Synthesis and antifungal activity of 1,2,3-triazole containing fluconazole analogues

Article abstract of DOI:10.1016/j.bmcl.2008.12.026

Fluconazole based novel mimics containing 1,2,3-triazole were designed and synthesized as antifungal agents. Their antifungal activities were evaluated in vitro by measuring the minimal inhibitory concentrations (MICs). Compounds 12, 15, and 16 were found to be more potent against Candida fungal pathogens than control drugs fluconazole and amphotericin B. The studies presented here provide structural modification of fluconazole to give 1,2,3-trazole containing molecules. Furthermore, these molecules were evaluated in vivo against Candida albicans intravenous challenge in Swiss mice and antiproliferative activities were tested against human hepatocellular carcinoma Hep3B and human epithelial carcinoma A431. It was found that compound 12 resulted in 97.4% reduction in fungal load in mice and did not show any profound proliferative effect at lower dose (0.001 mg/ml).

Full text of DOI:10.1016/j.bmcl.2008.12.026

Bioorganic & Medicinal Chemistry Letters 19 (2009) 759–763
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antifungal activity of 1,2,3-triazole containing
fluconazole analogues
b
b
b
Nilkanth G. Aher a, Vandana S. Pore a, , Nripendra N. Mishra , Awanit Kumar , Praveen K. Shukla ,
*
Aanchal Sharma c, Manoj K. Bhat c
a Organic Chemistry Division, National Chemical Laboratory, Pune 411 008, India
b Division of Fermentation Technology, Central Drug Research Institute, Lucknow 226001, India
c National Centre for Cell Science, Pune University Campus, Pune 411 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2008
Revised 10 November 2008
Accepted 5 December 2008
Available online 10 December 2008
Fluconazole based novel mimics containing 1,2,3-triazole were designed and synthesized as antifungal
agents. Their antifungal activities were evaluated in vitro by measuring the minimal inhibitory concen-
trations (MICs). Compounds 12, 15, and 16 were found to be more potent against Candida fungal patho-
gens than control drugs fluconazole and amphotericin B. The studies presented here provide structural
modification of fluconazole to give 1,2,3-trazole containing molecules. Furthermore, these molecules
were evaluated in vivo against Candida albicans intravenous challenge in Swiss mice and antiproliferative
activities were tested against human hepatocellular carcinoma Hep3B and human epithelial carcinoma
A431. It was found that compound 12 resulted in 97.4% reduction in fungal load in mice and did not show
any profound proliferative effect at lower dose (0.001 mg/ml).
Keywords:
1,2,3-Triazole
Conjugates
Bile acid
Fluconazole
Antifungal agent
Ó 2008 Elsevier Ltd. All rights reserved.
During passed two decades fungal infections have emerged as a
major cause of disease and mortality, in part as a consequence of
the increase in acquired immunodeficiency syndrome (AIDS), the
greater use of immunosuppressive drugs in transplantation and
chemotherapeutic agents in cancer, long term use of corticoste-
roids and even the indiscriminate use of antibiotics.1 Clinically,
candidosis, aspergillosis, cryptococcosis are the three major infec-
tions in the immunocompromised individuals.2 The common
antifungal agents currently used in clinic are polyenes (such as
amphotericin B3a and nystatin3b), echinocandins (such as caspo-
fungin and micafungin),3c allylamines (such as niftifine and
terbinafine),3d and azoles (such as fluconazole, ketoconazole, itrac-
onazole, etc.).3e
The current antifungal drugs are either highly toxic, for exam-
ple, amphotericin B or are becoming ineffective due to appearance
of resistant strains, for example, flucytosine and azoles. In spite of
significant research on antifungal agents, the azoles remain the
mainstay of therapy for systemic life threatening fungal infections
as they have fungistatic, orally active, and broad-spectrum activi-
ties against most yeasts and filamentous fungi. Fluconazole is a
1,2,4-triazole based drug that has established an exceptional ther-
apeutic record for Candida infections, including oropharyngeal and
esophageal candidiasis, vulvovaginal candidiasis, candidemia, and
disseminated candidiasis. It is an antifungal agent of choice for
the treatment of infections by Candida albicans and Cryptococcus
neoformans due to its potent activity, excellent safety profile, and
favorable pharmacokinetic characteristics.4 However, fluconazole
is not effective against invasive aspergillosis and is not fungicidal.
In addition, extensive use of fluconazole has increased the number
of fluconazole-resistant C. albicans isolates.5 Itraconazole is an
improvement of fluconazole in its broad-spectrum activity and
better toleration but shows low bioavailability and oral absorption.
Therefore, great efforts have been made to modify the chemical
structure of fluconazole, in order to broaden its antifungal
spectrum of activity and to increase its potency. Several new
azoles, containing 1,2,4-triazole and 1,3-difluorobenzene moieties,
such as voriconazole,6a posaconazole,6b ravuconazole,6c etc. are
marketed or in the late stages of clinical trials (Fig. 1).
Azoles exert antifungal activity through inhibition of CYP51 by a
mechanism in which the heterocyclic nitrogen (N-3 of imidazole or
N-4 of 1,2,4-tiazole) binds to the sixth coordination of heme iron
atom of the porphyrin in the substrate binding site of the enzyme.7
Based on the structure of the active site of CYP51 and the extensive
investigation of the structure–activity relationships of azole anti-
fungals, it was found that 1,2,4-triazole ring and 2,4-difluoro-
phenyl group are essential for the high antifungal activity.8
Several reports on the synthesis and biological activity of struc-
turally modified new analogues of fluconazole are known in the lit-
erature.9–13 We focused our attention on replacement of one of the
* Corresponding author. Tel.: +91 20 25902327; fax: +91 20 25902624.
E-mail address: vs.pore@ncl.res.in (V.S. Pore).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.026

760
N. G. Aher et al. / Bioorg. Med. Chem. Lett. 19 (2009) 759–763
CH3
N
CH3
N
F
OH
HO
HO
N
N
N
N
S
N
N
N
N
N
F
N
N
F
F
N
N
F
F
F
CN
O
Fluconazole
Ravuconazole
Voriconazole
O
N
N
O
O
N
F
N
O
N
N
N
O
N
Cl
N
F
N
N
N
N
O
OH
Cl
Itraconazole
N
N
Posaconazole
N
Figure 1. Azole antifungals containing 1,2,4-triazole.
1,2,4-triazole rings of fluconazole with monosubstituted or 1,4-
disubstituted 1,2,3-triazoles. 1,2,3-Triazole moieties are stable to
metabolic degradation and are capable of hydrogen bonding,
which can be favorable in binding of biomolecular targets and for
solubility.14 1,2,3-Triazole moiety does not occur in nature,
although the synthetic molecules containing 1,2,3-triazole unit
show diverse biological activities including antibacterial, herbi-
cidal, fungicidal, antiallergic, and anti-HIV.15 Huisgen’s 1,3-dipolar
cycloaddition of terminal acetylenes and organic azides gives a
mixture of 1,4- and 1,5-disubstituted-1,2,3-triazoles.16a Cu(I) cata-
lyzed 1,3-dipolar cycloaddition has been a method of choice for the
synthesis of 1,4-disubstituted-1,2,3-triazoles.16b–d Our preliminary
work on development of new antifungal triazoles included synthe-
sis of fluconazole/bile acid conjugates 1–4 via Cu(I) catalyzed 1,3-
dipolar cycloaddition (Fig. 2).17
earlier report17 from 1,3-diflurobenzene 5 through intermediate 6
and ketone 7 (Scheme 1).
Propargylation of the ketone 7 by using propargyl bromide and
zinc dust in DMF/THF gave racemic compound 8 in 95% yield. An-
other intermediate, namely azide 10 was synthesized from ketone
7. Reaction of ketone 7 with trimethylsulfoxonium iodide in the
presence of sodium hydride afforded oxirane 9 in 91% yield.12
Opening of oxirane 9 with NaN3 in DMF at 60–65 °C resulted into
azide 10 in 75% yield as a racemic mixture.19
Acetylenic compound 8 on cycloaddition reaction with azidotri-
methylsilane under microwave irradiation at 245 W in DMF/H2O
using catalytic amount of copper sulfate and sodium ascorbate
gave trimethylsilyl deprotected20 monosubstituted 1,2,3-triazole
containing fluconazole analogue 11 in 87% yield (Scheme 2).
The reaction of the same acetylenic compound 8 with 1-azi-
dooctane, under similar reaction conditions afforded 1,4-disubsti-
tuted 1,2,3-triazole analogue 12 having long alkyl chain, in 94%
yield. The azide 10 was reacted with trimethylsilyl acetylene
(microwave irradiation at 175 W because of the low boiling point
of trimethylsilyl acetylene) to give trimethylsilyl deprotected mon-
osubstituted 1,2,3-triazole compound 13 in 74% yield along with
trimethylsilyl containing compound 14 in 21% yield. Reaction of
azide 10 with 1-octyne afforded compound 15 having long alkyl
chain attached to 1,2,3-triazole ring. Similar reaction of the azide
10 with propargyl ester of deoxycholic acid, which was synthe-
sized according to our earlier report,21 yielded diastereomeric mix-
ture of bile acid–fluconazole conjugate 16 in 95% yield. Similarly
cycloaddition reaction of 10 with propargyl esters of cholic acid
yielded conjugate 17 in 94% yield. All the compounds 11–17 were
characterized by spectroscopic data as well as elemental analysis.
All the compounds 11–17 were tested for the in vitro antifungal
activity. The antifungal activity was evaluated against different fun-
gal strains such as Candida albicans, Candida neoformans, Sporothrix
schenckii, Trichophyton mentagrophytes, Aspergillus fumigatus, Can-
dida parapsilosis (ATCC 22019). Minimum inhibitory concentration
(MIC) and IC50 values were determined using standard broth micro-
dilution technique as per NCCLS guidelines.22 Fluconazole, ampho-
tericin B, and ketoconazole were used as standard drugs for the
comparison of antifungal activity. All the biological data of the
tested compounds are depicted in Table 1 as MIC and IC50 values.
All these newly synthesized compounds were found to show
good antifungal activity. From the biological data (Table 1), it
was observed that compounds 11 and 13 having monosubstituted
1,2,3-triazole ring which are isosteres of fluconazole and com-
These molecules 1–4 having epimeric mixture at C-2 atom of
fluconazole moiety showed moderate antifungal activity against
Candida species (MIC ranging from 3.12 to 6.25 lg/ml).
In this letter, we describe the synthesis and biological evalua-
tion of fluconazole analogues containing monosubstituted (11,
13) and 1,4-disubstituted (12, 14, and 15) 1,2,3-triazoles. Synthesis
of ester linked bile acid fluconazole conjugates (16 and 17) is also
described in which, amphiphilicity of bile acid moiety was thought
to be helpful as drug transporter.18
The two common intermediates, terminal acetylene 8 and azide
10 have been used for the synthesis of new fluconazole analogues
11–17. The terminal acetylene 8 was synthesized according to our
OH
R =
R1
OH
F
N
R
OH
N
N
N
1 R1 = H
N
N
F
2 R1 = OH
O
OCH3
OH
R1
R =
Fluconazole/
Bile acid conjugate
3 R1 = H
4 R1 = OH
Figure 2. Fluconazole/bile acid conjugates.

N. G. Aher et al. / Bioorg. Med. Chem. Lett. 19 (2009) 759–763
761
N
OH
F
N
O
O
Cl
N
F
N
F
F
N
a
b
N
c
F
F
7
8
F
F
6
5
d
O
N
OH
N
N
F
N
F
N3
N
N
e
10
9
F
F
Scheme 1. Reagents and conditions: (a) AlCl3, 1,2-dichloroethane, chloroacetyl chloride, 25 °C, 7 h; (b) 1,2,4-triazole, NaHCO3, toluene, reflux, 4 h (overall 55% in two step);
(c) Zn, propargyl bromide, DMF/THF, 25 °C, 5 h, 95%; (d) trimethylsulfoxonium iodide, NaH, DMSO/THF, 25 °C, 2 h, 91%; (e) NaN3, DMF, 60–65 °C, 12 h, 75%.
OH
N
OH
N
N
F
OH
N
N
N
F
NH
N
C8H17
N
F
N3 TMS
a
N
N
N
N
N
N
N
N
N
N
1-azidooctane
a
N
8
11
F
12
F
F
OH
OH
OH
N
N
N
N3
N
F
N
N
N
N
1octyne
a
N
N
TMS
b
F
F
R
C6H13
F
F
F
10
13 R = H
15
14 R = TMS
a
OR
N
O
OH
F
N
OH
OH
N
N
16 R =
N
N
F
O
OH
RO
17 R =
OH
OH
Scheme 2. Reagents and conditions: (a) CuSO4Á5H2O (5 mol%), sodium ascorbate (40 mol%), DMF/H2O (4:1), microwave (245 W), 10 min; (b) CuSO4Á5H2O (5 mol%), sodium
ascorbate (40 mol%), DMF/H2O (4:1), microwave (175 W), 10 min.
Table 1
In vitro antifungal activities of compounds 11–17 and standard antifungal drugs fluconazole, ketoconazole, and amphotericin B (MIC and IC50 in lg/ml)
Compound
Inhibitory concentration in
SS
l
g/ml against
TM
CA
CN
AF
CP
MIC
3.16
0.002
1.48
IC50
2.74
0.001
0.72
MIC
IC50
0.69
<0.006
0.03
MIC
12.4
IC50
4.43
0.008
5.77
3.11
0.043
0.76
11.27
1.45
0.026
0.08
MIC
IC50
MIC
IC50
MIC
IC50
11
12
13
14
15
16
17
Flu.
Keto.
Amp. B
3.12
0.002
0.78
1.56
0.02
0.01
0.19
1.0
49.03
0.480
12.16
15.56
6.72
>50
18.41
1.0
4.0
46.99
0.249
6.45
8.57
2.46
46.47
8.9
0.6
2.12
0.02
>50
1.12
>50
49.81
6.9
>50
>50
2.0
>50
0.8
>50
43.19
5.0
6.24
31.24
1.06
0.008
0.38
29.10
0.01
12.82
44.53
0.39
0.396
5.15
1.0
16.83
0.002
6.83
33.10
0.12
0.38
2.93
0.21
0.024
0.11
0.036
10.62
3.16
0.14
0.84
12.56
2.0
3.26
3.04
1.01
0.032
<0.001
0.442
0.5
0.002
0.12
0.018
<0.001
0.35
0.13
0.001
0.09
<0.01
<0.001
0.03
0.45
0.001
0.04
0.001
0.06
0.031
0.12
2.0
0.5
0.031
0.12
0.12
Bold values indicate the values of more active compounds in the series.
Abbreviations used: CA, Candida albicans; CN, Cryptococcus neoformans; SS, Sporothrix schenckii; TM, Trichophyton mentagrophytes; AF, Aspergillus fumigatus; CP, Candida
parapsilosis (ATCC 22019); Flu., fluconazole; Keto., ketoconazole; Amp. B, amphotericin B.

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N. G. Aher et al. / Bioorg. Med. Chem. Lett. 19 (2009) 759–763
pound 14 containing trimethylsilyl group, showed good in vitro
antifungal activity against fungal pathogens C. albicans, C. neofor-
mans, and S. schenckii, which was comparable with fluconazole
but these compounds were less active than amphotericin B and
ketoconazole (imidazole based current antifungal drug). These
molecules were found to be less active against T. mentagrophytes,
A. fumigatus, and C. parapsilosis (ATCC 22019).
1,4-Disubstituted 1,2,3-triazole containing compounds 12 and
15 with long alkyl chains showed very good antifungal activity
against all the tested fungal pathogens. Compound 12 showed
Compound 12 resulted in 97.4% reduction while compound 15
resulted in 95% reduction in fungal load in mice at a dose of
50 mg/kg po. Although the bile acid conjugate 16 showed good
activity in vitro, it did not exhibit significant in vivo activity
(38.2% reduction in fungal load) in this model.
The lead compounds 12, 15 and conjugates 16, 17 were tested
for their antiproliferative activity against human cancer cells
Hep3B and A431. All the four compounds as well as standard drugs
fluconazole, amphotericin B, and ketoconazole were less toxic at
lower dose (0.001 mg/ml) while at higher dose (1 mg/ml), they
were toxic to both Hep3B and A431 cells (Fig. 3).
much better activity for C. albicans (IC50 0.001
lg/ml), C. neofor-
mans (IC50 <0.006 g/ml), and C. parapsilosis (IC50 0.002
compared with fluconazole, amphotericin B, and ketoconazole,
while compound 15 was found to be less active than compound
l
l
g/ml) as
All the four compounds12, 15, 16, and 17 were more toxic than
fluconazole and were less toxic than ketoconazole in both the cell
lines. In Hep3B cell lines compound 15 was more toxic than fluco-
nazole but less toxic than other compounds as well as amphoteri-
cin B and ketoconazole. Compounds 16 and 17 were comparable
with amphotericin B in their toxicity.
12 but showed better activity against C. albicans (IC50 0.018
ml), C. neoformans (IC50 <0.01 g/ml), and C. parapsilosis (IC50
0.043 g/ml) as compared with fluconazole and amphotericin B.
lg/
l
l
Compounds 16 and 17 which are ester linked bile acid fluconazole
conjugates were found to be more potent against Candida strains.
Compound 16 showed much better activity for C. albicans (IC50
In A431 cells, compounds 12 and 15 were found to be more
toxic than fluconazole but were less toxic than other compounds
as well as amphotericin B and ketoconazole. The antiproliferative
activities of compounds 16 and 17 were comparable to amphoter-
icin B in A431 cells.
<0.001
<0.043
l
l
g/ml), C. neoformans (IC50 <0.001
g/ml), and C. parapsilosis (IC50 0.12
l
g/ml), S. schenckii (IC50
lg/ml) as compared
with fluconazole and amphotericin B.
The results therefore suggest that the antiproliferative activity
of compound 12 was similar to fluconazole in A431 cells, while it
was toxic for Hep3B cells than fluconazole. The compound 15
was less toxic than ketoconazole and amphotericin B but moder-
ately toxic than flucanozole in both the cell lines. Taken together,
these results indicated that the lead compounds 12 and 15 do
not have any profound effect on proliferation of human cancer cell
lines at lower concentrations and moreover their activity is compa-
rable to that of standard drugs.
Compounds 16 and 17 were found to be more potent than our
earlier reported fluconazole–bile acid conjugates 1–4.17
We also evaluated the in vivo activity of more potent compound
12, 15, and 16 against C. albicans intravenous challenge in Swiss
mice (Table 2).
In conclusion, fluconazole based novel mimics containing 1,2,3-
triazole were designed and synthesized. These molecules were
tested for their antifungal activity. Out of these easily accessible
molecules, 1,4-disubstituted-1,2,3-triazole compounds 12 and 15,
containing long alkyl chains, showed very good antifungal activity
against Candida species when compared with the standard drugs
fluconazole, ketoconazole, and amphotericin B and did not show
any profound proliferative effect. The in vivo assay also indicated
that these lead molecules are very good candidates for drug design.
A large library of compounds can be easily synthesized from the
intermediates 8 and 10 for extensive structure–activity relation
studies so that one can reach to the more appropriate drug candi-
date. Synthesis of pure enantiomers is in progress in our labora-
tory. These are expected to show better activity than racemic
Table 2
In vivo efficacy of 12, 15, and 16 against systemic challenge of Candida albicans in
mousea
Sr. No.
Animal
groups
Average CFU/g
kidney tissue
% Reduction
in CFU load
1
2
3
4
5
6
Control
3.4 Â 106
8.8 Â 104
2 Â 106
1.7 Â 105
ND
Nil
12, 50 mg/kg (OD)
12, 25 mg/kg (OD)
15, 50 mg/kg (OD)
15, 25 mg/kg (OD)
16, 50 mg/kg (OD)
97.4
41.2
95.0
ND
2.1 Â 106
38.2
a
Five mice per group were used; the test compounds were given orally, once a
day in PEG 200 for 7 days. On day 9 the mice were sacrificed and CFU in kidney
tissue were determined; ND, not detected.
100
80
100
80
60
60
Compound 16
40
Compound 16
Compound 17
Compound 12
40
Compound 17
Compound 12
Compound 15
Amphotericin B
Fluconazole
Ketoconazole
Compound 15
20
Amphotericin B
Fluconazole
20
Ketoconazole
0
0
1E-3
0.01
0.1
1
1
1E-3
0.01
0.1
Concentration (mg/ml)
Concentration (mg/ml)
A (Hep3B cells)
B (A431 cells)
Figure 3. Graphical representation for antiproliferative activities of compounds in Hep3B cells (A) and A 431 cells (B).

N. G. Aher et al. / Bioorg. Med. Chem. Lett. 19 (2009) 759–763
763
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V.S.P. thanks Director NCL for in-house project funding (MLP
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.12.026. Experimen-
tal procedures as well as materials and methods for bioevaluation
and spectroscopic data of compounds 7, 9, 10, 11, 12, 13, 14, 15, 16,
17.
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