Synthesis and antifungal activity of 2-aryl-1,2,4-triazolo[1,5-a]pyridine derivatives

Article abstract of DOI:10.1002/ardp.200500227

A series of novel antifungal triazole derivatives 2-aryl-1,2,4-triazolo[1, 5-a]pyridine 9a-m were synthesized and tested in vitro for their growth inhibitory activities against C. albicans and T. rubrum. The MIC values indicate that the activities of three compounds were superior or comparable to fluconazole against both tested fungi, worthy of further investigation of its antifungal activities.

Full text of DOI:10.1002/ardp.200500227

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Arch. Pharm. Chem. Life Sci. 2006, 339, 262–266
Full Paper
Synthesis and Antifungal Activity of
2-Aryl-1,2,4-triazolo[1,5-a]pyridine Derivatives
Yun Luo, Yongzhou Hu
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou,
China
A series of novel antifungal triazole derivatives 2-aryl-1,2,4-triazolo[1,5-a]pyridine 9a–m were
synthesized and tested in vitro for their growth inhibitory activities against C. albicans and T.
rubrum. The MIC values indicate that the activities of three compounds were superior or compa-
rable to fluconazole against both tested fungi, worthy of further investigation of its antifungal
activities.
Keywords: Synthesis / Antifungal / 2-Aryl-1,2,4-triazolo[1,5-a]pyridine /
Received: October 20, 2005; Accepted: December 20, 2005
DOI 10.1002/ardp.200500227
Introduction
Results and discussion
The rising incidence of fungal infections, along with the The thirteen 2-aryl-1,2,4-triazolo[1,5-a]pyridine com-
emergence of fungal resistance to conventionally util- pounds 9a–m were tested in vitro for their growth-inhibi-
ized azole antifungals and severe toxicity of amphoteri- tory activities against pathogenic fungi by the standard
cin B, has added considerable urgency to the pursuit of method. The MIC (minimum inhibitory concentration)
safe and effective therapies in the past decade [1–3]. In values against Candida albicans 7374 and Trichophyton
continuation of our current research on the synthesis rubrum 6180 are presented in Table 2. We chose flucona-
and biological evaluation of small bioactive heterocyclic zole and amphotericin B as fungicidal standard agent [6].
molecules [4, 5], a new series of 2-aryl-1,2,4-triazolo[1,5-
As indicated in the Table 2, compounds 9a, 9f and 9j
a]pyridines were synthesized and their potential antifun- showed the same potent antifungal activities against C.
gal activities were evaluated.
albicans (MIC50 32 mg/mL) as fluconazole (MIC50 32 mg/
mL). And compounds 9g, 9k and 9l showed also good
activities against C. albicans (MIC50 64 mg/mL).
Chemistry
The 2-aryl-1,2,4-triazolo[1,5-a]pyridine structure was
The activities of these thirteen compounds against T.
synthesized by 1,3-dipolar cycloaddition of substituted N- rubrum were less potent than those against C. albicans.
aminopyridinium mesitylenesulfonate with aromatic However, compound 9a, 9f (MIC50 128 mg/mL) were
nitriles in the presence of potassium hydroxide solution. superior to those of fluconazole (MIC50 256 mg/mL) and
Different heterocycles were introduced to this structure. 9c, 9e, 9j, 9k, 9l, 9m (MIC50 256 mg/mL) were comparable
Thirteen compounds 9a–m were designed and synthe- to those of fluconazole against T. rubrum.
sized for evaluating their possible antifungal effect
The number of cases of in vitro resistance of flucona-
(Scheme 1). The compounds 9a–m were characterized by zole has risen dramatically. It is interesting to know that
1H-NMR, 13C-NMR, and physical data are given in Table 1.
from our thirteen new compounds, six 9a, 9f, 9g, 9j, 9k,
and 9l, have activities against Candida albicans (MIC50 32–
64 mg/mL), in which 9a, 9f, and 9j were superior or com-
parable to those of fluconazole against both tested fungi.
So far, we have not obtained the structure-activity rela-
tionship for this kind of new compounds. Because of lack-
Correspondence: Yongzhou Hu, Department of Medicinal Chemistry,
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou
310031, China.
E-mail: huyz@zjuem.zju.edu.cn
Fax: +86 571 87217412
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Synthesis of Novel Antifungal Triazole Derivatives
263
Scheme 1. Synthesis and structure of 2-aryl-1,2,4-triazolo[1,5-a]pyridine compounds 9a–m. *DMF: N,N-dimethyl formamide, CTAB:
cetyl-trimethylammonium bromide. a: Et3N / DMF / 08C / 0.5 h; b: 70% HClO4 / 1,4-dioxane / 0 8C / 20 min; c: 2-methyl pyridine or 3-
methyl pyridine / CH2Cl2 / rt / 1 h; d: 4-benzyloxybenzonitrile / 2N KOH / EtOH / rt / 24 h; e: H2 / 10% Pd-C / DMF / 6 h; f: 1,2-dibro-
moethane or 1,4-dibromobutane / CTAB / NaOH / H2O / flush.
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Table 1. Structure data of the products 9a–m.
No.
m.p.
[8C]
Yield
[%]
Formula
1H-NMR (400 or 500 MHz, CDCl3 d ppm) for thirteen compounds
13C-NMR (100.6 MHz, CDCl3) for 9g
9a
134–136
97
C19H22N4O2
2.62 (brs, 4H, –CH2NCH2–), 2.83–2.86 (m, 5H, –NCH2– and 5-CH3), 3.76 (t, J
= 4.5 Hz, 4H, –CH2OCH2–), 4.20 (t, J = 5.6 Hz, 2H, –CH2O–), 6.81 (d, J = 7.0
Hz, 1H, 6-H), 7.02, 8.25 (AA9BB9, each 2H, J = 8.7 Hz, 26Ar-2H), 7.42 (t, J =
7.0 Hz, J = 8.8 Hz, 1H, 7-H), 7.61 (d, J = 8.8 Hz, 1H, 8-H)
9b
139–141
88
C18H17N5O
2.84 (s, 3H, 5-CH3), 4.31 (t, 2H, –OCH2CH2–), 4.39 (t, 2H, –OCH2CH2–), 6.81
(d, 1H, 6-H), 8.28, 7.00 (AA9BB9, each 2H, 26Ar-2H), 7.11 (d, 1H, imidazole
59-H), 7.44 (t, 1H, 7-H), 7.61 (d, 1H, 8-H), 7.66 (s, 1H, imidazole 49-H), 8.20 (s,
1H, imidazole 29-H)
9c
9d
9e
141–143
212–214
132–134
85
95
96
C17H16N6O
C22H19N5OS
C21H18N6O
2.84 (s, 3H, 5-CH3 ), 4.42 (t, 2H, –OCH2CH2–), 4.62 (t, 2H, –OCH2CH2–), 6.83
(d, 1H, 6-H), 8.27, 6.99 (AA9BB9, each 2H, 26Ar-2H), 7.43 (t, 1H, 7-H), 7.63
(d, 1H, 8-H), 7.99 (s, 1H, triazole 39-H), 8.25 (s, 1H, triazole 59-H)
2.82 (s, 3H, 5-CH3), 3.68 (t, 2H, –OCH2CH2–), 4.36 (t, 2H, –OCH2CH2–), 6.80
(d, 1H, 6-H), 8.23, 6.97 (AA9BB9, each 2H, 26Ar-2H), 7.23 (m, 3H, 36Ar-H),
7.40 (t, 1H, 7-H), 7.52 (t, 1H, Ar-H), 7.60 (d, 1H, 8-H), 12.62 (s, 1H, NH)
2.90 (s, 3H, 5-CH3 ), 4.62 (t, 2H, –OCH2CH2–), 5.15 (t, 2H, –OCH2CH2–), 6.88
(d, 1H, 6-H), 8.27, 7.00 (AA9BB9, each 2H, 26Ar-2H), 7.10 (t, 1H, 7-H), 7.65 (t,
1H, Ar-H), 7.68 (t, 1H, Ar-H), 7.79 (d, 1H, 8-H), 8.14 (d, 1H, Ar-H), 8.34 (d, 1H,
Ar-H)
9f
79–81
98
82
C20H25N5O
C18H17N5O
2.31 (s, 3H, –NCH3), 2.54 (brs, 8H, –CH2CH2NCH2CH2–), 2.67 (s, 3H ,8-CH3),
2.86 (t, J = 5.8, 2H, –NCH2), 4.18 (t, J = 5.8, 2H, –CH2O–), 6.87 (t, J = 6.9, 1H,
6-H), 7.01, 8.21 (AA9BB9, each 2H, J = 8.8, 26Ar-2H), 7.24 (d, J = 6.9, 1H, 7-H),
8.42 (d, J = 6.9, 1H, 5-H)
9g
147–149
2.69 (s, 3H, 8-CH3 ), 4.30 (t, 2H, –OCH2CH2–), 4.40 (t, 2H, –OCH2CH2–), 6.90
(t, 1H, 6-H), 8.28, 7.00 (AA9BB9, each 2H, 26Ar-2H), 7.10 (d, 2H, imidazole
49-H, 59-H), 7.26 (d, 1H, 7-H), 7.64 (s, 1H, imidazole 29-H), 8.45 (d, 1H, 5-H)
13C-NMR (100.6 MHz, CDCl3): d 163.24 (C=N, triazole), 159.33 (C–O, Bn),
152.15 (C=N, triazole), 129.23 (3 CH, pyridine), 128.04, 126.79, 125.74,
124.73, 113.25 (arom C or CH), 114.56 (4 CH, Bn), 67.19 (CH2–O), 46.39
(CH2–N), 14.02 (CH3).
9h
9i
154–156
210–212
146–148
85
97
96
C17H14N6O
C22H19N5OS
C21H18N6O
2.69 (s, 3H, 8-CH3 ), 4.42 (t, 2H, –OCH2CH2–), 4.63 (t, 2H, –OCH2CH2–), 6.90
(t, 1H, 6-H), 8.27, 6.99 (AA9BB9, each 2H, 26Ar-2H), 7.26 (d, 1H, 7-H), 7.99 (s,
1H, triazole 39-H), 8.22 (s, 1H, triazole 59-H), 8.45 (d, 1H, 5-H)
2.82 (s, 3H, 8-CH3 ), 3.72 (t, 2H, –OCH2CH2–), 4.38 (t, 2H, –OCH2CH2–), 7.16
(t, 1H, 6-H), 8.12, 7.20 (AA9BB9, each 2H, 26Ar-2H), 7.25 (m, 3H, Ar-H), 7.29
(d, 1H, 7-H), 7.40 (m, 1H, Ar-H), 8.74 (d, 1H, 5-H)
9j
2.88 (s, 3H, 8-CH3 ), 4.06 (t, 2H, –OCH2CH2–), 4.32 (t, 2H, –OCH2CH2–), 6.86
(t, 1H, 6-H), 8.29, 7.08 (AA9BB9, each 2H, 26Ar-2H), 7.32 (d, 1H, 7-H), 7.47 (t,
1H, Ar-H), 7.66 (t, 1H, Ar-H), 7.81 (d, 1H, Ar-H), 8.14 (d, 1H, Ar-H), 8.34 (d,
1H, 5-H)
9k
9l
149–151
106–108
151–153
82
80
76
C20H21N5O
C19H20N6O
C28H24N6O2
1.80 (m, 2H, –OCH2CH2CH2CH2–), 2.04 (m, 2H, –OCH2CH2CH2CH2–), 2.84 (s,
3H, 5-CH3), 4.06 (m, 4H, –OCH2CH2CH2CH2–), 6.83 (d, 1H, 6-H), 6.97 (m, 3H,
Ar-2H, imidazole 59-H), 7.09 (s, 1H, imidazole 29-H), 7.41 (t, 1H, 7-H), 7.53
(s,1H, imidazole 49-H), 7.63 (d, 1H, 8-H), 8.27 (d, 2H, Ar-2H)
1.83 (m, 2H, –OCH2CH2CH2CH2–), 2.14 (m, 2H, –OCH2CH2CH2CH2–), 2.88 (s,
3H, 5-CH3), 4.06 (t, 2H, –OCH2CH2CH2CH2–), 4.29 (t, 2H, –OCH2CH2CH2CH2–
), 6.81 (d, 1H, 6-H), 8.25, 6.99 (AA9BB9, each 2H, 26Ar-2H), 7.41 (t, 1H, 7-H),
7.61 (d, 1H, 8-H), 7.96 (s, 1H, triazole 39-H), 8.11 (s, 1H, triazole 59-H)
9m
2.07 (s, 6H, 268-CH3 ), 4.52 (t, 2H, –OCH2CH2–), 4.84 (t, 2H, –OCH2CH2–),
6.91 (t, 2H, 266-H), 7.60 (m, 2H, 267H), 8.28, 7.12 (AA9BB9, each 4H,
46Ar-2H), 8.45 (d, 2H, 265-H)
ing details of these structures, we can not yet reveal the azolo[1,5-a]pyridine structure has growth inhibitory
dependency of the activity of the studied molecules on activities against tested fungi, especially against C. albi-
their structures. This result suggested that the 1,2,4-tri- cans, worthy of further investigation.
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Arch. Pharm. Chem. Life Sci. 2006, 339, 262–266
Synthesis of Novel Antifungal Triazole Derivatives
265
Table 2. Antifungal activities of 2-aryl-1,2,4-triazolo[1,5-a]pyri-
dines 9a-m.
ture was stirred at room temperature for one hour, then ethyl
ether was added to obtain the white precipitation. The product 5
was filtered and recrystallized by ethanol-acetic ether. Yield of
two steps: 80%; m.p.: 121–1238C.
Compound
C. albicans 7374
T. rubrum 6180
MIC50 [mg/mL]
MIC50 [mg/mL]
Synthesis of 2-(4-benzyloxy-phenyl)-5-
methyl[1,2,4]triazolo[1,5-a]pyridine 6a
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
32
>256
128
256
128
32
128
>256
256
>256
256
A solution of 5a [7] (2.46 g, 8 mmol) and 4-benzyloxybenzonitrile
(2.10 g, 10 mmol) in ethanol (15 mL) was cooled in ice-water,
then 2N KOH (4.2 mL) was added drop-wise. After being raised to
room temperature, the mixture was stirred for further 24 h and
then concentrated under pressure to remove ethanol. The resid-
ual liquid was extracted with CHCl3. The CHCl3 layer was dried
over anhydrous Na2SO4 and evaporated to dryness. The residue
was purified by column chromatography to afford compound
6a. Yield: 33.5%; MS (m/z): 315 [M+]; IR (KBr): 1640, 1615, 1540,
1240.
128
64
>256
>256
>256
256
256
256
128
256
32
64
64
9m
128
32
4
256
256
64
Fluconazole
Amphotericin B
2-(4-Benzyloxy-phenyl)-8-methyl[1,2,4]triazolo[1,5-
a]pyridine 6b
Compound 6b was prepared by the procedure described above.
Yield: 39.9%; MS (m/z): 315 [M+].
We gratefully acknowledge Professor Yan Jie and Mrs. Ruan
Pin for performing antifungal tests.
Synthesis of 4-(5-methyl[1,2,4]triazolo[1,5-a]pyridine-2-
yl)phenol 7a
Experimental
To a solution of 6a (2.8 g) in DMF (150 mL), 10% Pd-C (0.28 g) was
added. The product was obtained by hydrogenolysis reaction.
Yield: 90%; MS (m/z): 225 [M+]; IR (KBr): 3450, 1620, 1595, 1500.
Materials
Most chemicals were purchased from Acros Organics Company
(J & K chemical LTD, Shanghai, P. R. China). Melting points were
determined by BUCHI Melting Point B-450 (Bꢀchi Labortechnik,
Flawil, Switzerland). 1H-NMR spectra were recorded in CDCl3 on
Bruker Avance DMX 400 using TMS as an internal standard (Bru-
ker, Billerica, MA, USA). The IR spectra were recorded in potas-
sium bromide on Bruker Victor 20. Mass spectral data were
obtained by electron ionization on GC-HP-5989 spectrometer
(Hewlett Packard, Palo Alto, CA, USA).
4-(5-Methyl[1,2,4]triazolo[1,5-a]pyridine-2-yl)phenol 7b
Compound 7b was prepared by the procedure described above.
Yield: 91%; MS (m/z): 225 [M+].
Synthesis of 2-[2-bromoethoxyl)phenyl]-5-
methyl[1,2,4]triazolo[1,5-a]pyridine 8a
A solution of 7a (1.50 g, 6 mmol), 1,2-dibromoethane (33.8 g,
180 mmol), NaOH (2.4 g, 60 mmol) in 3.6 mL water and tetrabu-
tylammonium iodide (0.2 g) was refluxed for 5 h, then cooled to
room temperature. The solution was extracted with CH2Cl2. The
CH2Cl2 layer was washed with water and dried over anhydrous
Na2SO4, then evaporated to dryness. The residue was purified by
column chromatography to afford compound 8a. Yield: 85.8%;
MS (m/z): 331 ([M+]:332).
Preparation of compounds 1–5
Ethyl N-mesityloxysulfinyloxyacetimidate 3
A solution of mesityl sulfochloridite 1 (5.0 g, 48 mL) and triethy-
lamine (6.75 mL) in DMF (15 mL) was cooled to –58C. Ethyl N-
hydroxyacetimidate 2 (10.6 g, 48.5 mmol) was added followed
by triethylamine (0.5 mL). The mixture was stirred at room tem-
perature for 0.5 h and then poured into ice-water. The white pre-
cipitation was filtered and washed with ice-water. Yield 70.1%;
m.p.: 56–588C.
2-[4-(2-Bromoethoxyl)pheny]-8-methyl[1,2,4]triazolo[1,5-
a]pyridine 8b and 2-[4-(4-bromo-butoxyl)pheny]-8-
methyl[1,2,4]triazolo[1,5-a]pyridine 8c
Compounds 8b and 8c were prepared by the procedure
described above. 8b: Yield: 87.9%; MS (m/z): 331([M+:332]). 8c:
Yield: 58.6%; MS (m/z): 359 [M+].
Mesityl aminooxy sulfinate 4
To a solution of 3 (7.3 g, 26 mmol) in 1.4-dioxane (5.6 mL), 70%
HClO4 (3.4 mL) was added drop-wise at –58C. After stirring for
20 min, the solution was poured into ice-water. The white preci-
pitation was filtered and washed until neutral. The product 4
was used for the next step immediately.
2-[4-(2-(Morpholin-4-yl)ethoxy)phenyl]-5-
methyl[1,2,4]triazolo[1,5-a]pyridine 9a
A mixture of 8a (0.25 g, 0.75 mmol) and morpholine (0.66 mL,
7.5 mmol) was dissolved in CHCl3 (50 mL), stirred at room tem-
perature for 6 h, then concentrated under pressure to remove
CHCl3. The residual liquid was extracted with CHCl3. The CHCl3
layer was washed with water, dried over anhydrous Na2SO4 and
1-Amino-methylpyridinium mesityl sulfite 5
The above mentioned product was extracted with dichloro-
methane. The dichloromethane layer was added directly to a
solution of methylpyridine in dichloromethane (6 mL). The mix-
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Arch. Pharm. Chem. Life Sci. 2006, 339, 262–266
evaporated to dryness. The residue was purified by column chro-
matography to afford compound 9a.
Compounds 9d, 9f, 9i were prepared by the procedure
described above.
fold manner in the medium (SD broth). The final concentration
of antifungal agents was between 0.25 and 256 lg/mL. The
inoculated sizes contained 26108 CFU/mL. MIC values were read
after 7 days at 288C.
Synthesis of 2-[4-(2-(imidazol-1-yl)ethoxy)phenyl]-5-
methyl[1,2,4]triazolo[1,5-a]pyridine 9b
References
To a well-stirred suspension of 60% NaH (0.67 g, 16.7 mmol) in
dry DMF (5 mL), imidazole (0.68 g, 10 mmol) was added slowly.
The resulting mixture was stirred for 20 min and then allowed
to rise to 50 8C. A solution of 8a (1.33 g, 4 mmol) in THF (20 mL)
was added drop-wise for 3–5 h. After the reaction was com-
pleted, ice-water was added. The mixture was extracted with
CHCl3. The CHCl3 layer was dried over anhydrous Na2SO4 and eva-
porated to dryness. The residue was purified by column chroma-
tography to afford compound 9b.
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