Design, synthesis, and antifungal activity of triazole and benzotriazole derivatives

Article abstract of DOI:10.1016/j.ejmech.2008.07.012

This study describes the design, synthesis and evaluation of a novel series of 1,2,4-triazole and benzotriazole derivatives as inhibitors of cytochrome P450 14α-demethylase (14DM). The chemical structures of the new compounds were confirmed by elemental a

Full text of DOI:10.1016/j.ejmech.2008.07.012

European Journal of Medicinal Chemistry 44 (2009) 3064–3067
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Design, synthesis, and antifungal activity of triazole
and benzotriazole derivatives
,
a
,
b
a
a
Zahra Rezaei a , Soghra Khabnadideh , Keyvan Pakshir , Zahra Hossaini , Fatemeh Amiri ,
*
*
Elham Assadpour a
a Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences,
Shiraz, Iran
b Department of Parasitology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
This study describes the design, synthesis and evaluation of a novel series of 1,2,4-triazole and benzo-
Received 3 February 2008
Received in revised form 21 May 2008
Accepted 11 July 2008
triazole derivatives as inhibitors of cytochrome P450 14a-demethylase (14DM). The chemical structures
of the new compounds were confirmed by elemental and spectral (1H NMR, 13C NMR, Mass) analyses.
Compounds were designed by a generating virtual library of compounds and docking them into the
enzyme active site. Furthermore, they were found to have in vitro activity against Microsporum canis,
Trichophyton mentagrophyte, Trichophyton rubrum, Epidermophyton floccosum, and Candida albicans
comparable to fluconazole and clotrimazole.
Available online 19 July 2008
Keywords:
14a-Demethylase
Antifungal activity
Triazole
Ó 2008 Elsevier Masson SAS. All rights reserved.
Benzotriazole
1. Introduction
Antifungal azoles, fluconazole with triazole ring and
clotrimazole with imidazole ring are strong inhibitors of lanosterol
The incidence of systemic fungal infections has been increasing
dramatically due to an increase in the number of immunocompro-
mised hosts. Patients undergoing anticancer chemotherapy, organ
transplants or long treatment with antimicrobial agents and patients
with AIDS are immunosuppressed and very susceptible to life
threateningsystemicfungalinfections likecandidiasis, cryptococcosis
and aspergillosis. In recent years the developments of resistance to
currentlyavailable antifungal azoles in Candida spp., as well as clinical
failuresinthetreatmentoffungalinfectionshavebeenreported[1–4].
Triazole may be considered as a bioisostere of imidazole which is
incorporated into the structures of many antifungal compounds [5].
With the aim of obtaining new antifungal compounds, we synthe-
sized a series of triazole and benzotriazole derivatives.
14
a-demethylase (cytochrome P-45014a-DM) which have been
widely used in antifungal chemotherapy. The fungicides containing
triazole have high prevention and cure against fungi and have the
function to increase the yield [8].
In this study a series of new 1,2,4-triazole and benzotriazoles
related to clotrimazole and fluconazolewere synthesized and then the
compounds docked in the active site of 14a-demethylase using
Autodock program. In addition we investigated the activity of the
compounds against Microsporum canis, Trichophyton mentagrophyte,
Trichophytonrubrum, Epidermophyton floccosum, andCandidaalbicans.
2. Chemistry
CYP51 is an essential enzyme in the sterol biosynthetic pathway
in eukaryotes, where inhibition by azole drugs in fungi leads to
a depletion of ergosterol [6]. The key interactions in the active site
are these components: (i) the amidine nitrogen atom (N-3 in the
imidazoles, N-4 in the triazoles) to bind to the heme iron of
enzyme; (ii) aromatic rings; (iii) the large nonpolar portion of
molecule [7].
Triazole or benzotriazole rings, trityl moiety or alkyl halide,
potassium bicarbonate, tetraethylammonium iodide (TEAI) and
NaOH in acetonitrile (30–40 ml) were refluxed for 24–90 h. Then
the reaction mixture was filtered and the solid washed with
acetonitrile and dried over anhydrous Na2SO4. The filtered evapo-
rated in vacuo and the crude product was purified by column
chromatography using chloroform–ethanol for triazole derivatives
and dichloromethane–ethyl acetate for benzotriazole derivatives to
get the final compounds. The yield of reaction was 81–90%. The
synthetic route to these compounds is shown in Scheme 1 for
triazole derivatives and in Scheme 2 for benzotriazole derivatives.
* Corresponding authors. Tel.: þ98 711 2425305; fax: þ98 711 2424126.
E-mail addresses: rezaeiza@sums.ac.ir (Z. Rezaei), khabns@sums.ac.ir
(S. Khabnadideh).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.07.012

Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 3064–3067
3065
R1
N
R1
Cl
N
H
+
Acetonitrile, Reflux
TEAI, NaOH, K CO3
N
N
N
2
N
R2
R2
1) R1=R2=H
2) R1=H, R2= OCH3
3) R1=R2=OCH3
N
N
Acetonitrile, Reflux
TEAI, NaOH, K2CO3
CH2-(CH2)n-CH3
CH3-(CH2)n-CH2Br
N
N
H
+
N
N
7) n=3
8) n=6
Scheme 1. Synthesis of 1,2,4-triazole derivatives.
There are several reports on alkylation of 1,2,4-triazole and 1,2,3-
benzotriazole [9–12]. 1,2,4-Triazoles can be alkylated on N1 or N4 and
1,2,3-benzotriazoles on N1 or N2. The controlled, regioselective alkyl-
ation of them, is difficult. Our strategy was a modification of these
methods to get N1-substituted of the azoles in higher yield. Therefore,
we applied the acetonitrile as solvent, tetra ethyl ammonium iodide,
anhydrous potassium carbonate, and sodium hydroxide as catalysts.
Sabouraud dextrose agar (SDA), potato dextrose agar (PDA) and
RPMI 1640 were used for agar dilution and macrodilution methods.
The clinical isolates of fungi including M. canis, T. mentagrophytes, T.
rubrum, E. floccosum and C. albicans were purified and subcultured
on SC, SCC, and PDA media before testing. The stock solution of
compounds was prepared in DMSO at a concentration of 1000–
5000
mg/ml. The compounds were diluted in solid and broth media
to obtain final concentration from 0.0625 to 4
mg/ml, using PDA and
RPMI 1640 media. The inocula of the molds and yeast were
prepared from 2- to 7-day mature colonies grown. Fluconazole and
clotrimazole were used as positive and the solvents of the
compounds as negative blanks.
3. Modeling studies
The compounds were drawn in the hyperchem 7 and minimized
using the AM1 method with a gradient cut-off of 0.01 Kcal/mol. The
protein was obtained from Protein Data Bank (1E9X) and then
water molecules were removed from the protein for docking. All
the compounds as well as fluconazole were docked into the active
5. Results and discussion
site of 14a-demethylase using Autodock 3.0.5.
5.1. Modeling
4. Antifungal assays
We chose a number of different possibilities for the components
in the compounds to interact with the active site of 14a-
Microorganisms were obtained from the Mycology and Parasi-
tology Department of the Shiraz University of Medical Sciences.
demethylase. It is also important to select compounds which have
drug-like properties. All the compounds have a molecular weight
R1
N
N
R1
N
N
Acetonitrile, Reflux
Cl
+
N
N
H
TEAI, NaOH, K2CO3
R2
R2
4) R1=R2=H
5) R1=H, R2=OCH3
6) R 1=R 2=OCH3
N
N
Acetonitrile, Reflux
TEAI, NaOH, K2CO3
N
N
CH3-(CH2)n-CH2Br
+
N
N
H
CH2-(CH2)n-CH3
9) n=3
10) n=6
Scheme 2. Synthesis of 1,2,3-benzotriazole derivatives.

3066
Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 3064–3067
Table 1
shown in Table 2. As shown in Table 2 all the compounds tested
showed antifungal activity against T. rubrum. The structural activity
study shows that antifungal activity is dependent on the hetero-
cyclic moiety as well as on the nature of the substituents. The
maximum inhibition was observed in compound 1 with the lowest
Docking results of synthesized compounds into the active site of MT-CytP51 (1E9X)
Compound
Final docked energy (Kcal/mol)
log p
Molecular weight
1
2
3
4
5
6
7
8
ꢁ5.17
ꢁ6.55
ꢁ2.25
ꢁ4.37
ꢁ5.41
ꢁ2.87
ꢁ7.29
ꢁ8.73
ꢁ7.26
ꢁ9.77
ꢁ10.55
4.43
4.68
4.93
5.38
5.12
4.87
4.43
4.45
1.45
3.03
0.84
311
341
371
361
391
421
139
181
189
231
306
MIC (1 mg/ml) against E. floccosum. Compound 1 has smaller size
than the other compounds and may be attributed to the better
penetration into fungi cell. The benzotriazoles compounds 4, 5, and
6 had low antifungal activity. The activity was decreased by the
presence of methoxy group on the triazoles and benzotriazoles
moiety (compounds 2, 3, 5, and 6). Compounds 8 and 9 also
possessed great inhibitory effect on tested fungus.
9
10
Fluconazole
6. Conclusion
ranging from 139 to 421 and the log p range of the molecules was
between 1.4 and 5.3 (Table 1). The compounds were drawn in the
hyperchem 7. All the compounds as well as fluconazole were
In conclusion 10 new compounds related to clotrimazole and
fluconazole were synthesized and the major products were purified
using column chromatography and then the structures of them
were confirmed by 1H NMR, 13C NMR and MS spectroscopies and
elemental analysis. These compounds showed similar antifungal
activity against some fungi to fluconazole and there was a correla-
tion between docking energy and growth inhibition for some
compounds.
docked into the active site of 14a-demethylase which was obtained
from Protein Data Bank (1E9X) using Autodock 3.0.5. Docking score
showed that these compounds docked to the active site of
the enzyme comparable to fluconazole (Table 1). All new azole
compounds plus fluconazole were characterized by a docking mode
in the active site of the cytochrome P450 14a-sterol demethylase.
Trityl triazole derivatives (compounds 1–3) had more negative
docking energy in comparison with trityl benzotriazole derivatives
(compounds 4–6). But alkyl derivatives (compounds 7–10) docked
to the active site of the enzyme with the most negative docking
energy. There is some correlation between antifungal activity and
docking energy. Thus for example compounds 8 and 9 show potent
growth inhibition and have good docking energy. In other
compounds there was a lower correlation between docking energy
and growth inhibition as in antifungal assays. In these cases there
are factors such as penetration that may be important.
7. Experimental
All solvents and reagents were purchased from Sigma or Merck
Chemical Companies. The products were purified by column
chromatography techniques. NMR spectra were recorded on
a Brucker Avance DPX 250 MHZ instrument. Mass spectra were
recorded on a Hewlett-Packard GC–MS.
7.1. General procedure for the synthesis of compounds
5.2. Antifungal assays
Four millimoles of 1,2,4-triazole (0.276 g) or 1,2,3-benzotriazole
(0.476 g), 3 mmol of trityl moiety or alkyl halide were added to
a solution of tetra ethyl ammonium iodide (0.065 g, 0.25 mmol),
anhydrous potassium carbonate (0.55 g, 4 mmol), and sodium
hydroxide (0.16 g, 4 mmol) in acetonitrile and then stirred for 24–
90 h at reflux temperature. After completion of the reaction, the
suspension was filtered and the solid washed with acetonitrile
(3 ꢀ10 ml) and dried over anhydrous Na2SO4. The filtered evapo-
rated by rotary evaporator. The product was purified by column
chromatography using chloroform–ethanol as eluent to get the
final compounds (Schemes 1 and 2).
The clinical isolates of fungi including M. canis, T. menta-
grophytes, T. rubrum, E. floccosum and C. albicans were purified and
subcultured on SC, SCC, and PDA media before testing. The stock
solution of compounds was prepared in DMSO at a concentration of
1000–5000 mg/ml. Agar dilution assay and macrodilution method
were used to establish the minimum inhibitory concentration (MIC)
of synthetic derivatives [13,14]. The compounds were diluted in
solid and broth media to obtain final concentration from 0.0625 to
64 mg/ml, using PDA and RPMI 1640 media. The inocula of the molds
and yeast were prepared from 2- to 7-day mature colonies grown.
Fluconazole and clotrimazole were used as positive and the
solvents of the compounds as negative blanks. The results are
7.1.1. 1-Trityl-1H-1,2,4-triazole (1)
The time of reaction was 37 h (90%, mp ¼ 204). 1H NMR (CDCl3)
d
(ppm): 8.06 (s, 1H, triazole), 8.03 (s, 1H, triazole), 7.36 (s, 6H,
Table 2
phenyls), 7.2–7.2 (m, 9H phenyls). 13C NMR
d (ppm): 142.5, 139.8,
Minimum inhibitory concentrations (MICs) of the synthesized compounds
131.2, 127.4, 125.5, 74.2. MS (m/z %) 311(Mþ, 100), 243 (100), 165
(55), 77 (28), 51 (12). Anal. Calcd for C21H17N3: C, 81.02; H, 5.46; N,
13.5; Found: C, 80.21; H, 5.65; N, 13.1.
Compound T. mentagrophyte C. albicans T. rubrum
M. canis
E. floccosum
MIC (
m
g/ml)
MIC (
m
g/ml) MIC (
m
g/ml) MIC (
m
g/ml) MIC ( g/ml)
m
1
2
3
4
5
6
7
8
9
10
32
16
32
–
64
64
64
16
32
64
–
–
–
64
–
–
–
16
32
–
64
32
8
64
32
64
–
–
–
64
16
16
64
1
8
16
64
64
–
64
8
16
32
4
7.1.2. (4-Methoxyphenyl)(diphenyl)1H-1,2,4,-triazole-1yl-
methane (2)
64
64
32
64
16
32
64
0.5
32
This product was synthesized after 27 h (87%, mp ¼ 248). 1H
NMR (CDCl3)
d (ppm): 8.05 (s, 1H, triazole), 7.99 (s, 1H, triazole),
7.25–7.33 (m, 6H, phenyls), 6.81–7.15 (m, 8H, phenyls), 3.8 (s, 3H,
OCH3). 13C NMR
d (ppm): 154.2, 141.5, 139.2, 131.5, 125.8, 122.1,
119.7, 74.3, 50.2. MS (m/z %) 341(Mþ, 50), 273 (100), 242 (5), 195
(12), 165 (24), 77 (23), 51 (7). Anal. Calcd for C22H19N3O1: C, 77.41;
H, 5.57; N, 12.31; Found: C, 76.71; H, 5.35; N, 12.01.
Clotrimazole 0.05
Fluconazole
4
.065
1
32
16
0.25

Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 3064–3067
3067
7.1.3. 1-[Di(4-methoxyphenyl)(phenyl) methyl]-1H-1,2,
4-triazole (3)
(t, 2H, J ¼ 6.8 Hz, N–CH2) 1.8–2 (m, 2H, N–CH2–CH2), 1.1–1.3 (m, 10H
(–CH2–)5), 0.79–0.93 (t, 3H, J ¼ 5.8 Hz, CH3). 13C NMR
d (ppm):
The reaction completed after 24 h (83%, mp ¼ 268). 1H NMR
144.5, 51.4, 31.2, 30.2, 29.8, 26.5, 26.1, 22.4. MS (m/z %) 181(Mþ, 30),
152 (10), 97 (15), 97 (40), 83 (80), 70 (100), 55 (80), 41 (100). Anal.
Calcd for C10H19N3: C, 66.29; H, 10.46; N, 23.2; Found: C, 65.45; H,
9.87; N, 22.74.
(CDCl3)
d (ppm): 7.93 (s, 1H, triazole), 7.88 (s, 1H, triazole), 7.21 (s,
4H, phenyls), 7.18 (s, 2H, phenyls), 6.68–7.12 (m, 7H, phenyls), 3.69
(s, 3H, OCH3), 3.66 (s, 3H, OCH3). 13C NMR
d (ppm): 151.2, 140.1,
139.4, 130.8, 128.5, 124.5, 74.1, 52.3. MS (m/z %) 371 (Mþ, 45), 303
(100), 271 (12), 243 (100), 195 (15), 165 (10), 77 (50), 51 (7). Anal.
Calcd for C23H21N3O2: C, 74.39; H, 5.66; N, 11.32; Found: C, 72.29; H,
5.95; N, 10.98.
7.1.9. 1-Pentyl-1H-1,2,3-benzotriazole (9)
This compound was synthesized after 42 h (83%, mp ¼ 271.5). 1H
NMR (CDCl3)
d
(ppm): 7.9–8 (d, 2H, J ¼ 6.8, benzotriazole), 7.1–7.3
(d, 2H, J ¼ 7.8 Hz, benzotriazole), 4.4 (t, 2H, J ¼ 8 Hz, N–CH2), 1.8 (m,
7.1.4. 1-Trityl-1H-1,2,3-benzotriazole (4)
4H (–CH2–)2), 0.7 (t, 3H, J ¼ 8.1 Hz, CH3). 13C NMR
d (ppm): 145.5,
This compound was synthesized after 63 h (90%, mp ¼ 215). 1H
131.1, 126.8, 125.7, 118.4, 110.1, 50.5, 30.7, 22.1, 15.1. MS (m/z %) 189
(Mþ, 73), 174 (6), 161 (21), 146 (31), 132 (58), 118 (50), 91 (100), 66
(45), 43 (100). Anal. Calcd for C11H15N3: C, 69.84; H, 7.93; N, 22.22;
Found: C, 68.73; H, 6.54; N, 21.77.
NMR (CDCl3)
d
(ppm): 7.8 (d, 1H, J Hz ¼ 6.4, benzotriazole), 7.2–7.3
(m, 6H, phenyls), 6.8–7.1 (m, 2H, benzimidazole and 9H, phenyls),
6.3 (d, 1H, J ¼ 11.2 Hz, benzotriazole). 13C NMR
d (ppm): 151.6, 142.8,
135.9, 131.7, 125.7, 123.5, 121.4, 118.4, 81.7. MS (m/z %) 361(Mþ, 1),
243 (100), 165 (55), 77 (15), 51 (8). Anal. Calcd for C25H19N3: C,
76.72; H, 5.26; N, 11.63; Found: C, 77.91; H, 5.580; N, 11.29.
7.1.10. 1-Octyl-1H-1,2,3,-benzotriazole (10)
This compound was synthesized after 72 h (81%, mp ¼ 309.7).
1H NMR (CDCl3)
d (ppm): 8.4–8.7 (m, 2H, benzotriazole), 7.9–8.1 (m,
7.1.5. 1H-1,2,3-Benzotriazol-1-yl(4-methoxyphenyl)diphenyl-
methane (5)
2H, benzotriazole), 5.4 (t, 2H, J ¼ 7.1 Hz, N–CH2), 2.8 (m, 2H, N–CH2–
CH2–), 2.1(m, 8H, (–CH2–)4), 1.6 (m 2H, CH2–CH3), 0.7 (t, 3H, J ¼ 7.1,
This compound was synthesized after 42 h (85%, mp ¼ 220). 1H
CH3). 13C NMR
d (ppm): 141.5, 135.7, 129.3, 121.1, 115.7, 95.0, 86.2,
NMR (CDCl3)
d
(ppm): 7.3 (d, 1H, J Hz ¼ 6.0, benzotriazole), 7.07–7.2
55.4, 51.9, 33.2, 20.1,12.5. MS (m/z %) 231 (Mþ, 23), 202 (7),188 (10),
174 (18), 160 (12), 146 (42), 132 (77), 119 (35). Anal. Calcd for
C14H21N3: C, 72.72; H, 9.09; N, 18.18; Found: C, 71.71; H, 8.99; N,
17.91.
(m, 3H, benzotriazole and 9H, phenyls), 6.75–6.86 (m, 5H, phenyls),
3.7 (d, 3H, J ¼ 8 Hz, OCH3). 13C NMR
d (ppm): 154.3, 150.2, 144.0,
131.1, 127.9, 119.9, 115.4, 79.8, 55.1. MS (m/z %) 391 (Mþ, 1), 273
(100), 243 (60), 195 (23), 165 (60), 77 (100), 51 (40). Anal. Calcd for
C26H21N3O1: C, 79.79; H, 5.37; N, 10.74; Found: C, 77.71; H, 5.15; N,
10.31.
Acknowledgments
This work was supported by Shiraz University of Medical
Sciences. We are also thankful to Shiraz University, Dr. Habib Fir-
ouzabadi and Dr. S. Mohammad Reza Jafari.
7.1.6. 1H-1,2,3,-Benzotriazol-1-yl[di(4-
methoxyphenyl)]phenylmethane (6)
This compound was synthesized after 24 h (81%, mp ¼ 222). 1H
NMR (CDCl3)
d
(ppm): 8.1 (d, 1H, J ¼ 7.4 Hz, benzotriazole), 7.3–7.5
References
(m, 1H, benzotriazole and 6H, phenyls), 6.8–6.9 (d, 2H, J ¼ 8 Hz,
benzotriazole), 6.4–6.6 (m, 7H, phenyls), 3.7 (d, 6H, J ¼ 7.1 Hz,
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d (ppm): 155.7, 141.5, 139.8, 135.6, 132.8, 129.8,
119.5, 119.1, 81.2, 51.1. MS (m/z %) 421 (Mþ, 14), 303 (100), 273 (6),
243 (100), 165 (13), 77 (54), 51 (16). Anal. Calcd for C27H23N3O2: C,
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7.1.7. 1-Pentyl-1H-1,2,4,-triazole (7)
This compound was synthesized after 90 h (85%). 1H NMR
(CDCl3) d (ppm): 8.03 (s, 1H, triazole), 7.84 (s, 1H, triazole) 4–4.22 (t,
2H, J ¼ 4 Hz, N–CH2) 1.65–1.94 (m, 2H, N–CH2–CH2), 1.11–1.42 (m,
4H (–CH2–)2), 0.72–0.92 (t, 3H, J ¼ 8 Hz, CH3). 13C NMR
d (ppm):
148.5, 52.8, 31.2, 29.7, 21.3, 15.8. MS (m/z %) 139 (Mþ, 14), 126 (17),
111 (15), 97 (15), 83 (20), 69 (35), 55 (50), 43 (100). Anal. Calcd for
C7H13N3: C, 60.43; H, 9.35; N, 30.21; Found: C, 60.71; H, 9.15; N,
29.81.
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1349–1351.
7.1.8. 1-Octyl-1H-1,2,4,-triazole (8)
This compound was synthesized after 90 h (90%). 1H NMR
(CDCl3) d (ppm): 8.04 (s,1H, triazole), 7.92 (s,1H, triazole) 4.07–4.24