is essential
for neuroprotective activity.
R1 R2
R2 60 CH3
N
61 OCH3 H
62 t-butyl H
63 CF3 H
R1 64 N(CH 3)2 H
A series of N-alkyl-carbazole derivatives synthesized by Saturnino et al. [64], have been investigated
for their ability to promote an increase of soluble amyloid-β (Aβ) peptides. Among the tested
compounds, 65 was found to be responsible for a 30%–35% increase in the concentration of soluble
Aβ peptides whereas compound 66 showed 65%–70% increase in concentration of soluble Aβ peptides
at 10 µM (Figure 20). In both compounds, the distance between oxygen on the chain and the N-atom of
carbazole scaffold play a decisive role in the interaction with Aβ peptides.
H3C
H3C
OH
N
N
CH3
(CH2)6
(CH2)5
O O
O O
H 3C H3C
O 65 O
66
Among many genes reported to impact adult neurogenesis is the gene encoding NPAS3, a central
nervous system-specific transcription factor that is associated with learning disability and mental
illness [65,66]. NPAS3 deficit mice displayed the behavioral abnormalities [67] and a profound loss of
adult hippocampal neurogenesis [68]. An aminopropyl-carbazole 67, designated as P7C3, exerts its
pro-neurogenic activity by protecting newborn neurons from apoptosis and was capable of enhancing
hippocampal neurogenesis in NPAS3 defecit mice. Pieper et al. [69] carried out a SAR study with
thirty seven analogues of P7C3. The compound P7C3A20 (compound 68) was found to possess greater
potency and efficacy than P7C3, whereas the (R)-enantiomer of P7C3-OMe (69) retained an activity
equivalent to that of the parent compound (Figure 21).
Br
Br
R1
H OH
N N R2
H
N N OCH3
R1 R2
Br
67 OH H
Br 69
68 F OCH3
MacMillan et al. [70] have developed a series of P7C3 derivatives and, among them, compounds
70–74 were found to be more active than the parent compound (Figure 22).
R1
Br
R2 R3
H
N N R1
OCH3
N R2
Br R1 R2 R3 R1 R2
70 CH3 OH H Br
73 OH
N
H
H
71 Br H CH3 74 F N
72 Br F H
assay. The compound P7C3-S184 (78) has been reported as a β-secretase inhibitor and prevented the
formation of Aβ-peptide from amyloid precursor protein thereby proposed as a therapeutic approach for
Alzheimer’s disease (Figure 23).
Br R
Cl
OH S
75 OH
N R H
N N N
CH3
76 N
H3C
Br
77 O
Cl
78
Yoon et al. [72] have developed and screened 25 aminopropyl-carbazole derivatives that can enhance
neurogenesis of cultured neural stem cells. Among these analogues, compounds 79–81 demonstrated
excellent proneurogenic and neuroprotective activity with no apparent toxicity (Figure 24).
Br CH3
OH
H
N N R1
Br
OH O S O
R2
N N OCH3
Br R1 R2
79 H CH3
80 OCH3 OCH3 Br
81
Epilepsy is the most frequent neurologic infection characterized by excessive temporary neuronal
discharge [73]. The overall prevalence of the disease is 1.0% of the population and up to 50 million
people worldwide. Previous studies showed that a significant percent of individuals (20%–30%) using
anti-epileptic drugs are resistant to the currently used therapeutic agent [74]. Therefore researchers
are trying to find more active and less toxic compounds to control the seizures and produce a more
comfortable life for the patients [75,76].
The N-substituted carbazoles 82–87 have been introduced by Rjamanickam et al. [77] and were
screened for their antilepileptic and antinociceptive activities (Figure 25). Compound 86 showed highly
significant anti-epileptic potential at a concentration of 20 mg/kg. This may be due to the substituent,
Molecules 2015, 20 13511
82 COOCH 3 OH
N 83
H2C
KOOCH 2C Cl
N
R1 84
R2
Cl
R1 R2
85 COOCH3 OH
N 86
H 3C CH
KOOCH2C Cl
N
R1
R2 87
Cl
3. Conclusions
Carbazole is a unique template associated with several biological activities. Due to the diverse and
versatile biological properties of carbazole derivatives, particularly N-substituted carbazoles, they are of
Molecules 2015, 20 13512
great interest to the research community. In particular, their antimicrobial, anticancer and antinociceptive
activities makes these compounds attractive candidates, not only for microbe borne diseases, but also
for the several other conditions like Alzheimer’s disease and epilepsy. This article has presented a
comprehensive review of potent N-substituted carbazoles reported for their biological activities. More
research must be carried out to explore their therapeutic potential for many other diseases like AIDS,
hepatitis and diabetes.
Conflicts of Interest
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