Design, synthesis and biological evaluation of novel 1,2,3-triazolyl β -hydroxy alkyl/carbazole hybrid molecules

Article abstract of DOI:10.1007/s11030-016-9678-7

The design, synthesis and biological study of several novel 1,2,3-triazolyl β -hydroxy alkyl/carbazole hybrid molecules as a new type of antifungal agent has been described. In this synthesis, the N-alkylation reaction of carbazol-9-ide potassium salt with 3-bromoprop-1-yne afforded 9-(prop-2-ynyl)-9H-carbazole. The ‘Click’ Huisgen cycloaddition reaction of 9-(prop-2-ynyl)-9H-carbazole with diverse β -azido alcohols in the presence of copper-doped silica cuprous sulphate led to target molecules in excellent yields. The in vitro antifungal and antibacterial activities of title compounds were screened against various pathogenic fungal strains, Gram-positive and/or Gram-negative bacteria. In particular, 1-(4-((9H-carbazol-9-yl) methyl)-1H-1,2,3-triazol-1-yl)-3-butoxypropan-2-ol (10e) proved to have potent antifungal activity against all fungal tests compared with fluconazole and clotrimazole as studied reference drugs. Our molecular docking analysis revealed an appropriate fitting and a potential powerful interaction between compound 10e and an active site of the Mycobacterium P450DM enzyme. The strong hydrogen bondings between β -hydroxyl and ether groups in 10e were found to be the main factors that drive the molecule to fit in the active site of enzyme. The in silico pharmacokinetic studies were used for a better description of 10a–10n as potential lead antifungal agents for future investigations.

Full text of DOI:10.1007/s11030-016-9678-7

Mol Divers
DOI 10.1007/s11030-016-9678-7
ORIGINAL ARTICLE
Design, synthesis and biological evaluation of novel 1,2,3-triazolyl
β-hydroxy alkyl/carbazole hybrid molecules
1
1
1
Mohammad Navid Soltani Rad · Somayeh Behrouz · Marzieh Behrouz ·
1
2
2
2
Akram Sami · Mehdi Mardkhoshnood · Ali Zarenezhad · Elham Zarenezhad
Received: 3 November 2015 / Accepted: 22 May 2016
©
Springer International Publishing Switzerland 2016
Abstract The design, synthesis and biological study of sev-
eral novel 1,2,3-triazolyl β-hydroxy alkyl/carbazole hybrid
molecules as a new type of antifungal agent has been
described. In this synthesis, the N-alkylation reaction of
carbazol-9-ide potassium salt with 3-bromoprop-1-yne af-
forded 9-(prop-2-ynyl)-9H-carbazole. The ‘Click’ Huis-
gen cycloaddition reaction of 9-(prop-2-ynyl)-9H-carbazole
withdiverseβ-azidoalcoholsinthepresenceofcopper-doped
silica cuprous sulphate led to target molecules in excellent
yields. The in vitro antifungal and antibacterial activities
of title compounds were screened against various patho-
genic fungal strains, Gram-positive and/or Gram-negative
bacteria. In particular, 1-(4-((9H-carbazol-9-yl) methyl)-
a better description of 10a–10n as potential lead antifungal
agents for future investigations.
Keywords Antifungal · Antibacterial · Carbazole ·
β-Hydroxy 1, 2, 3-triazole · Mycobacterium P450DM
Introduction
Infections caused by pathogenic microorganisms are still
a continuous and serious threat to human life worldwide
[1]. Typically, the infections caused by opportunistic fungal
pathogens are a well-known reason for morbidity in patients
with impaired immune system, such as patients undergoing
organ transplants, HIV and cancer chemotherapy [2–5]. Up
to now, numerous antifungal agents with different modes
of action mechanism have been developed for medical uses
[6]. However, the medical care with current antifungal drugs
is limited for several reasons including resistance against
fungal species, toxicity, pharmacokinetic deficiencies and
undesirable side effects [7,8]. In the last decades, the growing
concerns about antifungal drugs have created a substantial
need for developing newer types of antifungal drugs. In this
connection, extensive efforts have been made to design and
synthesize new antifungal agents with a wide spectrum of
activities.
The azole derivatives are known for exhibiting good
bioavailability, high therapeutic index, favourable safety pro-
file and low toxicity [9,10]. It is well established that azole
cores in most azole antifungal drugs are the main pharma-
cophoric sites for establishing antifungal activity. Ergosterol
is an essential component for constructing the cell mem-
brane in fungi cells. It is well indicated that azole antifungals
inhibit biosynthesis of ergosterol via the coordination with
the iron core present in the haem cofactor at the active site
1
H-1,2,3-triazol-1-yl)-3-butoxypropan-2-ol (10e) proved to
have potent antifungal activity against all fungal tests com-
pared with fluconazole and clotrimazole as studied reference
drugs. Our molecular docking analysis revealed an appro-
priate fitting and a potential powerful interaction between
compound 10e and an active site of the Mycobacterium
P450DM enzyme. The strong hydrogen bondings between
β-hydroxyl and ether groups in 10e were found to be the
main factors that drive the molecule to fit in the active site of
enzyme. The in silico pharmacokinetic studies were used for
Electronic supplementary material The online version of this
article (doi:10.1007/s11030-016-9678-7) contains supplementary
material, which is available to authorized users.
B Mohammad Navid Soltani Rad
soltani@sutech.ac.ir
B Somayeh Behrouz
behrouz@sutech.ac.ir
1
Department of Chemistry, Shiraz University of Technology,
71555-313 Shiraz, Iran
2
Fasa University of Medical Sciences, Fasa, Iran
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Fig. 1 Structures of several
clinically used azole antifungals
N
N
OH
N
N
N
N
F
N
Cl
N
N
N
F
Bifonazole
Clotrimazole
Fluconazole
N
N
N
N
Cl
N
OH
Cl
N
N
O
N
O
Cl
Cl
Cl
Cl
Cl
Cl
Miconazole
Cl
Tebuconazole
Oxiconazole
of cytochrome P450-dependent 14 α-lanosterol demethylase
CYP51, P45014DM) [11]. This enzyme has an essential role
in biosynthesis of ergosterol and hence can be considered as
a favourable target for most azole antifungal drugs [11–13].
The structures of several clinically used azole antifungals are
shown in Fig. 1.
From recent advances in Cu(I)-catalyzed azide-alkyne
cycloaddition (CuAAC) for regioselective synthesis of 1,4-
disubstituted 1,2,3-triazoles, 1,2,3-triazole rings have em-
erged as ideal surrogates or bioisosteres of previously iden-
tified azole cores of well-established antifungals [14,15].
diverse pharmaceutical properties. The structures and prop-
erties of some carbazole-triazole hybrid molecules are shown
in Figs. 2 and 3.
(
Formerly, the triazole-carbazole hybrid molecules 6–
9 were reported as promising molecules having apparent
antibacterial and antifungal activities (Fig. 3) [25,26,31,32].
Therefore, with inspiration from the remarkable biologi-
cal activities of 1,2,3-triazole and carbazole and also in
continuation of our interest in discovering the new azole
bioactive compounds [33–40], herein we would like to report
the design and synthesis of some 1,2,3-triazolyl β-hydroxy
alkyl/carbazole hybrids as a new type of antifungal agent
(Fig. 3). In this synthesis, 1,2,3-triazole cores were conju-
gated with carbazole through CuAAC to achieve the novel
hybrid molecules 10a–10n. As shown in Fig. 3, our new
compounds (10a–10n) have structural resemblance to com-
pounds 7–9 with a main difference that our compounds have
the β-hydroxyl moiety. It is assumed that the presence of
this hydroxyl group can increase the binding affinity of our
compounds to active sites of enzyme or receptors [41].
1,2,3-Triazole derivatives display a wide range of biological
activities, such as antibiotic, antiviral, anti-allergic, anti-
inflammatory, anticancer, and antifungal [6,16].
Affinity of 1,2,3-triazolyl cores to bind at the surface
of receptors or enzymes is contributed by the potential
to undergo hydrogen bonding, dipole-dipole, as well as
hydrophobic interactions with the target biomolecules [17].
Thus, the incorporation of 1,2,3-triazolyl cores into the scaf-
folds of bioactive molecules is interesting [16,18].
In recent years, the drug design based on molecular
hybridization has attracted massive interests in medicinal
chemistry. Due to this approach, two bioactive pharma-
cophores are conjugated through a spacer into a single
structure to behave as dual-acting drugs and/or to lessen
the side effects [19,20]. Carbazole-triazole hybrid molecules
have found extensive applications in the design and syn-
thesis of many carbazole-triazole hybrid-based drugs, drug
candidates [21–26] and optoelectronic devices [27–30]. To
this end, the carbazole-triazole hybrid moieties have been
widely applied in scaffolds of many molecules exhibiting
Results and discussion
Chemistry
The synthetic route to access 10a–10n is achieved by the
general pathway illustrated in Schemes 1, 2, 3 and 4. As
shown in Scheme 1, the first step includes the preparation
of 9-(prop-2-ynyl)-9H-carbazole (12), which is a key start-
ing material for Huisgen’s azide–alkyne cycloaddition. The
1
23

Mol Divers
N
NR'R''
N
N
AcO
O
N
N
N
Me
N
N
N
OAc
OAc
N
N
N
Me
OAc
1
2
3
NH
R', R'' = H, alkyl, SO Ar
OHC
2
(
pim Kinase Inhibitor)
(Acetylcholinesterase Inhibitor)
Cl
Cl
S
N
N
N
HO
N
N
N
N
OH
OH
N
N
O
Cl
OH
Cl
4
5
Fig. 2 Structures of some carbazole-triazole hybrid molecules
Fig. 3 Structures and
biological properties of
F
Br
R
triazole-carbazole hybrids 6–9
and general structure of
N
N N
N
N
N
N
1
,2,3-triazolyl β-hydroxy
N
N
N
alkyl/carbazole hybrid
molecules 10a–10n
N
N
Me
4
Me
7
6
8
R = alkyl, aryl
(
Antifungal Agent)
(
Antimycobacterial Agent)
(Antimycobacterial Agent)
HO
R
N
N
N
N
N
N
N
N
Cl
9
Cl
10a-10n
R= alkyl, alkoxy, aryloxy
Cl
(
Antibacterial and Antifungal Agent)
Our New Compounds
Scheme 1 Synthesis of
9
-(prop-2-ynyl)-9H-carbazole
KOH, 70 °C
(12)
Br
EtOH, 4 h
DMSO, r.t., 3 h
N
N
K
N
H
11
1
2
synthesis of alkyne 12 was previously reported by different
groups [42,43]. However, utilization of the reported pro-
cedures resulted in unsatisfactory yields of 12. Thus, we
considered an alternative procedure in which alkyne 12 was
simply prepared from reaction of 3-bromoprop-1-yne with
carbazole potassium salt 11 in DMSO at ambient temper-
ature for 3h (94%). It is worth mentioning that carbazole
salt 11 was earlier prepared by dissolving 9H-carbazole in a
In the second step, the desired organic azides were syn-
thesized (Scheme 2). In the design of 10a–10n, the use of
β-azido alcohols was preferred to simple alkyl azides, since
the presence of a hydroxyl group may drive the molecule to
the active site of enzyme via hydrogen bonds and dipole inter-
actions. In this context, several structurally diverse β-azido
alcohols 13a–13n bearing various substituents were prepared
by regioselective ring opening of the corresponding epoxides
with NaN3 [44] (Schemes 2, 3).
◦
KOH/EtOH solution followed by heating at 70 C for 4h.
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OH
The synthesis of 13i–13n was achieved in two steps. The
first one included the reaction of non-chiral epibromohydrin
with appropriate phenols using K CO in MeCN at reflux
O
NaN , H O/acetone (1:1)
R1
3
2
N3
R1
R2
reflux, 3 h
R2
2
3
condition (Scheme 3). Because of the ambident-electrophilic
nature of epibromohydrin, its reaction with different phenols
usually produces a racemic mixture of epoxides 14 and bro-
mohydrins 15. In the subsequent step, 13i–13n were obtained
3
1
3a-13h
OH
N3
13a:
1
2
1
1
1
1
1
1
1
3b: R =Me, R =H
3c: R1=Et, R =H
3d: R =Me, R =Me
3e: R =CH OBu, R =H
3f: R =CH OCHMe , R =H
3g: R =CH O CC(=CH )Me, R =H
3h: R =CH OPh, R =H
in racemic forms via mixing the crude media with NaN in
2
acetone/H O (1:1) at reflux conditions. It is worth mention-
2
1
2
ing that both 14 and 15 are prone to react with NaN to yield
3
1
2
a single product and thus the separation of 14 from 15 is not
mandatory (Scheme 3).
The last step of this synthetic approach consists of
CuAAC between 9-(prop-2-ynyl)-9H-carbazole (12) and β-
azido alcohols (13a–13n) to afford final products 10a–10n
2
1
2
2
2
1
2
2
2
2
1
2
2
Scheme 2 Synthesis of β-azido alcohols 13a–13h
(Scheme 1). Recently, we developed the copper-doped sil-
ica cuprous sulphate (CDSCS) as an efficient heterogeneous
nano-catalyst for Cu(I)-catalyzed ‘Click’ cycloaddition of β-
azido alcohol and alkyne in THF/H2O (1:1, v/v) solution
at room temperature [37]. Using this catalyst, the cycload-
dition reaction of 12 with 13a–13n was regioselectively
leading to 10a–10n in excellent yields. As can be seen
in Scheme 4, several structurally diverse 1,2,3-triazolyl β-
hydroxy alkyl/carbazole hybrid molecules 10a–10n were
prepared in racemic forms that only vary in β-hydroxy alkyl
Since some starting epoxides used in this synthesis were
not commercially available, two different pathways were
employed to produce 13a–13n. Compounds 13a–13h were
prepared in racemic forms due to Scheme 2 by coupling
of NaN3 with the desired non-chiral epoxides in reflux-
ing acetone/H2O (1:1). In this reaction condition, NaN3
normally attacks the less hindered C-atom of the terminal
epoxide.
Scheme 3 Synthesis of β-azido
alcohols 13i–13n
OH
R1
R2
R1
O
OH
R1
O
K
2
CO
3
, TBAB
Br
+
Br
O
R2
R3
O
R3
+
MeCN,reflux, 10 h
R2
14
15
R3
1
2
3
R1
13i:
R =H, R =H, R =Me
3
OH
NaN
3
, H
2
O/acetone (1:1)
2
13j: R1=H R =H, R =OMe
N3
O
R2
R3
1
2
3
1
1
1
1
3k: R =H, R =Me, R =Cl
3l: R =H, R =H, R =Cl
3m: R =Cl, R =H, R =H
3n: R =Cl, R =H, R =Cl
reflux, 3 h
1
2
3
1
3i-13n
1
2
3
1
2
3
R1
R2
HO
O
R3
HO
R1
R2
N
N
N
N
N
1
2, CDSCS (0.05 mol %)
12, CDSCS (0.05 mol %)
N
13a-13h
N
13i-13n
THF/H
2
O (1:1), r.t., 0.6-1 h
N
THF/H O (1:1), r.t., 0.6-1 h
2
10a-10h
10i-10n
CDSCS: SiO
2
3
OSO Cu
HO
N
N
N
N
1
2
3
1
0a:
10i: R =H, R =H, R =Me
3
1
0j: R1=H R
2
=H, R =OMe
1
2
1
2
3
1
1
1
1
1
1
1
0b: R =Me, R =H
10k: R =H, R =Me, R =Cl
1
2
3
0c: R1=Et, R
2
=H
10l: R =H, R =H, R =Cl
1
2
1
2
3
0d: R =Me, R =Me
10m: R =Cl, R =H, R =H
1
2
1
2
3
0e: R =CH
2
OBu, R =H
10n: R =Cl, R =H, R =Cl
1
1
2
0f: R =R =CH
2
OCHMe
2
, R =H
1
2
0g: R =CH
0h: R =CH
2
O
2
CC(=CH
2
)Me, R =H
1
2
2
OPh, R =H
Scheme 4 CuAAC of 9-(prop-2-ynyl)-9H-carbazole (12) and β-azido alcohols (13a–13n)
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residues. Different substituents comprising alkyl (10a–10d),
alkoxy (10e, 10f), methacrylate ester (10g) and aryloxy
residues (10h–10n) were considered in the structure of title
compounds.
Table 1 In vitro antibacterial and antifungal study of 10a–10n
Compd.
MIC50(μg/mL)a
S.A.
E.C.
C.A.
C.K.
A.N.
T.R.
1
0a
10b
0c
6.25
6.25
1.562
12.5
12.5
12.5
6.25
12.5
1.562
12.5
6.25
6.25
3.125
6.25
0.781
–
12.5
6.25
3.125
25
12.5
6.25
6.25
1.562
1.562
12.5
6.25
6.25
6.25
3.125
12.5
12.5
3.125
12.5
–
12.5
3.125
12.5
6.25
3.125
3.125
12.5
25
100
25
50
25
25
100
100
50
12.5
50
50
100
25
50
–
25
Antifungal and antibacterial studies
6.25
50
1
The in vitro antifungal activity for 1,2,3-triazolyl β-hydroxy
alkyl/carbazole hybrid molecules 10a–10n was assessed
against some pathogenic fungi comprising Candida albicans
10d
10e
10f
10g
3.125
6.25
25
12.5
3.125
12.5
6.25
12.5
12.5
1.562
12.5
25
(
ATCC 10231), Candida krusei (ATCC 6258), Aspergillus
niger (ATCC 16404) and Trichophyton rubrum (PTCC
143). In addition, all compounds were also screened
12.5
50
1
1
1
1
1
1
1
0h
5
0i
12.5
12.5
6.25
6.25
6.25
12.5
–
6.25
12.5
12.5
50
against two pathogenic bacteria including Staphylococ-
cus aureus (PTCC 1133) and Escherichia coli (PTCC
0j
0k
0l
1330). For both antifungal and antibacterial activities, the
MIC50 (minimum inhibitory concentration, μg/mL) val-
ues were reported according to protocols established by
the Clinical and Laboratory Standards Institute, USA (for-
merly the National Committee for Clinical Laboratory Stan-
dards) [45]. The tested fungal and bacteria strains were
obtained either from the American Type Culture Collec-
tion (ATCC) or the Persian Type Culture Collection (PTCC).
The MIC50 values were determined for 10a–10n using ser-
ial dilution method in DMSO as a solvent. The sterile
growth mediums including Sabouraud dextrose broth and
Muller–Hinton agar were used for fungal and bacteria tests,
respectively.
0m
0n
12.5
25
6.25
–
Ampi.b
Gent.c
Clot.d
Fluc.d
–
0.781
–
–
–
–
–
–
1.562
1.562
3.125
3.125
25
25
6.25
12.5
–
–
Examined bacteria: S.A. Staphylococcus aureus (PTCC 1133) and E.C.
Escherichia coli (PTCC 1330); Tested fungi: C.A Candida albicans
(ATCC 10231), C.K. Candida krusei (ATCC 6258), A.N. Aspergillus
niger (ATCC 16404), T.R. Trichophyton rubrum (PTCC 5143)
a
Minimum inhibitory concentration
Ref. drug for Gram-positive bacteria: Ampi. ampicillin
Ref. drug for Gram-negative bacteria: Gent. gentamycin
Reference drugs for fungal species: Clot. clotrimazole, Fluc. flucona-
b
c
The MIC50 values were recorded in a culture with turbid-
ity <50% inhibition relative to the growth of the control.
d
zole
◦
The fungal and bacteria strains were incubated at 37 C, and
the growth MIC50 was determined at different times (12, 24,
bacteria were studied namely Staphylococcus aureus (PTCC
36 and 48 h). As can be seen in Table 1, 10e was the most
1133) and Escherichia coli (PTCC 1330) as representa-
potent agent against all tested fungal pathogens and proved
to have a broad activity for all studied fungal strains and
its reactivity is comparable with clotrimazole and flucona-
zole as reference drugs. For T. rubrum, 10e even was more
potent than fluconazole. Except that of C. Krusei, 10d also
exhibited similar reactivity to 10e against all tested fungal
organisms. Although 10b was inactive against C. albicans;
however, it proved to have an efficient activity against all
examined fungi. Compounds 10f, 10g, 10i, 10k and 10m
showed the selective antifungal activity against some tested
fungal pathogens. The other tested compounds were inactive
or displayed marginal activity. From the structure activity
relationship standpoint, since 10a–10n only varies in side
chains; therefore, the differences in antifungal activities are
attributed to these variations. In general, it is assumed that
the presence of aliphatic side chains showed more satisfac-
tory result in comparison with aryl moieties even bearing
different substituents.
tives for Gram-positive and Gram-negative bacteria, respec-
tively.
Gentamycin and ampicillin were used as reference drugs
for Gram-negative and Gram-positive bacteria, respectively.
As the data in Table 1 indicate, most of the examined com-
pounds have negligible antibacterial activity against both
tested bacteria as compared to the standard drugs. In this
context, only 10c proved to have the promising antibacterial
activity against both studied bacteria to some extent.
Molecular docking study
Molecular docking study is an attractive method to predict
the interactions of the new drug candidates with the tar-
get enzyme and/or receptor binding sites. Since 10e was
determined as the most potent antifungal agent, thus the
binding mode of 10e in the active site of cytochrome
P450-dependent 14 α-lanosterol demethylase was investi-
All compounds were also screened to indicate their
antibacterial activities. In this connection, two pathogenic
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Mol Divers
the optimized geometry of 10e. Initially, fluconazole was
redocked at the active site of enzyme to validate our docking
protocol (Fig. 4). As reported previously, the root- mean-
square deviation (RMSD) values should be <2Å [47]. Using
the MVD software, the RMSD value between the docked and
co-crystallized fluconazole was found to be 1.34 Å which
confirms our docking protocol.
Azole antifungals are capable to inhibit CYP51 through
the binding to N-atoms in azoles with the iron core inside
the haem. Podust and coworkers reported that the substrate-
binding pocket of Mycobacterium P450DM is positioned
above the porphyrin (haem) core [48]. This open pocket
above the haem iron residue has a ceiling that consists
of several lipophilic amino acid residues (Phe78, Met79,
Phe83 and Phe255). In addition, access to pyrrole rings
is restricted by Ala256, Thr260 and Leu321 [48]. In the
case of fluconazole, the N4 of the 1,2,4-triazole moiety
participates in a strong hydrogen bonding with Thr260.
In addition, 1,2,4-triazole ring is positioned perpendicu-
larly to the plane of porphyrin with distance of 3.56 Å
between the N4 atom in the azole ring and the iron core
of haem. Moreover, Phe83 and Phe255 also contribute in
non-bonded interactions. Interestingly, similar to flucona-
zole, 10e is accommodated at the same binding site and
showed a strong interaction with the enzyme active site.
Because of the similar functionalities in both 10e and flu-
conazole, we expected a similar binding mode for 10e with
the enzyme as seen with fluconazole. Similar to other azole
antifungal drugs, it was believed that binding of 10e with the
haem iron atom should be achieved through one of the N-
atoms in the 1,2,3-triazole core; however, such an interaction
was not observed. The 1,2,3-triazole ring usually demon-
strates a weak binding affinity compared to the imidazole
or 1,2,4-triazole moieties against the haem residue [49].
However, contrary to our expectations, the docking results
revealed a higher binding affinity and thus a stronger inter-
action of 10e with the enzyme compared with fluconazole.
The calculated ꢀG values for fluconazole and 10e are –
Fig. 4 a Hydrogen bonding of fluconazole (red) in active site of
Mycobacterium P450DM, b Combined view of docked conformation of
fluconazole (grey) and compound 10e (pink) in active site of Mycobac-
terium P450DM. (Color figure online)
88.42 and –109.76 (kcal/mol), respectively, indicating there
is an energy gap of about 21.34 (kcal/mol). This energy gap
attributes the stronger binding of 10e at the active site of
the enzyme. The binding geometry and interaction of 10e
with the active site of Mycobacterium P450DM are shown
in Fig. 5.
Figure 5b clearly shows the hydrogen bondings of β-
hydroxyl and ether moieties with Ile323 and Ile322. These
hydrogen bond interactions play a critical role in the higher
affinity of 10e to the active site of the enzyme. The aliphatic
side chain tethered to the triazole ring bound in a hydrophobic
pocket above the haem group with residues including Ile27,
Met79, Phe78, Ile82, Ile322, Ile323, Val434 and Val438. In
addition, the bulky carbazole ring stands over the haem moi-
ety in a way that its plane is perpendicular over the porphyrin
gated carrying out a molecular docking study. For this,
the crystal structure of the enzyme (from Mycobacterium
tuberculosis; Mycobacterium P450DM) in complex with flu-
conazole (PDB code: 1EA1) was selected as the template
which was retrieved from the Protein Data Bank (http://
www.rcsb.org). Molegro Virtual Docker (MVD) software
was employed using its default settings to carry out the dock-
ing study [46].
The enzyme was then modified by removing all water
molecules and other present ligands. The active site of the
enzyme was defined to comprise the residues within a 7Å
radius around the bound inhibitor. The DFT method at
the B3LYP/6-311+G** level of theory was used to assign
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Fig. 7 HOMO/LUMO view for the optimized geometry of 10e
Quantum study
To rationalize the higher binding affinity of 10e compared to
fluconazole in the active site of the enzyme, the energy of the
highest occupied molecular orbital (HOMO) and the lowest
unoccupied molecular orbital (LUMO) were calculated at the
B3LYP/6–31G** level of theory for the optimized structure
of 10e (Fig. 7).
In addition to the HOMO–LUMO energy level, we also
calculated and compared the hardness and softness values
for 10e and fluconazole. The HOMO–LUMO energy gaps of
4.64eV (HOMO= −5.72 eV and LUMO= −1.08 eV) and
6.16 eV (HOMO= −7.12 eV and LUMO= −0.96 eV) were
obtained for 10e and fluconazole, respectively (Table 2). This
difference in HOMO–LUMO energy gap between 10e and
fluconazole indicates that 10e is a softer molecule compared
Fig. 5 a Docked conformation of compound 10e (pink) in active site
of Mycobacterium P450DM, b Hydrogen bond of compound 10e (pink)
in the active site of Mycobacterium P450DM. (Color figure online)
plane. This spatial arrangement occupies the room over sub-
strate access channel because of the presence of the carbazole
ring. Thus, 10einhibitstheMycobacteriumP450DMenzyme
through a way which deviates from fluconazole known today
as the ‘Umbrella’ effect [50]. In Fig. 6, the interaction of each
fragment in 10e specified by docking analysis is shown.
Fig. 6 Role of each molecular
fragment in 10e for the
inhibition of Mycobacterium
P450DM as indicated by
molecular docking
Hydrogen bond
acceptor group
Lipophilic group
N
which fits in a
N
O
N
lipophilic pocket
Bulky group which
stands over the
heme core and
blocks the room
above
OH
N
Hydrogen bond
donor-acceptor
group
Spacer or linker
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Mol Divers
Table 2 Calculated HOMO, LUMO, hardness and softness of 10e and
Table 3 Toxicity risks predicted by OSIRIS Property Explorer for 10a–
fluconazole using B3LYP/6–31G** level of theory
10n
HOMOa
LUMOa
Hardnessa
Softnessb
Compd.
Mutagenic
Tumorigenic
Irritant
Reproductive
effect
Ligand
1
0e
−5.72
−7.12
−1.08
−0.97
2.32
3.08
0.43
0.32
1
1
1
1
1
0a
0b
0c
0d
0e
LRa
MRb
LR
LR
LR
LR
HR
LR
LR
LR
LR
LR
LR
HR
LR
LR
LR
HRc
LR
LR
LR
LR
LR
LR
HR
LR
LR
LR
LR
HR
LR
LR
LR
LR
LR
LR
HR
LR
HR
LR
LR
LR
LR
LR
MR
HR
LR
LR
LR
LR
LR
LR
HR
LR
HR
LR
LR
LR
HR
HR
LR
HR
MR
LR
Fluc.
a
Unit in electron volt (ev)
Unit in ev
b
−1
with fluconazole. Moreover, the calculated softness for 10e
also confirms a softer nature of 10e in comparison with flu-
conazole. The softness of 10e enhances its polarizability and
thus may exhibit higher antagonistic activity compared with
fluconazole.
10f
10g
10h
10i
1
1
1
1
1
0j
0k
0l
In silico pharmacokinetic profile, drug-likeness and toxicity
predictions
0m
0n
Fluc.
Clot.
a
Nowadays many approaches based on in silico predictions
like physicochemical properties, drug-likeness and toxic-
ity risks for drug candidates have found extensive utility
Low risk
Medium risk
High risk
b
c
[
51]. Since the initial findings by Lipinski, known today
as Lipinski’s rule of five (RO5) [52,53], various molecu-
lar descriptors and physicochemical parameters have been
developed to predict the drug-likeness and toxicity risks
of drug-like molecules. According to RO5, the key factors
used to assess likelihood of oral absorption are (i) molecu-
lar weight (MW) <500 Dalton; (ii) A desired log P value
tested fungal. The low risk for mutagenic and tumorigenic
was determined for 10e as the most potent antifungal agent,
whereas it exhibited the high risk of toxicity due to its irri-
tant and reproductive effect. The other studied compounds
displayed low to high risk of toxicity (Table 3).
(octanol-water partition coefficient) no more than 5; (iii) Not
more than 5 hydrogen bond donors (sum of NH and OH); (iv)
Not more than 10 hydrogen bond acceptors (sum of N and O)
and (v) 10 or fewer rotatable bonds. Molecules that violate
any of these rules may show sub-optimal pharmacokinetic
properties for oral administration [52,53].
Using aforementioned programs, we also assessed the
Lipinski’s parameters as well as other descriptors for 10a–
10n (Table 4). As can be seen in Table 4, the number of
hydrogen bond acceptors (nHba)=3–5, number of hydro-
gen bond donors (nHbd)=1 and number of rotatable bonds
(nrotb)=3–9werealmostsimilartocommercialdrugswhich
lieinrangeofRO5. Allcomputedmolecularweightsfor 10a–
10n were also in range of 306–466 (<500g/mol). The total
polar surface area (TPSA) of a molecule is defined as the sur-
face sum over all polar atoms, primarily oxygen and nitrogen
and also including the attached hydrogen atoms. TPSA, as
a molecular descriptor, is used to predict drug absorption,
including intestinal absorption, bioavailability and blood–
brain barrier penetration.
In this study, to assess the in silico pharmacokinetic pro-
files for 10a–10n, we used validated open-source programs
such as OSIRIS Property Explorer [54,55], Advanced Chem-
istry Development (ACD) [56], Marvin ChemAxon [57] and
molinspiration property calculator [58], and then compared
the results with those obtained for fluconazole and clotrima-
zole as reference drugs. The OSIRIS is an online program
that works on the basis of molecular fragments. This soft-
ware involves the database of traded drugs and commercially
available compounds (none drug-like compounds). This pro-
gram estimates the risks of side effects, such as mutagenic,
tumorigenic, irritant and reproductive effects. The analysis of
theoretical toxicity risks for 10a–10n using OSIRIS program
is summarized in Table 3. As can be seen in Table 3, 10a, 10c,
In most known drugs, TPSA values were calculated to
2
be <140Å ; in this regard, it was found that 10a–10n exhib-
2
ited the TSPA values between 55.87 to 82.17 Å . Descriptors
comprising clog P, log S and log D are critically important
physicochemical parameters that indicate the drug’s pharma-
cokinetic and the extent of drug delivery. An octanol–water
partition coefficient clog P indicates the lipophilicity of a
drug. Drugs with high lipophilicity value are unable to pass
the blood–brain barrier. Most established drugs are known
10d, 10f, 10h and 10j demonstrated the low risk of toxicity
regarding to all studied parameters. Among these non-toxic
agents, only 10d and 10f proved to have antifungal activity,
whereas the other agents displayed weak activity against all
1
23

Mol Divers
Table 4 Physicochemical properties predicted by OSIRIS Property Explorer, Advanced Chemistry Development (ACD), Marvin ChemAxon and
Molinspiration Property Calculator for 10a–10n
Compd.
nHba
nHbd
nrotb
TPSA
clog P
Log S
Log D
MW
MR
Drug-likeness
Drug score
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
0f
3
3
3
3
4
4
4
4
4
5
4
4
4
4
5
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
3
4
5
4
9
7
8
7
7
8
7
7
7
7
5
4
55.87
55.87
55.87
55.87
65.10
65.10
82.17
65.10
65.10
74.33
65.01
65.01
65.01
65.01
81.65
17.82
3.26
1.96
2.41
2.34
2.77
2.22
2.39
2.98
3.32
2.91
3.93
3.58
3.58
4.19
−0.11
5.32
−3.29
−2.75
−3.02
−2.86
−3.21
−3.05
−2.99
−3.7
3.57
2.73
3.19
2.80
3.43
2.97
3.80
4.00
4.47
3.75
4.98
4.52
4.52
5.04
−0.04
5.60
346
306
320
320
378
364
390
398
412
428
446
432
432
466
306
344
103.46
91.80
−8.87
−5.51
−5.31
−5.66
−11.39
−3.43
−26.9
−2.69
−3.92
−2.56
−4.52
−1.32
−1.45
−1.42
−1.13
0.92
0.40
0.21
0.43
0.44
0.14
0.43
0.09
0.40
0.21
0.38
0.17
0.23
0.30
0.04
0.46
0.30
96.32
96.43
111.96
107.26
111.50
117.60
122.64
124.07
127.45
122.41
122.41
127.21
76.62
0g
0h
0i
−4.05
−3.72
−4.78
−4.44
−4.44
−5.17
−2.17
−7.72
0j
0k
0l
0m
0n
Fluc.
Clot.
102.14
to have clog P values <5. The calculated clog P values
for 10a–10n were around 1.96 to 4.19 which are below the
threshold defined by RO5 (<5). Log S represents the aque-
ous solubility of a drug candidate that significantly affects
its absorption and distribution characteristics. It is estimated
that most recent drugs have a log S value > − 4. As can
be seen in Table 4, 10a–10h and 10j have log S values >−
while other compounds displayed slightly larger values than
which is made by the fragmentation of 3300-traded drugs as
well as 15,000 commercially available chemicals to access a
complete list of all available fragments. Molecules that pre-
dominantly contain fragments that are frequently found in
commercial drugs have a positive drug-likeness. Although
the calculated drug-likeness parameters for title compounds
displayed the negative values, this is not be disappointing
since many well-established drugs like fluconazole also dis-
played a negative drug-likeness (Table 4). On the other hand,
even when clotrimazole’s clog P, log S and log D values were
out of range, this drug displayed a positive drug-likeness
record (Table 4). Drug score is a parameter that indicates if
a compound could be considered as a drug candidate. Drug
score combines parameters such as drug-likeness, clog P, log
S, molecular weight and toxicity risks. Drug score values for
10a–10n were in the range of 0.04–0.44 which are less than
fluconazole(=0.46);however, compounds10a, 10c, 10d, 10f,
10h and 10j have higher drug score values than clotrimazole.
In particular, compound 10d with an admissible drug score
value (=0.44) and also an appropriate antifungal activity can
be considered as a potential drug candidate.
−4. Log D, or distribution coefficient, is similar to log P;
however, it is a pH-dependent parameter which normally is
measured at the physiological pH. Bhal and coworkers have
reported that log D can be a better descriptor for determin-
ing the lipophilicity factor in the context of the RO5 [59].
For non-ionisable compounds, log D and log P, at physi-
ological pH are nearly the same. For 10a–10n, the log D
values vary from 2.73 to 5.04 and are within the acceptable
RO5 range. Molar refractivity (MR) is a measure of the total
polarizability of a drug depending on temperature, the index
of refraction and the pressure. Most drug-like molecules have
a molar refractivity between 40 and 130. A larger value of
molar refractivity represents a larger molecular weight or
volume in which enhances the polarizability as well as mole-
cular softness values. When the molar refractivity increases,
the drug-like molecule tends to have an antagonistic property.
For 10a–10n, their molar refractivity values were computed
about 91.80 to 127.45. These large molar refractivity values
indicate an antagonistic behaviour for all synthesized com-
pounds. Fragment based drug-likeness is a parameter that
depends on some descriptors like topological, clog P, mole-
cular weights and fingerprints of molecular design limited
structure. The drug-likeness is obtained from a fragment-list
Conclusions
In summary, we explained the design and synthesis of a
novel series of 1,2,3-triazolyl β-hydroxy alkyl/carbazole
hybrid molecules (10a–10n) as a new type of antifun-
gal agent. In this synthesis, the treatment of potassium
carbazol-9-ide 11 with 3-bromoprop-1-yne in DMSO at
room temperature led to alkyne 12 as a key precursor for
1
23

Mol Divers
‘
Click’ synthesis of 10a–10n. Finally, CDSCS catalyzed
solvent was then evaporated and dried to afford compound
11 as a bright brown solid which was used in the next step
without further purification.
the cycloaddition reaction of alkyne 12 with β-azido alco-
hols 13a–13n afforded the target molecules in racemic
form. The in vitro antifungal and antibacterial activities of
10a–10n were examined against several pathogenic fungi,
Synthesis of 9-(prop-2-ynyl)-9 H -carbazole 12
Gram-positive and/or Gram-negative bacteria. The biologi-
cal investigation revealed that compound 10e was the most
potent agent against all examined fungal pathogens and its
activity was comparable to fluconazole and clotrimazole.
Docking analysis predicts strong binding of 10e in the active
site of Mycobacterium P450DM enzyme and its binding
is considerably higher than fluconazole. In addition, mole-
cular modelling indicates that the inhibition of Mycobac-
terium P450DM via 10e was achieved through an inter-
action which is different from fluconazole–Mycobacterium
P450DM enzyme interaction. The in silico pharmacokinetic
profile, drug-likeness and toxicity predictions performed for
all compounds determined that compounds 10e and 10d
can be considered as potential drug candidates for future
research.
In a round-bottomed flask (100 mL), 3-bromoprop-1-yne
(1.55 g, 0.013 mol) was added dropwise to a solution of
potassium carbazol-9-ide (2.05 g, 0.01 mol) in DMSO (15
mL). The mixture was stirred at room temperature for 3h
(TLC control). Then, the crude product was dissolved in
CHCl (100 mL) and washed with H O (3 × 150 mL). The
3
2
organic layer was dried (10 g of Na SO ) and concentrated
2
4
to afford the corresponding product. The crude product was
purified by column chromatography on silica gel eluting with
EtOAc-n-hexane (1:8) which yielded 1.93g (94%) of 12 as a
◦
◦
pale-yellow solid, mp: 173−175 C (Lit. [42]:172−174 C).
General procedure for the synthesis of β-azido alcohols
13a–13n
The β-azido Alcohols 13a–13n were prepared by our previ-
Experimental
General
ously described method in the literature [37,38].
General procedure for the synthesis of 1,2,3-triazolyl
β-hydroxy alkyl/carbazole hybrid 10a–10n
All materials were purchased from either Fluka or Merck
exceptthatof copper-dopedsilicacuproussulphate(CDSCS)
which was prepared according to the literature [37]. Sol-
vents were purified using standard procedures and stored
over 3Å molecular sieves. Reactions were monitored by
TLC using SILG/UV 254 silica-gel plates. Column chro-
matography was performed on silica gel 60 (0.063–0.200
mm, 70–230 mesh; ASTM). Melting points were measured
using Electrothermal IA 9000 melting point apparatus in
open capillary tubes and are uncorrected. IR spectra were
obtained using a Shimadzu FT-IR-8300 spectrophotome-
In a round-bottomed flask (100 mL), a mixture of alkyne 12
(2.05 g, 0.01 mol), appropriate β-azido alcohol (0.012 mol)
and CDSCS (0.3 g, 0.05 mol%) in THF/H O (1:1 v/v, 20 mL)
2
was stirred at room temperature until TLC monitoring indi-
catednofurtherprogressofthereaction(0.6-1h). Thecatalyst
was then filtered off, washed with THF/H O (5 × 10 mL)
2
and the filtrate was evaporated under vacuum to remove the
solvent. The remaining foam was dissolved in CHCl (100
3
mL) and subsequently washed with water (2×100 mL). The
organic layer was dried (Na SO ) and evaporated. The crude
2
4
1
13
ter. H- and C-NMR spectra were recorded on a Brüker
Avance-DPX-250 spectrometer operating at 250/62.5 MHz,
respectively. Chemical shifts are given in δ relative to tetram-
ethylsilane (TMS) as an internal standard, coupling constants
product was purified by column chromatography on silica gel
eluting with proper solvents.
2-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1yl)
cyclohexanol (10a)
1
J are given in Hz. Abbreviations used for H NMR signals
are s singlet, d doublet, t triplet, q quartet, m multiplet, b
broad, dd doublet of doublet. GC/MS was performed on a
Shimadzu GC/MS-QP 1000-EX apparatus (m/z; rel.%). Ele-
mental analyses were performed on a Perkin–Elmer 240-B
microanalyzer.
Column chromatography on silica gel (EtOAc-n-hexane,
1:2) gave compound 10a as a white solid (2.91 g, 84%).
◦
1
mp: 196–197 C; H NMR (250 MHz, CDCl ): δ = 1.26 −
3
1.34 (m, 4H, 2CH ), 1.65–1.75 (m, 4H, 2CH ), 2.82 (s,
2
2
1H, OH), 3.81–3.92 (m, 2H, NCHCHOH), 5.51 (s, 2H,
Preparation of potassium carbazol-9-ide 11
NCH2C = C), 7.20−7.44 (m, 8H, Ar-H), 8.05 ppm (s, 1H,
C(5)-H of triazole); 13C NMR (62.5 MHz, CDCl3): δ =
22.3, 24.5, 27.3, 32.0, 58.7, 63.6, 68.7, 112.5, 118.2,
119.4, 120.4, 122.5, 123.5, 131.3, 142.3 ppm; IR (KBr):
In a round-bottomed flask (100 mL), a mixture of 9H-
carbazole (1.67 g, 0.01 mol) and KOH (0.67 g, 0.012 mol) in
◦
−1
EtOH (40 mL) was heated at 70 C for 4 h (TLC control). The
ν = 3230, 3069, 2957, 1482 cm ; MS (m/z,%): 346 (21.7,
1
23

Mol Divers
+
M ); Anal. calcd for C21H22N4O: C 72.81, H 6.40, N 16.17,
1-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
found: C 72.89, H 6.53, N 16.25.
3-butoxypropan-2-ol (10e)
Column chromatography on silica gel (EtOAc-n-hexane,
1:1) gave compound 10e as a brown oil (3.40 g, 90%).
1
-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-
1
yl)propan-2-ol (10b)
H NMR (250 MHz, CDCl3): δ = 0.93 (t, J = 7.5 Hz,
3H, CH3),1.35-1.42 (m, 2H, CH2CH3), 1.55-1.58 (m, 2H,
Column chromatography on silica gel (EtOAc-n-hexane,
OCH2CH2), 2.53 (s, 1H, OH), 3.27 (t, J = 5.0 Hz, 2H,
OCH2CH2), 3.37−3.39 (m, 2H, OCH2CH), 4.20−4.22 (m,
1H, CHOH), 4.34 − 4.39 (m, 2H, NCH2CH), 5.08 (s, 2H,
NCH2C=C), 7.20−7.23 (m, 4H, Ar-H), 7.43−7.45 (m, 4H,
Ar-H), 8.04 ppm (s, 1H, C(5)-H of triazole); 13C NMR (62.5
MHz, CDCl3) : δ = 14.8, 21.4, 33.3, 58.1, 64.4, 66.5, 73.1,
75.2, 111.9, 118.8, 120.3, 121.5, 122.7, 123.5, 131.3, 143.5
2
:1) gave compound 10b as a white solid (2.66 g, 87%).
◦
1
mp: 160-161 C; H NMR (250 MHz, CDCl3): δ = 0.95
(d, J = 5.9 Hz, 3H, CH3), 2.95 (s, 1H, OH), 3.77–3.90
(m, 3H, NCH2CH), 5.36 (s, 2H, NCH2C = C), 7.04–7.13
(m, 4H, Ar-H), 7.28–7.30 (m, 4H, Ar-H), 7.92 ppm (s, 1H,
1
3
C(5)-H of triazole); C NMR (62.5 MHz, CDCl3): δ =
−1
2
1
1
3.1, 63.3, 64.9, 69.4, 112.5, 118.8, 119.8, 120.1, 122.4,
ppm; IR (film): ν = 3450, 3025, 2963, 1472, 1241 cm
;
+
23.4, 130.4, 144.1 ppm; IR (KBr): ν = 3395, 3104, 2934,
MS (m/z, %): 378 (26.1, M ); Anal. calcd for C22H26N4O2:
−1
+
463 cm ; MS (m/z, %): 306 (19.4, M ); Anal. calcd for
C 69.82, H 6.92, N 14.80, found: C 69.71, H 6.98, N 14.86.
C18H18N4O: C 70.57, H 5.92, N 18.29, found: C 70.68, H
6.05, N 18.20.
1-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
3-isopropoxypropan-2-ol (10f)
1
-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-
Column chromatography on silica gel (EtOAc-n-hexane,
2:1) gave compound 10f as a creamy solid (3.32 g, 91%).
yl)butan-2-ol (10c)
◦
1
mp: 112 − 113 C; H NMR (250 MHz, CDCl3): δ = 0.99
(d, J = 7.7 Hz, 6H, 2CH3), 3.11-3.17 (m, 2H, OCH2),
3.23-3.27 (m, 1H, CHOH), 3.37 (sept, J = 6.0 Hz, 1H,
CH(CH3)2), 3.96 (s, 1H, OH), 4.13 (dd, J = 6.7, 12.5
Hz, 1H, NCHAHBCH), 4.26 (dd, J = 3.7, 14.0 Hz, 1H,
NCHA HBCH), 5.52 (s, 2H, NCH2C = C), 7.17–7.23
(m, 4H, Ar-H), 7.37–7.41 (m, 4H, Ar-H), 8.03 ppm (s,
1H, C(5)-H of triazole); 13C NMR (62.5 MHz, CDCl3):
δ = 25.6, 58.1, 64.0, 67.6, 72.6, 73.7, 112.4, 117.5, 119.1,
120.5, 122.7, 124.1, 131.1, 144.8 ppm; IR (KBr): ν = 3556,
Column chromatography on silica gel (EtOAc-n-hexane,
2
1
7
:1) gave compound 10c as a creamy solid (2.75 g, 86%). mp:
◦
1
18−119 C; HNMR(250MHz, CDCl3): δ = 0.86(t, J =
.5 Hz, 3H, CH3), 1.31−1.36 (m, 2H, CH2CH3), 2.93
(
1
s, 1H, OH), 3.67 − 3.74 (m, 1H, CHOH), 3.88-3.94 (m,
H, NCHAHBCH), 4.12 (dd, J = 2.5, 12.5 Hz, 1H,
NCHA HBCH), 5.45 (s, 2H, NCH2C = C), 7.16-7.40 (m, 8H,
Ar-H), 8.01 ppm (s, 1H, C(5)-H of triazole); 13C NMR (62.5
MHz, CDCl3): δ = 9.3, 29.8, 61.7, 64.4, 70.7, 112.9, 119.2,
−1
+
120.1, 121.6, 123.4, 124.6, 131.8, 145.2 ppm; IR (KBr):
3018, 2938, 1452, 1237cm ;MS(m/z, %):364(22.5, M );
−1
ν = 3342, 3049, 2960, 1442 cm ; MS (m/z, %): 320 (18.1,
Anal. calcd for C H N O : C 69.21, H 6.64, N 15.37,
2
1
24
4
2
+
M ); Anal. calcd for C19H20N4O: C 71.23, H 6.29, N 17.49,
found: C 69.35, H 6.72, N 15.30.
found: C 71.31, H 6.38, N 17.40.
3
2
-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
-hydroxypropyl methacrylate (10g)
1
2
-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
-methylpropan-2-ol (10d)
Column chromatography on silica gel (EtOAc-n-hexane,
:1) gave compound 10g as a creamy solid (3.43 g, 88%).
2
◦
1
Column chromatography on silica gel (EtOAc-n-hexane,
:1) gave compound 10d as a white solid (2.72 g, 85%).
mp: 119−120 C; H NMR (250 MHz, CDCl3): δ = 2.49 (s,
3H, CH3), 3.27-3.40 (m, 3H, NCH2CH), 3.78 (s, 1H, OH),
4.18 (dd, J = 8.0, 13.7 Hz, 1H, OCHAHB), 4.44 (dd, J =
3.2, 13.7 Hz, 1H, OCHA HB), 4.86 (d, J = 5.3 Hz, 1H, =
CHAHB), 5.11 (d, J = 5.3 Hz, 1H, = CHA HB), 5.68 (s, 2H,
NCH2C = C), 7.20-7.24 (m, 2H, Ar-H), 7.46-7.50 (m, 2H,
Ar-H), 7.81 (d, J = 8.2 Hz, 2H, Ar-H), 7.99 (s, 1H, C(5)-H
of triazole), 8.15 ppm (d, J = 7.8 Hz, 2H, Ar-H); 13C NMR
(62.5 MHz, CDCl3): δ = 18.6, 58.5, 63.7, 65.9, 70.5, 111.3,
118.3, 119.3, 120.8, 122.0, 123.2, 126.9, 131.1, 137.8, 143.6,
169.6 ppm; IR (KBr): ν = 3327, 3050, 2972, 1724, 1473,
2
◦
1
mp: 114 − 115 C; H NMR (250 MHz, CDCl3): δ = 1.03
(
s, 6H, 2CH3), 2.75 (s, 1H, OH), 3.99 (s, 2H, NCH2C),
5
.48 (s, 2H, NCH2C = C), 7.17–7.21 (m, 4H, Ar-H), 7.35-
.40 (m, 4H, Ar-H), 8.01 ppm (s, 1H, C(5)-H of triazole);
C NMR (62.5 MHz, CDCl3): δ = 29.8, 64.2, 66.2, 68.8,
11.8, 118.4, 119.3, 121.6, 123.3, 124.5, 131.4, 145.5 ppm;
7
1
3
1
−1
IR (KBr): ν = 3358, 3015, 2935, 1463 cm ; MS (m/z, %):
+
320 (21.7, M ); Anal. calcd for C19H20N4O: C 71.23, H
6.29, N 17.49, found: C 71.29, H 6.34, N 17.42.
1
23

Mol Divers
267 cm 1; MS (m/z, %): 390 (28.9, M ); Anal. calcd for
−
+
+
(29.4, M ); Anal. calcd for C H24N4O3: C 70.08, H 5.65,
25
1
C22H22N4O3: C 67.68, H 5.68, N 14.35, found: C 67.57, H
N 13.08, found: C 69.98, H 5.73, N 13.16.
5
.73, N 14.27.
1
3
-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
-(4-chloro-3-methylphenoxy)propan-2-ol (10k)
1
3
-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
-phenoxypropan-2-ol (10h)
Column chromatography on silica gel (EtOAc-n-hexane,
2
:1)gavecompound10kasacreamysolid(3.89g, 87%). mp:
Column chromatography on silica gel (EtOAc-n-hexane,
:1) gave compound 10h as a creamy solid (3.66 g, 92%).
◦
1
1
67−168 C; H NMR (250 MHz, CDCl3): δ = 2.25 (s, 3H,
2
CH3), 3.96-3.98 (m, 2H, NCH2CH), 4.22 (s, 1H, OH), 4.49–
◦
1
mp: 158−159 C; H NMR (250 MHz, CDCl3): δ = 3.95 (d,
4
6
.71 (m, 3H, OCH2, CHOH), 5.09 (s, 2H, NCH2C = C),
J = 4.8 Hz, 2H, NCH2CH), 4.22-4.23 (m, 1H, CHOH), 4.41
.81-6.85 (m, 3H, Ar-H), 7.13-7.30 (m, 8H, Ar-H), 7.77 ppm
(s, 1H, OH), 4.46 (dd, J = 7.0, 13.4 Hz, 1H, OCHAHB),
13
(
s, 1H, C(5)-H of triazole); C NMR (62.5 MHz, CDCl3) :
4.66 (dd, J = 2.5, 13.2 Hz, 1H, OCHA HB), 5.09 (s, 2H,
δ = 20.4, 58.7, 63.9, 66.8, 71.4, 111.5, 113.5, 117.6, 119.9,
NCH2C = C), 6.83-6.85 (m, 5H, Ar-H), 7.13–7.25 (m, 8H,
Ar-H), 7.92 ppm (s, 1H, C(5)-H of triazole); 13C NMR (62.5
MHz, CDCl3): δ = 57.1, 64.9, 66.5, 72.4, 111.9, 115.0, 117.5,
1
1
1
20.7, 121.6, 122.8, 123.3, 125.9, 130.2, 131.7, 137.5,
44.4, 157.4 ppm; IR (KBr): ν = 3391, 3029, 2953, 1456,
−1
+
258, 762 cm ; MS (m/z, %): 446 (30.8, M ); Anal. calcd
1
18.8, 119.7, 120.4, 121.9, 123.2, 128.8, 130.4, 144.2, 158.9
for C H23ClN4O2: C 67.18, H 5.19, Cl 7.93, N 12.54, found:
C 67.25, H 5.29, Cl 8.02, N 12.65.
2
5
−1
ppm; IR (KBr): ν = 3264, 3050, 2925, 1463, 1239cm
;
+
MS (m/z, %): 398 (25.6, M ); Anal. calcd for C24H22N4O2:
C 72.34, H 5.57, N 14.06, found: C 72.23, H 5.50, N 14.17.
1-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
3-(4-chlorophenoxy)propan-2-ol (10l)
1
3
-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
-(p-tolyloxy)propan-2-ol (10i)
Column chromatography on silica gel (EtOAc-n-hexane,
:1) gave compound 10l as a creamy solid (3.94 g, 91%).
2
◦
1
mp: 110 − 111 C; H NMR (250 MHz, CDCl3): δ = 3.55
Column chromatography on silica gel (EtOAc-n-hexane,
1
(d, J = 5.0 Hz, 1H, NCHAHBCH), 3.63 (s, 1H, OH), 3.78
2
:1) gave compound 10i as a brown oil (3.75 g, 91%). H
NMR (250 MHz, CDCl3): δ = 2.15 (s, 3H, CH3), 3.91–3.94
m, 2H, NCH2CH), 4.08-4.11 (m, 1H, CHOH), 4.39 (s, 1H,
OH), 4.45 (dd, J = 6.6, 13.7 Hz, 1H, OCHAHB), 4.63 (dd, J
6.5, 13.6 Hz, 1H, OCHA HB), 5.13 (s, 2H, NCH2C = C),
.79-6.88 (m, 6H, Ar-H), 7.13–7.22 (m, 6H, Ar-H), 7.77 ppm
(d, J = 5.0 Hz, 1H, NCHA HBCH), 4.05 (dd, J = 5.0, 17.5
Hz, 2H, OCH2), 4.19-4.21 (m, 1H, CHOH), 5.33 (s, 2H,
NCH2C = C), 6.48-6.62 (m, 4H, Ar-H), 7.03–7.11 (m,
(
8
H, Ar-H), 7.90 ppm (s, 1H, C(5)-H of triazole); 13C NMR
=
6
(
62.5 MHz, CDCl3): δ = 59.6, 64.4, 65.9, 72.8, 113.1, 116.7,
118.5, 119.7, 120.6, 122.1, 124.2, 126.0, 130.2, 131.7, 144.8,
s, 1H, C(5)-H of triazole); 1 C NMR (62.5 MHz, CDCl3):
δ = 24.0, 58.2, 64.3, 65.9, 73.3, 112.5, 115.7, 118.6, 119.8,
20.5, 122.7, 124.0, 129.7, 131.0, 132.3, 144.4, 159.8 ppm;
3
(
1
57.3 ppm; IR (KBr): ν = 3228, 3100, 2937, 1595, 1228,
−1
+
755 cm ; MS (m/z, %): 432 (28.4, M ); Anal. calcd for
1
−
1
C24H21ClN4O2: C 66.59, H 4.89, Cl 8.19, N 12.94, found:
C 66.48, H 4.80, Cl 8.26, N 13.04.
IR (film): ν = 3379, 3058, 2923, 1468, 1276 cm ; MS (m/z,
%
+
): 412 (27.3, M ); Anal. calcd for C H24N4O2: C 72.80,
2
5
H 5.86, N 13.58, found: C 72.73, H 5.94, N 13.50.
1
3
-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
-(2-chlorophenoxy)propan-2-ol (10m)
1
3
-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
-(4-methoxyphenoxy)propan-2-ol (10j)
Column chromatography on silica gel (EtOAc-n-hexane,
1
2:1) gave compound 10m as a brown oil (3.85 g, 89%). H
Column chromatography on silica gel (EtOAc-n-hexane,
:1) gave compound 10j as a brown solid (3.94 g, 92%)
NMR (250 MHz, CDCl3): δ = 3.86-3.90 (m, 3H, NCH2CH),
4.21 (s, 1H, OH), 4.44(dd, J = 7.6, 13.8 Hz, 1H, OCHAHB),
4.59 (dd, J = 3.4, 13.8 Hz, 1H, OCHA HB), 5.13 (s, 2H,
NCH2C = C), 6.85 (d, J = 8.3 Hz, 2H, Ar-H), 7.07-7.29
3
◦
1
mp: 125−126 C; H NMR (250 MHz, CDCl3): δ = 2.05 (s,
H, OCH3), 3.94 (dd, J = 5.0, 10.2 Hz, 2H, NCH2CH), 4.04
s, 1H, OH), 4.12-4.18 (m, 3H, OCH2, CHOH), 5.70 (s, 2H,
3
(
1
3
(m, 10H, Ar-H), 8.18 ppm (s, 1H, C(5)-H of triazole);
C
NCH2C = C), 6.67-6.77(m, 4H, Ar-H), 7.20–7.23 (m, 4H,
Ar-H), 7.41-7.46 (m, 4H, Ar-H), 8.06 ppm (s, 1H, C(5)-H
of triazole); 13C NMR (62.5 MHz, CDCl3): δ = 56.0, 58.1,
NMR (62.5 MHz, CDCl3) : δ = 58.5, 64.8, 67.4, 70.7, 112.8,
116.6, 118.6, 119.4, 120.5, 121.6, 122.2, 123.0, 123.8, 128.0,
130.0, 131.7, 143.6, 151.5 ppm; IR (film): ν = 3423, 3026,
2981, 1486, 1263, 759 cm ; MS (m/z, %): 432 (30.1, M );
Anal. calcd for C24H21ClN4O2: C 66.59, H 4.89, Cl 8.19, N
12.94, found: C 66.64, H 4.96, Cl 8.31, N 13.01.
−1
+
6
1
=
2.3, 65.9, 71.0, 112.3, 115.6, 116.8, 118.9, 120.1, 121.6,
23.1, 124.3, 131.8, 144.0, 150.3, 159.9 ppm; IR (KBr): ν
−1
3235, 3045, 2948, 1462, 1246 cm ; MS (m/z, %): 428
1
23

Mol Divers
1
3
-(4-((9H-Carbazol-9-yl)methyl)-1H-1,2,3-triazol-1-yl)-
-(2,4-dichlorophenoxy)propan-2-ol (10n)
10. Xu Y, Sheng C, Wang W, Che X, Cao Y, Dong G, Wang S, Ji H,
Miao Z, Yao J, Zhang W (2010) Structure-based rational design,
synthesis and antifungal activity of oxime-containing azole deriv-
atives. Bioorg Med Chem Lett 20:2942–2945. doi:10.1016/j.bmcl.
Column chromatography on silica gel (EtOAc-n-hexane,
:1) gave compound 10n as a white solid (4.20 g, 90%).
2010.03.014
2
11. Kathiravan MK, Salake AB, Chothe AS, Dudhe PB, Watode RP,
Mukta MS, Gadhwe S (2012) The biology and chemistry of anti-
fungal agents: a review. Bioorg Med Chem 20:5678–5698. doi:10.
◦
1
mp: 115 − 116 C; H NMR (250 MHz, CDCl3) : δ = 3.63
(
4
6
d, J = 4.8 Hz, 2H, NCH2CH), 3.91 (s, 1H, OH), 4.15-
1016/j.bmc.2012.04.045
.28 (m, 3H, OCH2, CHOH), 5.38 (s, 2H, NCH2C = C),
.48 (d, J = 8.8 Hz, 1H, Ar-H), 6.96-6.98 (m, 1H, Ar-
1
2. Odds F, Brown AJP, Gow NAR (2003) Antifungal agents: mech-
anisms of action. Trends Microbiol 11:272–279. doi:10.1016/
S0966-842X(03)00117-3
H), 7.11–7.19 (m, 3H, Ar-H), 7.32-7.43 (m, 5H, Ar-H),
1
3. Strushkevich N, Usanov SA (2010) Structural basis of human
CYP51 inhibition by antifungal azoles. J Mol Biol 397:1067–1078.
doi:10.1016/j.jmb.2010.01.075
7
.95 (s, 1H, Ar-H), 7.99 ppm (s, 1H, C(5)-H of triazole);
C NMR (62.5 MHz, CDCl3): δ = 58.2, 64.0, 67.4,
1.0, 113.5, 118.6, 119.5, 120.1, 121.1, 122.0, 123.8, 125.0,
27.5, 128.1, 130.2, 132.1, 144.0, 150.1 ppm; IR (KBr):
1
3
7
1
14. Rostovtsev VV, Green LG, Fokin VV, Sharples KB (2002) A step-
wise Huisgen cycloaddition process: copper(I)-catalyzed regiose-
lective “ligation” of azides and terminal alkynes. Angew Chem Int
Ed 41:2596–2599
−1
ν = 3396, 3050, 2935, 1479, 1238, 761cm ; MS (m/z, %):
+
467 (34.5, M ); Anal. calcd for C24H20Cl2N4O2: C 61.68,
15. Tornøe CW, Christensen C, Meldal M (2002) Peptidotriazoles on
solid phase: [1,2,3]-triazoles by regiospecific copper(I)-catalyzed
H 4.31, Cl 15.17, N 11.99, found: C 61.60, H 4.38, Cl 15.24,
N 11.
1,3-dipolar cycloadditions of terminal alkynes to azides. J Org
Chem 67:3057–3064. doi:10.1021/jo011148
1
6. Haider S, Alam MS, Hamid H (2014) 1, 2, 3-Triazoles: scaffold
with medicinal significance. Inflamm Cell Signal 1:e95. doi:10.
Acknowledgments The authors wish to thank Shiraz University of
Technology research council for partial support of this work.
14800/ics.95
1
7. MosesJE, MoorhouseAD(2007)Thegrowingapplicationsofclick
chemistry. Chem Soc Rev 36:1249–1262. doi:10.1039/B613014N
8. Zhou CH, Wang Y (2012) Recent researches in triazole compounds
as medicinal drugs. Curr Med Chem 19:239–280. doi:10.2174/
Compliance with ethical standards
1
Conflict of interest The authors declare that they have no conflict of
interest.
092986712803414213
1
9. Meunier B (2008) Hybrid molecules with a dual mode of action:
dreamorreality?AccChemRes41:69–77. doi:10.1021/ar7000843
0. Muregi FW, Ishih A (2010) Next-generation antimalarial drugs:
hybrid molecules as a new strategy in drug design. Drug Dev Res
71:20–32. doi:10.1002/ddr.20345
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