Molecules 2015, 20, 13496-13517; doi:10.

3390/molecules200813496
OPEN ACCESS

molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Review

Recent Developments and Biological Activities of N-Substituted

Carbazole Derivatives: A Review
Maryam Bashir †, Afifa Bano †, Abdul Subhan Ijaz † and Bashir Ahmad Chaudhary †,*

Department of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan;

E-Mails: [email protected] (M.B.); [email protected] (A.B.);
[email protected] (A.S.I.)

†
These authors contributed equally to this work.

* Author to whom correspondence should be addressed; E-Mail: [email protected];

Tel.: +92-61-921-0089; Fax: +92-61-921-0129.

Academic Editor: Eugene Babaev

Received: 22 March 2015 / Accepted: 24 June 2015 / Published: 23 July 2015

Abstract: Carbazoles represent an important class of heterocycles. These have been

reported to exhibit diverse biological activities such as antimicrobial, antitumor, antiepileptic,
antihistaminic, antioxidative, anti-inflammatory, antidiarrhoeal, analgesic, neuroprotective
and pancreatic lipase inhibition properties. A series of carbazole derivatives such as
N-substituted carbazoles, benzocarbazoles, furocarbazoles, pyrrolocarbazoles, indolocarbazoles,
imidazocarbazoles, etc. have been synthesized. The N-substituted derivatives have gained
the attention of researchers due to their therapeutic potential against neurological disorders
and cell proliferation. Herein an attempt is made to review the medicinal importance of
recently synthesized N-substituted carbazoles.

Keywords: N-substituted carbazoles; antimicrobial; anticancer; neuroprotective

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

Carbazole Thienocarbazoles Thiazolocarbazoles

N-substituted carbazoles
HN
N
O

N
H

N N
H O
N N
H H
Tetrahydro carbazoles
Oxazolinyl carbazoles Imidazocarbazoles Benzofurano carbazoles

N
H

Benzopyranocarbazoles

Figure 1. Structures of various classes of carbazoles.

2. Biological Activities of N-Substituted Carbazoles

2.1. Antimicrobial Activity

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

Figure 2. Structures of imidazole and triazole carbazoles 1–3.

A series of some novel N-substituted derivatives of 2,3,4,4a,9,13c-hexahydro-7-isopropyl-1,4a-

dimethyl-1H-dibenzo[a,c]carbazole-1-carboxylic acid methyl esters were synthesized by Gu et al. [40].
These newly synthesized compounds have been evaluated for their antimicrobial activity. The
N-ethyl-[N-methyl-piperazinyl] derivative 4 showed antibacterial activity against B. subtilis, S. aureus,
E. coli, P. fluorescens and antifungal activity against C. albicans, A. niger with MIC values ranging
from 1.9 to 7.8 µg/mL. The N-ethyl-[2-methyl-5-nitro imidazole] derivative 5 exhibited antimicrobial
activity against B. subtilis (MIC 0.9 µg/mL) comparable to that of the reference drug (amikacin).
Kaissy et al. [41] introduced an efficient procedure for the synthesis of N-acetylenic aminocarbazole
derivatives. These have been subjected to bioassay against B. subtilis, S. aureus, E. coli and P. aeruginosa.
The compound N-[1-buto-2y-nyl-4(NʹNʹ-methyl-phenyl]carbazole (6) exhibited very highly specific
activity against E. coli, a Gram negative bacterium, with a zone of inhibition of 25 mm in diameter at a
concentration of 800 µg/mL (Figure 3).
Molecules 2015, 20 13499

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

Figure 3. Structures of acetylenic amine and dibenzo-carbazoles 4–6.

N-substituted carbamates [(substituted phenyl/aliphatic-4-oxiran-2yl-methoxy)-9H-carbazole-9-

carboxylate] and sulphonamides [9-(substituted phenyl-sulphonyl)-4-(oxiran-2yl-methoxy)-9H-carbazole]
7–13 have been synthesized by Reddy et al. [42] and evaluated for their antimicrobial activities. The
compounds 7, 9, 10 and 13 showed excellent antibacterial activities against S. aureus, B. subtilis, E. coli
and antifungal activities against A. niger, C. albicans and F. oxysporium. The zones of inhibition were
in the range of 12.6–22.3 mm in diameter at a concentration of 100 µg/mL (Figure 4).

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

Figure 4. Structures of carbamate carbazoles 7–9 and sulphonamide carbazoles 11–13.

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

Figure 5. Structures of hydrazinoacetyl carbazoles 14–16.

The 1-carbazole-9-yl-2-(substituted phenyl)-1,4-dihydroimidazo-[4,5]-indole-1-yl-amino-ethanones

17–21 synthesized by Kaushik et al. [44] were subjected to bioassays for antibacterial activity against
S. aureus, B. subtilis, P. aeruginosa, E. coli and antifungal activity against C. albicans, A. niger by the
Molecules 2015, 20 13501

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

Figure 6. Structures of imidazo-indole carbazoles 17–19.

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

Figure 7. Structures of piperidinyl carbazole 22 and wiskostatin 23.

Two N-substituted carbazoles, 5-[3-(9H-carbazol-9-ylacetyl)triazanylidene]-4,6-dimethylpyrimidin-

2(5H)-one (24) and 4-[3-(9H-carbazol-9-yl acetyl)-triazanylidene]-5-methyl-2-phenyl-2,4-dihydro-3H-
pyrazol-3-one (25) have been synthesized by Salih et al. [47] (Figure 8).
Molecules 2015, 20 13502

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

Figure 8. Structures of pyrimidine carbazole 24 and pyrazole carbazole 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

Figure 9. Structures of piperazinyl-oxadiazole carbazoles 26–28.

2.2. Anti-Cancer Activity

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

Figure 11. Structures of N1-N10 bridged pyrrolo-carbazoles 32 and 33.

Molecules 2015, 20 13504

The 1-carbazole-9-yl-2-(substituted phenyl)-1,4-dihydroimidazo [4,5] indole-1-yl-amino-ethanones

synthesized by Kumar et al. [43] have been evaluated for antitumor potential for laryngeal carcinoma
cell lines (HEP2) and Ehrlich’s Ascites Carcinoma (EAC) cells. The compounds 15, 34 and 35 were
found to be active against tumor cell lines (Figure 12). The activity may be attributed due to the presence
of electron donating group which may increase the basicity of the compound.

R1
N

N R2
R1 R2 R3
R3
N HN
34 H OCH3 H

N
O
35 H H OCH3

Figure 12. Structures of hydrazinoacetyl carbazoles 34 and 35.

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

Figure 13. Structure of imidazo-indole carbazole 36.

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

Figure 14. Structures of indolo- and naphtho-carbazoles 37–40.

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

Figure 15. Structures of piperazinyl-oxadiazole carbazoles (41–45).

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

Figure 16. Structures of N-ethyl carbazoles 46–49.

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

Figure 17. Structures of pyrido-carbazoles 50–54.

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

Figure 18. Structures of indolo-, pyrimido- and N-alkyl-carbazoles 55–59.

2.3. Neuroprotective Activity

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

Figure 19. Structures of phenyl-carbazoles 60–64.

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

Figure 20. Structures of N-alkyl-carbazoles 65 and 66.

Molecules 2015, 20 13509

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

Figure 21. Structures of aminopropyl-carbazoles 67–69.

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

Figure 22. Structures of aminopropyl- and aminobutyl-carbazoles 70–74.

An aminopropyl-carbazole (P7C3) has been reported to block 1-methyl-4-phenyl-1,-2,-3,

-6-tetrahydropyridine (MPTP)-mediated cell death of dopaminergic neurons in Parkinson’s disease.
Cortes et al. [71] have screened P7C3 analogues (P7C3-S7, P7C3-S8, P7C3-S25, P7C3-S40, P7C3-S41,
P7C3-S54, P7C3-S165 and P7C3-S184) for neuroprotective efficacy. The compounds P7C3-S7 (75),
P7C3-S25 (76) and (S)-enantiomer of P7C3-S41 (77) were found to be active in MPTP protection
Molecules 2015, 20 13510

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

Figure 23. Structures of P7C3 derivatives 75–78.

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

Figure 24. Structures of aminopropyl-carbazoles 79–81.

2.4. Anti-Epileptic and Antinociceptive Activities

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

2-(2,-3-dimethyl-phenyl)-amino-benzoic acid. The compounds 82–87 have been reported to possess

analgesic potential. The details of the antinociceptive activity of these compounds are given in Table 1.
R1 R2

82 COOCH 3 OH

H3C CH3 HOOC

N 83

H2C
KOOCH 2C Cl

N
R1 84
R2

Cl
R1 R2

85 COOCH3 OH

H3C CH3 HOOC

N 86

H 3C CH
KOOCH2C Cl

N
R1
R2 87

Cl

Figure 25. Structures of N-alkyl-carbazoles 82–87.

Table 1. Antinociceptive evaluation of compounds (82–87).

Basel Reaction Time (s) before Reaction Time (s) after Administration (Mean ± SEM)
Treatment
Treatment (Mean ± SEM) 15 min 30 min 60 min 120 min
Control 4.1232 ± 0.2342 4.0228 ± 0.2322 4.1244 ± 0.2478 4.3244 ± 0.2286 4.3646 ± 0.2672
a
Std 4.5120 ± 0.9012 8.800 ± 0.9031 ** 10.22 ± 0.2642 ** 11.48 ± 0.3476 ** 13.22 ± 0.2974 **
82 4.9400 ± 0.6274 5.560 ± 0.6325 * 6.48 ± 0.2224 * 8.66 ± 0.2462 ** 10.34 ± 0.2874 **
83 4.8819 ± 0.4654 5.042 ± 0.4761 * 6.58 ± 0.2978 * 8.44 ± 0.2536 ** 10.48 ± 0.3576 **
84 4.7258 ± 0.4839 5.702 ± 0.4830 * 7.46 ± 0.2564 ** 9.26 ± 0.2978 ** 11.22 ± 0.6428 **
85 4.5276 ± 0.5432 5.226 ± 0.5428 ** 7.62 ± 0.2464 ** 8.70 ± 0.3260 ** 9.86 ± 0.2642 **
86 4.5276 ± 0.5324 5.406 ± 0.5428 * 7.44 ± 0.4242 ** 9.66 ± 0.2484 ** 10.26 ± 0.2564 **
87 4.6863 ± 0.4912 5.863 ± 0.3726 * 7.54 ± 0.4264 ** 9.02 ± 0.2478 ** 10.68 ± 0.2346 **
** p < 0.001 vs. control indicates highly significant; a Pentazocine standard; * p < 0.01 vs. control indicates significant.

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

The authors declare no conflict of interest.

References

1. Saini, M.S.; Kumar, A.; Dwivedi, J.; Singh, R. A review: Biological significances of heterocyclic
compounds. Int. J. Pharm. Sci. Res. 2013, 4, 66–77.
2. Rathavi, A.; Shukla, M.; Thakor, M.K. Synthesis and in vitro antibacterial and antifungal activity
of trisubstituted S-triazines. J. Chem. Biol. Phys. Sci. Sec. A 2014, 4, 85–92.
3. Dua, R.; Shrivastava, S.; Sonwane, S.K.; Srivastava, S.K. Pharmacological significance of
synthetic heterocycles scaffold: A review. Adv. Biol. Res. 2011, 5, 120–144.
4. Valverde, M.G.; Torroba, T. Sulfur-nitrogen heterocycles. Molecules 2005, 10, 318–320.
5. Nandy, B.C.; Gupta, A.K.; Mittal, A.; Vyas, V. Carbazole: It’s biological activity. J. Biomed.
Pharm. Res. 2014, 3, 42–48.
6. Knölker, H.J.; Reddy, K.R. Isolation and synthesis of biologically active carbazole alkaloids.
Chem. Rev. 2002, 102, 4303–4428.
7. Knölker, H.J.; Fröhner, W.; Reddy, K.R. Iron-mediated synthesis of carbazomycin G and
carbazomycin H, the first carbazole-1,4-quinol alkaloids from Streptoverticillium ehimense.
Eur. J. Org. Chem. 2003, 4, 740–746.
8. Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S. A novel total synthesis of
antibiotic carbazole alkaloid carbazomycin G. Tetrahedron 2000, 56, 5807–5811.
9. Cuong, N.M.; Wilhelm, H.; Porzel, A.; Arnold, N.; Wessjohann, L. 1-O-Substituted derivatives of
murrayafoline A and their antifungal. Nat. Prod. Res. 2008, 22, 1428–1434.
10. Bouaziz, Z.; Issa, S.; Gentili, J.; Gratz, A.; Bollacke, A.; Kassack, M.; Jose, J.; Herfindal, L.;
Gausdal, G.; Døskeland, S.O.; et al. Biologically active carbazole derivatives: Focus on
oxazinocarbazoles and related compounds. J. Enzym. Inhib. Med. Chem. 2015, 30, 180–188.
11. Ha, J.D.; Kang, S.K.; Cheon, H.G.; Choi, J.K. Synthesis of tetrahydrocarbazole derivatives as
potent β3-adrenoceptor agonists. Bull. Korean Chem. Soc. 2004, 25, 1784–1790.
12. Asche, C.; Frank, W.; Albert, A.; Kucklaender, U. Synthesis, antitumour activity and structure-activity
relationships of 5H-benzo[b]carbazoles. Bioorg. Med. Chem. 2005, 13, 819–837.
13. Hajbi, Y.; Neagoie, C.; Biannic, B.; Chilloux, A.; Vedrenne, E.; Bladeyrou, B.; Bailly, C.;
Mérour, J.Y.; Rosca, S.; Routier, S.; et al. Synthesis and biological activities of new
furo[3,4-b]carbazoles: Potential topoisomerase II inhibitors. Eur. J. Med. Chem. 2010, 45, 5428–5437.
Molecules 2015, 20 13513

14. Tylinska, B.; Howorko, R.J.; Mastalarz, H.; Klopotowska, D.; Fillip, B.; Wietrzyk, J. Synthesis and
structure-activity relationship analysis of new olivacine derivatives. Acta Pol. Pharm. Drug Res.
2010, 67, 495–502.
15. Giraud, F.; Akué-Gédu, R.; Nauton, L.; Candelon, N.; Debiton, E.; Théry, V.; Anizon, F.;
Moreau, P. Synthesis and biological activities of 4-substituted pyrrolo[2,3-a]carbazole Pim kinase
inhibitors. Eur. J. Med. Chem. 2012, 56, 225–236.
16. Akué-Gédu, R.; Letribot, B.; Saugues, E.; Debiton, E.; Anizon, F.; Moreau, P. Kinase inhibitory
potencies and in vitro antiproliferative activities of N-10 substituted pyrrolo[2,3-a]carbazole
derivatives. Bioorg. Med. Chem. Lett. 2012, 22, 3807–3809.
17. Lee, H.J.; Schaefer, G.; Heffron, T.P.; Shao, L.; Ye, X.; Sideris, S.; Malek, S.; Chan, E.;
Merchant, M.; La, H.; et al. Noncovalent wild-typesparing inhibitors of EGFR T790M.
Cancer Discov. 2013, 3, 168–181.
18. Inoue, M.; Suzuki, T.; Nakada, M. Asymmetric catalysis of Nozaki−Hiyama allylation and
methallylation with a new tridentate bis(oxazolinyl)carbazole Ligand. J. Am. Chem. Soc. 2003, 125,
1140–1141.
19. Kirsch, G.H. Heterocyclic analogues of carbazole alkaloids. Curr. Org. Chem. 2001, 5, 507–518.
20. Achab, S.; Diker, K.; Potier, P. A short route to functionalized imidazo[4,5-c]carbazoles. Synthesis
of the first example of the imidazo[4,5-c]β-carboline ring system. Tetrahedron Lett. 2001, 42,
8825–8828.
21. Chabane, H.; Lamazzi, C.; Thiery, V.; Guillaumet, G.; Besson, T. Synthesis of novel
2-cyanothiazolocarbazoles analogues of ellipticine. Tetrahedron Lett. 2002, 43, 2483–2486.
22. Oliveria, M.M.; Salvador, M.A.; Coelho, P.J.; Carvalho, L.M. New benzopyranocarbazoles:
Synthesis and photochromic behavior. Tetrahedron 2005, 61, 1681–1691.
23. Kawaguchi, K.; Nakano, K.; Nozaki, K. Synthesis, structures, and properties of unsymmetrical
heteroacenes containing both pyrrole and furan rings. Org. Lett. 2008, 10, 1199–1202.
24. Martin, A.E.; Prasad, K.J.R. Synthesis and characterization of carbazole derivatives and their
antimicrobial studies. Acta Pharm. 2006, 56, 79–86.
25. Guillonneau, C.; Pierre, A.; Charton, Y.; Guilbard, N.; Berthier, L.K.; Leonce, S.; Michael, A.;
Bisagni, E.; Atassi, G. Synthesis of 9-O-substituted derivatives of 9-hydroxy-5,6-dimethyl-6H-
pyrido[4,3-b]carbazole-1-carboxylic acid (2-(Dimethylamino)ethyl)amide and their 10- and
11-methyl analogues with improved antitumor activity. J. Med. Chem. 1999, 42, 2191–2203.
26. Bandgar, B.P.; Adsul, L.K.; Chavan, H.V.; Jalde, S.S.; Shringare, S.N.; Shaikh, R.; Meshram, R.J.;
Gacche, R.N.; Masand, V. Synthesis, biological evaluation, and docking studies of 3-(substituted)-
aryl-5-(9-methyl-3-carbazole)-1H-2-pyrazolines as potent anti-inflammatory and antioxidant agents.
Bioorg. Med. Chem. Lett. 2012, 22, 5839–5844.
27. Biamonte, M.A.; Wanner, J.; Roch, K.G.L. Recent advances in malaria drug discovery.
Bioorg. Med. Chem. Lett. 2013, 23, 2829–2843.
28. Caruso, A.; Chiret, A.S.V.; Lancelot, J.C.; Sinicropi, M.S.; Garofalo, A.; Rault, S. Efficient and
Simple Synthesis of 6-Aryl-1,4-dimethyl-9H-carbazoles. Molecules 2008, 13, 1312–1320.
29. Chakrabarty, M.; Ghosh, N.; Harigaya, Y. A clay-mediated, regioselective synthesis of
2-(aryl/alkyl)amino-thiazolo[4,5-c]carbazoles. Tetrahedron Lett. 2004, 45, 4955–4957.
Molecules 2015, 20 13514

30. Issa, S.; Walchshofer, N.; Kassab, I.; Termoss, H.; Chamat, S.; Geahchan, A.; Bouaziz, Z.
Synthesis and antiproliferative activity of oxazinocarbazole and N,N-bis(carbazolylmethyl)amine
derivatives. Eur. J. Med. Chem. 2010, 45, 2567–2577.
31. Danish, A.I.; Prasad, K.J.R. A one-pot synthesis of 1,2,4,5-tetraazaspiro [5.5]-6,7,8,
9-tetrahydrocarbazol-3-thiones and their antibacterial activities. Indian J. Heterocycl. Chem.
2006, 14, 19–22.
32. Indumati, T.; Fronczek, F.R.; Prasad, K.J.R. Synthesis of 2-amino-8-chloro-4-phenyl-5,11-
dihydro-6H-pyrido[2,3-a]carbazole-3-carbonitrile: Structural and biological evaluation. J. Mol. Struct.
2012, 1016, 134–139.
33. Kantevari, S.; Yempala, T.; Surineni, G.; Sridhar, B.; Sriram, D. Synthesis and antitubercular
evaluation of novel dibenzo[b,d]furan and 9-methyl-9H-carbazole derived hexahydro-2H-
pyrano[3,2-c]quinolines via Povarov reaction. Eur. J. Med. Chem. 2011, 46, 4827–4833.
34. Uttley, A.H.C.; Collins, C.H.; Naidoo, J.; George, R.C. Vancomycin-resistant enterococci. Lancet
1988, 1, 57–58.
35. Fox, R.; Neal, K.R.; Leen, C.L.S.; Ellis, M.E.; Mandal, B.K. Fluconazole resistant candida in
AIDS. J. Infect. 1991, 22, 201–204.
36. Pfaller, M.A.; Bale, M.; Buschelman, B. Selection of candidate quality control isolates and
tentative quality control ranges for in vitro susceptibility testing of yeast isolates by National
Committee for Clinical Laboratory Standards proposed standard methods. J. Clin. Microbiol.
1994, 32, 1650–1653.
37. Gu, W.; Wang, S.F. Synthesis and antimicrobial activities of novel 1H-dibenzo[a,c]carbazoles
from dehydroabietic acid. Eur. J. Med. Chem. 2010, 45, 4692–4696.
38. Yaqub, G.; Hannan, A.; Akbar, E.; Usman, M.; Hamid, A.; Sadiq, Z.; Iqbal, M. Synthesis,
antibacterial, and antifungal activities of novel pyridazino carbazoles. J. Chem. 2013, 2013, 818739,
doi:10.1155/2013/818739.
39. Zhang, F.F.; Gan, L.L.; Zhou, G.H. Synthesis, anti-bacterial and antifungal activites of some
carbazole derivatives. Bioorg. Med. Chem. 2010, 20, 1881–1884.
40. Gu, W.; Qiao, C.; Wang, S.F.; Hao, Y.; Miao, T.T. Synthesis and biological evaluation of novel
N-substituted 1H-dibenzo[a,c]carbazole derivatives of dehydroabietic acid as potential antimicrobial
agents. Bioorg. Med. Chem. Lett. 2014, 24, 328–331.
41. Kaissy, W.W.N.A.; Tuama, S.H.F.; Majidi, S.M.H.A. Synthesis, characterization and evaluation
of antimicrobial activity of some new acetylenic amine and 2- oxoazetidine of carbazole. Am. J.
Sci. Ind. Res. 2013, 4, 389–398.
42. Reddy, S.V.L.; Naresh, K.; Raju, C.N. New sulfonamide and carbamate derivatives of
4-(oxiran-2-ylmethoxy)-9Hcarbazole: Synthesis, characterization, antimicrobial and antioxidant
activities. Der Pharm. Lett. 2013, 5, 221–231.
43. Kumar, N.; Sharma, G.K.; Pathak, D. Microwave assisted and parallel synthesis of novel substituted
carbazole derivatives of biological interest. Int. J. Pharm. Chem. Sci. 2013, 2, 273–282.
44. Kaushik, K.; Kumar, N.; Pathak, D. Synthesis of some newer carbazole derivatives and evaluation
for their pharmacological activity. Der Pharm. Sin. 2012, 3, 470–478.
45. Segall, A.I.; Vitale, M.F.; Perez, V.L.; Pizzorno, M.T. HPLC analysis of 5H-benzo[a]carbazole
with antifungal activity. J. Pharm. Biomed. Anal. 2003, 31, 1021–1026.
Molecules 2015, 20 13515

46. Thevissen, K.; Marchand, A.; Chaltin, P.; Meert, E.M.K.; Cammue, B.P.A. Antifungal carbazoles.
Curr. Med. Chem. 2009, 16, 2205–2211.
47. Salih, N.; Salimon, J.; Yousif, E. Synthesis and antimicrobial activities of 9H-carbazole derivatives.
Arabian J. Chem. 2011, 2011, doi:10.1016/j.arabjc.2011.08.013.
48. Sharma, D.; Kumar, N.; Pathak, D. Synthesis, characterization and biological evaluation of some
newer carbazole derivatives. J. Serb. Chem. Soc. 2014, 79, 125–132.
49. Gautam, N.; Mantha, A.K.; Mittal, S. Essential oils and their constituents as anticancer agents:
A mechanistic view. BioMed Res. Int. 2014, 2014, 154106, doi:10.1155/2014/154106.
50. Giraud, F.; Bourhis, M.; Nauton, L.; Théry, V.; Herfindal, L.; Døskeland, S.O.; Anizon, F.;
Moreau, P. New N-1,N-10-bridged pyrrolo[2,3-a]carbazole-3-carbaldehydes: Synthesis and biological
activities. Bioorg. Chem. 2014, 57, 108–115.
51. Zhu, G.; Conner, S.E.; Zhou, X.; Chan, H.K.; Shih, C.; Engler, T.A.; Awar, R.S.A.; Brooks, H.B.;
Watkins, S.A.; Spencer, C.D.; et al. Synthesis of 1,7-annulated indoles and their applications in
the studies of cyclin dependent kinase inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 3057–3061.
52. Ciftci, G.A.; Temel, H.E.; Yildirim, S.U.; Kaplancikli, Z.A.; Altintop, M.D.; Genc, L. Apoptotic
effects of some carbazole derivatives on lung carcinoma and glioma cell lines. Med. Chem. Res.
2013, 22, 3751–3759.
53. Howorko, R.J.; Tylinska, B.; Biadun, B.; Gebarowski, T.; Gasiorowski, K. New pyridocarbazole
derivatives. Synthesis and their in Vitro anticancer activity. Act. Pol. Pharm. Drug Res. 2013, 70,
823–832.
54. Li, B.; Yue, Z.Z.; Feng, J.M.; He, Q.; Miao, Z.H.; Yang, C.H. Design and Synthesis of
Pyrido[3,2-α]carbazole derivatives and their analogues as potent antitumor agents. Eur. J. Med. Chem.
2013, 66, 531–539.
55. Roy, S.; Eastman, A.; Gribble, G.W. Synthesis of bisindolylmaleimides related to GF109203x
and their efficient conversion to the bioactive indolocarbazoles. Org. Biomol. Chem. 2006, 4,
3228–3234.
56. Nakamura, K.; Sugumi, H.; Yamaguchi, A.; Uenaka, T.; Kotake, Y.; Okada, T.; Kamata, J.;
Niijima, J.; Nagasu, T.; Koyanagi, N.; et al. Antitumor activity of ER-37328, a novel carbazole
topoisomerase II inhibitor. Mol. Cancer Ther. 2002, 1, 169–175.
57. Saturnino, C.; Palladino, C.; Napoli, M.; Sinicropi, M.S.; Botta, A.; Sala, M.; Carcereri de Prati, A.;
Novellino, E.; Suzuki, H. Synthesis and biological evaluation of new N-alkylcarbazole derivatives
as STAT3 inhibitors: Preliminary study. Eur. J. Med. Chem. 2013, 60, 112–119.
58. Kumar, G.P.; Khanum, F. Neuroprotective potential of phytochemicals. Pharmacogn. Rev. 2012, 6,
81–90.
59. Kumar, V. Potential medicinal plants for CNS disorders: An overview. Phytother. Res. 2006, 20,
1023–1035.
60. Praticò, D. Oxidative stress hypothesis in Alzheimer’s disease: A reappraisal. Trends Pharmacol. Sci.
2008, 29, 609–615.
61. Barnham, K.J.; Masters, C.L.; Bush, A.I. Neurodegenerative diseases and oxidative stress.
Nat. Rev. Drug Discov. 2004, 3, 205–214.
Molecules 2015, 20 13516

62. Doré, V.; Villemagne, V.L.; Bourgeat, P.; Fripp, J.; Acosta, O.; Chetélat, G.; Zhou, L.; Martins, R.;
Ellis, K.A.; Masters, C.L.; et al. Cross-sectional and longitudinal analysis of the relationship
between Aβ deposition, cortical thickness and memory in cognitively unimpaired individuals and
in Alzheimer disease. JAMA Neurol. 2013, 70, 903–911.
63. Zhu, D.; Chen, M.; Li, M.; Luo, B.; Zhao, Y.; Huang, P.; Xue, F.; Rapposelli, S.; Pi, R.; Wen, S.
Discovery of novel N-substituted carbazoles as neuroprotective agents with potent anti-oxidative
activity. Eur. J. Med. Chem. 2013, 68, 81–88.
64. Saturnino, C.; Iacopetta, D.; Sinicropi, M.S.; Rosano, C.; Caruso, A.; Caporale, A.; Marra, N.;
Marengo, B.; Pronzato, M.A.; Parisi, O.I.; et al. N-alkyl carbazole derivatives as new tools for
Alzheimer’s disease: Preliminary studies. Molecules 2014, 19, 9307–1917.
65. Kamnasaran, D.; Muir, W.; Ferguson-Smith, M.; Cox, D. Disruption of the neuronal PAS3 gene
in a family affected with schizophrenia. J. Med. Genet. 2003, 40, 325–332.
66. Pickard, B.S.; Pieper, A.A.; Porteous, D.J.; Blackwood, D.H.; Muir, W.J. The NPAS3
gene—Emerging evidence for a role in psychiatric illness. Ann. Med. 2006, 38, 439–448.
67. Erbel-Sieler, C.; Dudley, C.; Zhou, Y.; Wu, X.; Estill, S.J.; Han, T.; Diaz-Arrastia, R.;
Brunskill, E.W.; Potter, S.S.; McKnight, S.L. Behavioral and regulatory abnormalities in mice
deficient in NPAS1 and NPAS3 transcription factors. Proc. Natl. Acad. Sci. USA 2004, 101,
13648–13653.
68. Pieper, A.A.; Wu, X.; Han, T.W.; Estill, S.J.; Dang, W.; Wu, L.C.; Reece-Fincanon, S.; Dudley, C.A.;
Richardson, J.A.; Brat, D.J.; et al. The neuronal PAS domain protein 3 transcription factor controls
FGF-mediated adult hippocampal neurogenesis in mice. Proc. Natl. Acad. Sci. USA 2005, 102,
14052–14057.
69. Pieper, A.A.; Xie, S.; Capota, E.; Estill, S.J.; Zhong, J.; Long, J.M.; Becker, G.L.; Huntington, P.;
Goldman, S.E.; Shen, C.H.; et al. Discovery of a Pro-neurogenic, Neuroprotective Chemical. Cell
2010, 142, 39–51.
70. MacMillan, K.S.; Naidoo, J.; Liang, J.; Melito, L.; Williams, N.S.; Morlock, L.; Huntington, P.J.;
Estill, S.J.; Longgood, J.; Becker, G.L.; et al. Development of proneurogenic, neuroprotective small
molecules. J. Am. Chem. Soc. 2011, 133, 1428–1437.
71. Cortés, H.D.J.; Xu, P.; Drawbridge, J.; Estill, S.J.; Huntington, P.; Tran, S.; Britt, J.; Tesla, R.;
Morlock, L.; Naidoo, J.; et al. Neuroprotective efficacy of aminopropyl carbazoles in a mouse
model of Parkinson disease. PNAS 2012, 109, 17010–17015.
72. Yoon, H.J.; Kong, S.Y.; Park, M.H.; Cho, Y.; Kim, S.E.; Shin, J.Y.; Jung, S.H.; Lee, J.;
Farhanullah; Kim, H.J.; et al. Aminopropyl carbazole analogues as potent enhancers of
neurogenesis. Bioorg. Med. Chem. 2013, 21, 7165–7174.
73. McCagh, J.; Fisk, J.E.; Baker, G.A. Epilepsy, psychosocial and cognitive functioning. Epilepsy Res.
2009, 86, 1–14.
74. Shindikar, A.V.; Khan, F.; Viswanathan, C.L. Design, synthesis and in vivo anticonvulsant
screening in mice of novel phenylacetamides. Eur. J. Med. Chem. 2006, 41, 786–792.
75. Brodie, M.J. Do we need any more new antiepileptic drugs? Epilepsy Res. 2001, 45, 3–6.
76. Bialer, M.; Johannessen, S.I.; Kupferberg, H.J.; Levy, R.Y.; Loiseau, P.; Perucca, E. Progress report
on new antiepileptic drugs: A summary of the sixth Eilat conference (EILAT VI). Epilepsy Res.
2002, 51, 31–71.
Molecules 2015, 20 13517

77. Rajamanickam, V.; Rajasekarena, A.; Palanivelu, M.; Anandarajagopal, K.; Elahi, A.L.A.;
Umaranib, N. Anti-nociceptive and anti-epileptic evaluation of N-Mannich bases of some substituted
carbazoles. Int. J. Chem. Sci. 2008, 6, 1669–1675.

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