Microwave-assisted synthesis and antifungal activity of some new 1H-1,2,4-triazole derivatives

Article abstract of DOI:10.1134/S1070428008120178

A number of 3-aryl-4-arylmethylideneamino-4,5-dihydro-1H-1,2,4-triazol-5- ones were synthesized by reaction of the corresponding aromatic aldehydes with 4-amino-3-aryl-1H-1,2,4-triazol-5-ones in anhydrous ethanol under microwave irradiation. The newly synthesized 1H-1,2,4-triazole derivatives were tested for antimicrobial activity. They showed no antibacterial activity but slight mycostatic activity against some Candida species.

Full text of DOI:10.1134/S1070428008120178

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1816–1820. © Pleiades Publishing, Ltd., 2008.
Published in Russian in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 12, pp. 1843–1847.
Microwave-Assisted Synthesis and Antifungal Activity
of Some New 1H-1,2,4-Triazole Derivatives*
B. Kahvecia, M. Özila, E. Menteşea, O. Bekircanb, and K. Burukc
a Chemistry Department, Faculty of Arts and Sciences, Rize University, Rize, 53050 Turkey
e-mail: bahittin@yahoo.com
b Chemistry Department, Faculty of Arts and Sciences, Giresun University, Giresun, Turkey
c Department of Microbiology and Clinical Microbiology, Faculty of Medicine, Karadeniz Technical University,
Trabzon, 61080 Turkey
Received April 28, 2007
Abstract—A number of 3-aryl-4-arylmethylideneamino-4,5-dihydro-1H-1,2,4-triazol-5-ones were synthesized
by reaction of the corresponding aromatic aldehydes with 4-amino-3-aryl-1H-1,2,4-triazol-5-ones in anhydrous
ethanol under microwave irradiation. The newly synthesized 1H-1,2,4-triazole derivatives were tested for anti-
microbial activity. They showed no antibacterial activity but slight mycostatic activity against some Candida
species.
DOI: 10.1134/S1070428008120178
The use of microwave energy to enhance organic
reactions has recently attracted chemists’ attention [1].
Microwave-assisted syntheses ensure higher reaction
rates, improved yields, and easy experimental manip-
ulations [2–4]. Therefore, interest in microwave-
assisted organic syntheses has grown tremendously
[5–10]. Since 2001, the number of publications related
to microwave-assisted organic synthesis (MAOS) has
increased to such a level that it might be assumed that
in a few years most chemists will probably use micro-
wave energy to perform chemical reactions on a labo-
ratory scale.
producibility. Many academic and industrial research
groups are already using MAOS as a technology for
rapid reaction optimization, for efficient synthesis of
new chemical products, and for discovering and prob-
ing new chemical reactivity [11–14].
1,2,4-Triazole derivatives are interesting com-
pounds due to their application and biological activity,
including antibacterial, antifungal, and tuberculostatic
action [15–22].
In the present paper we describe the reaction of
3-aryl-4-amino-4,5-dihydro-1H-1,2,4-triazole-5-ones
II [23] with aromatic aldehydes under microwave irra-
diation, which leads to the formation of the corre-
sponding 3-aryl-4-arylmethylideneamino-4,5-dihydro-
1H-1,2,4-triazol-5-ones III (Scheme 1). The reactions
It is known that microwave irradiation not only
considerably reduces reaction times but also minimizes
side processes, increases the yields, and improves re-
Scheme 1.
N
NH
N
NH
R
H
ArCHO, EtOH, MW
N
OEt
+
N2H4 ·H2O
R
O
R
O
N
N
N
EtO
N
–2EtOH
NH2
IIa–IId
O
CHAr
Ia–Id
IIIa–IIIp
I, II, R = 2-ClC6H4CH2 (a), 3-ClC6H4CH2 (b), 2-MeC6H4CH2 (c), 3-MeC6H4CH2 (d); III, R = 2-ClC6H4CH2, Ar = Ph (a),
4-MeC6H4 (b), 4-t-BuC6H4 (c), 4-ClC6H4 (d), 3-BrC6H4 (e), 3,4-(MeO)2C6H3 (f), 3,4,5-(MeO)3C6H2 (g); R = 3-ClC6H4CH2, Ar =
Ph (h), 4-MeC6H4 (i), 4-t-BuC6H4 (j), 4-ClC6H4 (k), 3-BrC6H4 (l), 3,4-(MeO)2C6H3 (m), 3,4,5-(MeO)3C6H2 (n); R = 2-MeC6H4CH2,
Ar = Ph (o); R = 3-MeC6H4CH2, Ar = Ph (p).
* The text was submitted by the authors in English.
1816

MICROWAVE-ASSISTED SYNTHESIS AND ANTIFUNGAL ACTIVITY
1817
were carried out using anhydrous ethanol as solvent.
The reaction time was as short as 5 min, and the prod-
ucts (compounds IIIa–IIIp) were isolated in up to
96% yield. The product structure was confirmed by the
IR and 1H NMR spectra and elemental analyses.
by the agar well diffusion method and minimal inhibi-
tory concentrations determined by the broth microdilu-
tion technique are collected in table.
EXPERIMENTAL
Newly synthesized compounds IIIa–IIIp were test-
ed for antimicrobial activity against the following bac-
terial strains: Escherichia coli ATCC 25922, Pseudo-
monas aeruginosa ATCC 27 853, Staphylococcus
aureus ATCC 25923, and Bacillus subtilis ATCC
6633; in addition, their activity against four yeast
strains, Candida albicans ATCC 60 193, Candida
parapsilosis ATCC 22 019, Candida kefyr ATCC
46 764, and Candida glabrata ATCC 66 032, was
examined.
The melting points were determined in open capil-
laries on an oil-heated Büchi melting point apparatus
and are uncorrected. The IR spectra were recorded in
KBr pellets on a Perkin–Elmer 1600 FTIR spectro-
1
photometer. The H and 13C NMR spectra were meas-
ured on a Varian 200 spectrometer using DMSO-d6 as
solvent and TMS as internal standard. The elemental
compositions were determined on a Carlo Erba 1106
CHN analyzer; the experimental values were in agree-
ment (±0.4%) with the calculated ones. Initial aromatic
aldehydes were commercial products (Aldrich).
No antibacterial activity of 1,2,4-triazole deriva-
tives IIIa–IIIp toward the above bacterial strains was
found, while all these compounds showed antifungal
activity in yeasts of the Candida family (see table).
Inhibition of yeast growth on Sabouraud dextrose agar
plates indicated that compounds IIIa–IIIp exhibit
mycostatic activity (the corresponding data are not
given here). The inhibition zone diameters determined
4-Arylmethylideneamino-3-(R-benzyl)-4,5-dihy-
dro-1H-1,2,4-triazol-5-ones IIIa–IIIp (general pro-
cedure). A solution of 0.01 mol of aminotriazole IIa–
IId and 0.01 mol of the corresponding aromatic alde-
hyde in 10 ml of anhydrous ethanol was irradiated for
5 min in a microwave oven at a power of 350 W. The
Antimicrobial activity of compounds IIIa–IIIpa
Candida albicans
Candida glabrata
Candida parapsilosis
Candida kefyr
Compound no.
ZD
12
12
13
13
11
11
MIC
0.250
0.250
0.250
0.250
0.250
0.500
ZD
09
10
10
09
09
08
MIC
0.500
0.250
0.250
0.250
0.250
0.500
ZD
13
13
13
13
11
12
MIC
0.250
0.250
0.125
0.125
0.250
0.250
ZD
MIC
0.125
0.125
0.125
0.125
0.250
0.250
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
13
13
13
14
12
12
IIIg
13
10
12
11
13
12
11
13
12
12
18
0.125
0.500
0.250
0.500
0.250
0.500
0.500
0.250
0.125
0.125
0.250
09
08
09
08
10
09
08
09
10
10
16
0.125
0.500
0.250
0.500
0.250
0.500
0.500
0.250
0.250
0.250
1.000
13
10
12
12
14
11
12
13
12
12
20
0.125
0.250
0.250
0.250
0.125
0.250
0.250
0.125
0.125
0.125
0.250
14
12
13
12
14
12
12
14
12
13
22
0.125
0.250
0.125
0.250
0.125
0.125
0.250
0.125
0.125
0.125
0.125
IIIh
IIIi
IIIj
IIIk
IIIl
IIIm
IIIn
IIIo
IIIp
Fluconazole
a
ZD stands for zone diameter (mm), and MIC, for minimal inhibitory concentration (mg/ml).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

KAHVECI et al.
1818
solid material thus obtained was recrystallized from
appropriate solvent.
3-(2-Chlorobenzyl)-4-(3,4,5-trimethoxybenzyli-
deneamino)-4,5-dihydro-1H-1,2,4-triazol-5-one
(IIIg). Yield 80%, mp 196–197°C. IR spectrum, ν,
cm–1: 755, 1576, 1628, 1722, 3315. 1H NMR spectrum,
δ, ppm: 2.81 s (3H, CH3), 2.85 s (3H, CH3), 2.95 s
(3H, CH3), 3.99 s (2H, CH2), 6.76–7.76 m (6H, Harom),
9.97 s (1H, CH), 11.13 s (1H, NH). Found, %:
C 56.62; H 4.64; N 13.90. C19H19ClN4O4. Calculated,
%: C 56.65; H 4.75; N 13.91.
4-Benzylideneamino-3-(2-chlorobenzyl)-4,5-di-
hydro-1H-1,2,4-triazol-5-one (IIIa). Yield 29%,
mp 180–181°C. IR spectrum, ν, cm–1: 743, 1574–1586,
1
1707, 3367. H NMR spectrum, δ, ppm: 3.92 s (2H,
CH2), 7.04–7.73 m (9H, Harom), 10.01 s (1H, CH),
11.84 s (1H, NH). Found, %: C 61.34; H 4.10;
N 17.95. C16H13ClN4O. Calculated, %: C 61.44;
H 4.19; N 17.91.
4-Benzylideneamino-3-(3-chlorobenzyl)-4,5-di-
hydro-1H-1,2,4-triazol-5-one (IIIh). Yield: 30%,
mp 207–209°C. IR spectrum, ν, cm–1: 741, 1582, 1598,
3-(2-Chlorobenzyl)-4-(4-methylbenzylidene-
amino)-4,5-dihydro-1H-1,2,4-triazol-5-one (IIIb).
Yield: 86%, mp 204–205°C. IR spectrum, ν, cm–1:
1
1702, 3354. H NMR spectrum, δ, ppm: 3.87 s (2H,
1
CH2), 7.13–7.78 m (9H, Harom), 10.13 s (1H, CH),
11.42 s (1H, NH). Found, %: C 61.47; H 4.21;
N 17.89. C16H13ClN4O. Calculated, %: C 61.44;
H 4.19; N 17.91.
749, 820, 1548–1603, 1714, 3388. H NMR spectrum,
δ, ppm: 2.19 s (3H, CH3), 3.87 s (2H, CH2), 7.11–7.84 m
(8H, Harom), 10.15 s (1H, CH), 11.35 s (1H, NH).
Found, %: C 62.39; H 4.59; N 17.17. C17H15ClN4O.
Calculated, %: C 62.48; H 4.63; N 17.15.
3-(3-Chlorobenzyl)-4-(4-methylbenzylidene-
amino)-4,5-dihydro-1H-1,2,4-triazol-5-one (IIIi).
Yield 92%, mp 203–204°C. IR spectrum, ν, cm–1: 764,
4-(4-tert-Butylbenzylideneamino)-3-(2-chloro-
benzyl)-4,5-dihydro-1H-1,2,4-triazol-5-one (IIIc).
Yield 65%, mp 167–168°C. IR spectrum, ν, cm–1: 775,
1
855, 1533, 1622, 1714, 3353. H NMR spectrum, δ,
1
835, 1535, 1621, 1723, 3343. H NMR spectrum, δ,
ppm: 2.08 s (3H, CH3), 3.96 s (2H, CH2), 7.01–7.75 m
(8H, Harom), 10.09 s (1H, CH), 11.22 s (1H, NH).
Found, %: C 62.39; H 4.66; N 17.22. C17H15ClN4O.
Calculated, %: C 62.48; H 4.63; N 17.15.
ppm: 2.21 s (9H, CH3), 3.92 s (2H, CH2), 7.03–7.73 m
(8H, Harom), 9.95 s (1H, CH), 11.12 s (1H, NH). Found,
%: C 65.18; H 5.69; N 15.18. C20H21ClN4O. Calculat-
ed, %: C 65.12; H 5.74; N 15.19.
4-(4-tert-Butylbenzylideneamino)-3-(3-chloro-
benzyl)-4,5-dihydro-1H-1,2,4-triazol-5-one (IIIj).
Yield 54%, mp 167–168°C. IR spectrum, ν, cm–1: 738,
3-(2-Chlorobenzyl)-4-(4-chlorobenzylidene-
amino)-4,5-dihydro-1H-1,2,4-triazol-5-one (IIId).
Yield 69%, mp 210–211°C. IR spectrum, ν, cm–1: 744,
1
802, 1566, 1651, 1716, 3318. H NMR spectrum, δ,
1
821, 1589, 1624, 1697, 3374. H NMR spectrum, δ,
ppm: 2.33 s (9H, CH3), 3.87 s (2H, CH2), 7.05–7.76 m
(8H, Harom), 9.98 s (1H, CH), 11.10 s (1H, NH). Found,
%: C 65.06; H 5.70; N 15.14. C20H21ClN4O. Calculat-
ed, %: C 65.12; H 5.74; N 15.19.
ppm: 4.05 s (2H, CH2), 6.98–7.67 m (8H, Harom),
10.21 s (1H, CH), 11.43 s (1H, NH). Found, %:
C 55.25; H 3.46; N 16.22. C16H12Cl2N4O. Calculated,
%: C 55.35; H 3.48; N 16.14.
3-(3-Chlorobenzyl)-4-(4-chlorobenzylidene-
amino)-4,5-dihydro-1H-1,2,4-triazol-5-one (IIIk).
Yield: 37%, mp 147–148°C. IR spectrum, ν, cm–1:
4-(3-Bromobenzylideneamino)-3-(2-chloroben-
zyl)-4,5-dihydro-1H-1,2,4-triazol-5-one (IIIe). Yield
48%, mp 191–192°C. IR spectrum, ν, cm–1: 743, 766,
1
1
742, 821, 1516, 1593, 1711, 3309. H NMR spectrum,
1587, 1609, 1705, 3369. H NMR spectrum, δ, ppm:
δ, ppm: 3.88 s (2H, CH2), 6.99–7.75 m (8H, Harom),
10.19 s (1H, CH), 11.65 s (1H, NH). Found, %:
C 55.33; H 3.55; N 16.14. C16H12Cl2N4O. Calculated,
%: C 55.35; H 3.48; N 16.14.
4.22 s (2H, CH2), 7.20–7.88 m (8H, Harom), 9.15 s (1H,
CH), 11.02 s (1H, NH). Found, %: C 49.12; H 3.01;
N 14.29. C16H12BrClN4O. Calculated, %: C 49.07;
H 3.09; N 14.31.
4-(3-Bromobenzylideneamino)-3-(3-chloroben-
zyl)-4,5-dihydro-1H-1,2,4-triazol-5-one (IIIl). Yield
34%, mp 137–138°C. IR spectrum, ν, cm–1: 797, 819,
3-(2-Chlorobenzyl)-4-(3,4-dimethoxybenzyli-
deneamino)-4,5-dihydro-1H-1,2,4-triazol-5-one
(IIIf). Yield 96%, mp 247–248°C. IR spectrum, ν,
cm–1: 762, 1565, 1622, 1717, 3343. 1H NMR spectrum,
δ, ppm: 2.85 s (3H, CH3), 2.92 s (3H, CH3), 3.86 s
(2H, CH2), 6.80–7.45 m (7H, Harom), 10.09 s (1H, CH),
11.32 s (1H, NH). Found, %: C 57.98; H 4.67; N 14.94.
C18H17ClN4O3. Calculated, %: C 57.99; H 4.60; N 15.03.
1
1515, 1593, 1713, 3309. H NMR spectrum, δ, ppm:
4.10 s (2H, CH2), 7.03–7.76 m (8H, Harom), 10.03 s
(1H, CH), 11.20 s (1H, NH). Found, %: C 49.01;
H 3.13; N 14.34. C16H12BrClN4O. Calculated, %:
C 49.07; H 3.09; N 14.31.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

MICROWAVE-ASSISTED SYNTHESIS AND ANTIFUNGAL ACTIVITY
1819
3-(3-Chlorobenzyl)-4-(3,4-dimethoxybenzyli-
deneamino)-4,5-dihydro-1H-1,2,4-triazol-5-one
(IIIm). Yield 85%, mp 241–242°C. IR spectrum, ν,
cm–1: 765, 1562, 1625, 1708, 3323. 1H NMR spectrum,
δ, ppm: 2.84 s (3H, CH3), 2.90 s (3H, CH3), 3.91 s
(2H, CH2), 6.83–7.53 m (7H, Harom), 10.05 s (1H, CH),
11.24 s (1H, NH). Found, %: C 58.06; H 4.55;
N 15.09. C18H17ClN4O3. Calculated, %: C 57.99;
H 4.60; N 15.03.
Determination of minimal inhibitory concentra-
tion. Minimal inhibitory concentrations (MIC) were
determined by the broth microdilution method de-
scribed in [25]. Mueller-Hinton broth (MHB) for bac-
teria or YEPD broth (1% of yeast extract, 2% of
peptone, and 2% of dextrose) for yeasts, 100 μl, was
introduced into wells on microplates. A solution of
compound IIIa–IIIp (4 mg/ml), 100 μl, was intro-
duced into the first well of a row of plates and was
sequentially diluted. Microbial suspensions prepared in
MHB or YEPD broth at a concentration of about
1.5×106 organism/ml were added to each well to
attain final concentrations of compound IIIa–IIIp and
fluconazole of 1, 0.5, 0.25, 0.125, 0.062, 0.031, 0.016,
0.008, 0.004, 0.002, 0.001, and 0.0005 mg/ml. The
plates were incubated for 16–18 h at 37°C, and mini-
mal inhibitory concentrations were determined as the
lowest concentration of compound IIIa–IIIp at which
no visible growth was observed.
3-(3-Chlorobenzyl)-4-(3,4,5-trimethoxybenzyli-
deneamino)-4,5-dihydro-1H-1,2,4-triazol-5-one
(IIIn). Yield 79%, mp 195–196°C. IR spectrum, ν,
cm–1: 790, 1567, 1629, 1718, 3319. 1H NMR spectrum,
δ, ppm: 2.80 s (3H, CH3), 2.87 s (3H, CH3), 2.91 s
(3H, CH3), 4.04 s (2H, CH2), 6.76–7.71 m (6H, Harom),
10.07 s (1H, CH), 11.18 s (1H, NH). Found, %:
C 56.66; H 4.80; N 13.93. C19H19ClN4O4. Calculated,
%: C 56.65; H 4.75; N 13.91.
4-Benzylideneamino-3-(2-methylbenzyl)-4,5-
dihydro-1H-1,2,4-triazol-5-one (IIIo). Yield 96%,
mp 168–169°C. IR spectrum, ν, cm–1: 726, 1566, 1586,
Dimethyl sulfoxide was used as solvent, and
Ampicillin and Fluconazole, as controls. All tests were
repeated at least twice. The standard strains were ob-
tained from and the tests were performed at the Biotest
Laboratory, Department of Microbiology and Clinical
Microbiology, School of Medicine, Karadeniz Tech-
nical University (Turkey).
1
1708, 3171. H NMR spectrum, δ, ppm: 2.34 s (3H,
CH3), 4.04 s (2H, CH2), 7.10–7.80 m (9H, Harom),
9.70 s (1H, CH), 11.97 s (1H, NH). Found, %:
C 69.81; H 5.50; N 19.15. C17H16N4O. Calculated, %:
C 69.85; H 5.52; N 19.16.
The authors are grateful to Prof. M. Erturk, Director
of Biotest Laboratory, Medical School, Karadeniz
Technical University (Trabzon, Turkey) for technical
assistance.
4-Benzylideneamino-3-(3-methylbenzyl)-4,5-di-
hydro-1H-1,2,4-triazol-5-one (IIIp). Yield 83%,
mp 131–132°C. IR spectrum, ν, cm–1: 817, 1555, 1590,
1
1712, 3177. H NMR spectrum, δ, ppm: 2.25 s (3H,
CH3), 4.00 s (2H, CH2), 7.00–7.79 m (9H, Harom),
9.69 s (1H, CH), 11.87 s (1H, NH). Found, %:
C 69.86; H 5.59; N 19.16. C17H16N4O. Calculated, %:
C 69.85; H 5.52; N 19.16.
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