Green aqueous synthesis and antimicrobial evaluation of 3,5-disubstituted 1,2,4-triazoles

Article abstract of DOI:10.1007/s10593-020-02684-7

[Figure not available: see fulltext.] An eco-friendly and simple procedure was proposed for the synthesis of 3,5-disubstituted 1,2,4-triazoles by optimized reaction of benzamidine hydrochloride and various aryl hydrazides. H₂O and K₂

Full text of DOI:10.1007/s10593-020-02684-7

DOI 10.1007/s10593-020-02684-7
Chemistry of Heterocyclic Compounds 2020, 56(4), 482–487
Green aqueous synthesis and antimicrobial evaluation
of 3,5-disubstituted 1,2,4-triazoles
Hamid Beyzaei1*, Farideh Malekraisi1, Reza Aryan1, Behzad Ghasemi2
1 Department of Chemistry, Faculty of Science, University of Zabol,
Zabol 9861335856, Iran; e-mail: hbeyzaei@yahoo.com, hbeyzaei@uoz.ac.ir
2 Torbat Jam Faculty of Medical Sciences,
Torbat Jam 9571786917, Iran; e-mail: behzad.ghasemi99@gmail.com
Submitted January 15, 2020
Accepted after revision March 12, 2020
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(4), 482–487
An eco-friendly and simple procedure was proposed for the synthesis of 3,5-disubstituted 1,2,4-triazoles by optimized reaction of benz-
amidine hydrochloride and various aryl hydrazides. H2O and K2CO3 were applied as green and available solvent and base, respectively.
The products were generated in good to high yields in one step and sufficient purity after a simple workup. The designed process is
applicable to other organic syntheses especially from poorly water-soluble reactants such as hydrazines or hydrazides. Inhibitory activity
of all prepared derivatives was evaluated against 10 pathogenic bacteria strains including both Gram-positive and Gram-negative, as well
as 2 mold and 1 yeast strains. The prepared derivatives showed good antimicrobial activities. 1,2,4-Triazoles containing 2-hydroxynaphthalen-3-yl
and 5-chlorothiophen-2-yl substituents at position 3 showed the best antifungal and antibacterial properties, respectively.
Keywords: hydrazide, 1,2,4-triazole, antibacterial activity, antifungal activity, aqueous media, green synthesis.
1,2,4-Triazole ring forms an important structural motif
of natural products, pharmaceuticals, and biologically
active molecules (Fig. 1). Essramycin is a naturally occurring
antibiotic extracted from marine Streptomyces sp., isolate
Merv8102.1 Sitagliptin decreases level of glucagon, and is
prescribed to treat type 2 diabetes mellitus.2 Rizatriptan is a
selective serotonin receptor agonist having antimigrainous
effects.3 Maraviroc is used for the treatment of patients
infected with CCR5-tropic HIV-1 virus.4
1,2,4-Triazole antifungals as an important class of
medications affect a variety of pathogenic molds and
yeasts.5 Fluconazole, a popular antifungal drug, is a
selective agonist of CYP51 (an essential enzyme in
synthesizing fungal cell wall and lanosterol to ergosterol
convertor).6 Many publications have reported anti-
inflammatory,7,8 antinociceptive,7 analgesic,8 antioxidant,9
antiurease,9 antiacetylcholinesterase,9 anticancer,10,11 and
antimicrobial11 capacities of substituted or fused 1,2,4-
triazole derivatives. Excellent inhibitory activities were
observed with some 4-(benzylideneamino)-5-phenyl-4H-
O
N
CF3
N
O
H
N
N
F
F
N
N
N
N
Me
Essramycin
O
NH2
F
N
N
N
Sitagliptin
F
N
F
N
OH
N
F
F
Fluconazole
Me
HN
O
Me
N
Me
Me
N
N
N
N
N
N
N
H
Me
Maraviroc
Rizatriptan
Figure 1. Examples of 1,2,4-triazole ring-containing drugs
available on market.
0009-3122/20/56(4)-0482©2020 Springer Science+Business Media, LLC
482

Chemistry of Heterocyclic Compounds 2020, 56(4), 482–487
1,2,4-triazole-3-thiol Schiff bases against Microsporum
develop reactions in aqueous media.32 Although there have
been many advances in the design of environmentally
friendly organic solvents, water is still the best option. It is
a safe, available, inexpensive, and eco-friendly liquid that
can dissolve a variety of polar compounds and organic and
inorganic salts. Chemical kinetics and reaction mechanisms
can be affected by the presence of water as solvent. The
insolubility of many nonpolar or less polar compounds and
high-mass molecules in water leads to its limited
application. The solubility of compounds in aqueous
solutions can be improved via increasing the temperature,
the use of multisolvent systems, addition of surfactants,
and changing the pH.
To prove the utility of heterocyclic synthesis in aqueous
media and search for potent antimicrobial agents, a series
of 3-substituted 5-phenyl-1H-1,2,4-triazoles were synthe-
sized in good to excellent yields via cyclocondensation of
benzamidine hydrochloride and aryl hydrazides in basic
aqueous medium. The reaction proceeded efficiently in the
presence of K2CO3 as a green base. In vitro inhibitory
activity of the prepared 1,2,4-triazoles was studied against
some important fungal and bacterial pathogens.
gypseum and Staphylococcus aureus.12 Some of them
exhibited acceptable antifungal effects on Candida albicans
and Aspergillus niger, while were ineffective against
Escherichia coli. Good antimicrobial properties of three
fluconazol analogs, either alone or in binary mixtures, were
demonstrated against Trichoderma viride, Gloeophyllum
trabeum, Coriolus versicolor, and Aspergillus niger.13 In
addition, hybridization of 1,2,4-triazole derivatives with
various antibiotics reduces the toxicity and improves the
therapeutic effects, especially against drug-resistant bacteria.14
To inhibit the growth of bacteria, 1,2,4-triazoles can disrupt
nucleic acids, proteins, cell membrane and cell wall synthesis.15
The importance of molecules containing 1,2,4-triazole
moiety, especially in the field of medicinal chemistry, has
stimulated development of their synthesis methods.
Pellizzari and Einhorn–Brunner reactions are usual proce-
dures to prepare 1,2,4-triazole derivatives; they include
interaction of hydrazides with amides and hydrazines with
diacylamines, respectively.16,17 These valuable heterocycles
were also synthesized by cyclization of hydrazinecarb-
oximidamide,18 copper-catalyzed reaction of amidoximes
with nitriles,19 treatment of hydrazides with isothiocyanates
or carbon disulfide and hydrazine,20,21 interaction of carbo-
xylic acids with hydrazinophthalazine,22 electrochemical
four-component reaction of aryl hydrazines, paraform-
aldehyde, ammonium acetate, and alcohols,23 1,3-dipolar
cycloaddition of oximes with hydrazonoyl hydrochloride,24
and nickel-catalyzed cyclocondensation of hydrazides with
N-cyanobenzamide.25
3-Substituted 5-phenyl-1H-1,2,4-triazoles 3a–k were
prepared by reaction of aryl or heteroaryl hydrazides 1a–k
and benzamidine hydrochloride (2) under relatively mild
conditions (Scheme 1). H2O and K2CO3 were selected as
green solvent and base, respectively, due to low cost,
availability, and non-toxicity.33,34
Scheme 1. Green synthesis of 1,2,4-triazoles 3a–k
in aqueous media
Arylamidines are highly efficient reagents to synthesize
1,2,4-triazole derivatives. They dimerize or react with
imidates in basic solutions under catalytic oxidation to generate
symmetric or asymmetric 1,2,4-triazoles, respectively.26
Their interaction with nitriles in the presence of various
oxidants affords 1,2,4-triazoles in good yields.27 However,
substituted 1,2,4-triazoles can be also produced via direct
condensation of nitriles with hydrazides in n-BuOH under
microwave irradiation at 150°C.28 Amidrazones are useful
intermediates or starting materials for the preparation of
1,2,4-triazoles. The reaction of neutralized acetamidine hydro-
chloride with hydrazides in EtOH at room temperature
affords acetyl amidrazones; 1,2,4-triazoles are obtained
thereof under subsequent thermal cyclization in xylene.29
1,2,4-Triazoles were also directly synthesized via heating
of ethanolic solution containing benzamidine hydro-
chloride, hydrazides, and sodium methoxide.29 In addition,
amidrazones can be produced via reaction of arylamidines
or corresponding imidic esters with hydrazides in ethanolic
NaOEt or in PhH containing catalytic amounts of Et3N
under relatively mild conditions, and converted to
3,5-disubstituted 1,2,4-triazoles at higher temperatures.30,31
In our new procedure described below, some new and
known 1,2,4-triazole derivatives were eco-friendly prepared by
reaction of aqueous solutions containing benzamidine
hydrochloride, aryl hydrazides, and K2CO3.
The reaction conditions were optimized in terms of
presence or absence of base, the type of base, and tempera-
ture. Interaction of 1.0 mmol of benzhydrazide (1a) with an
equimolar amount of benzamidine hydrochloride (2) in 2 ml
H2O was studied under different conditions. The volume of
H2O was chosen as the minimum required to dissolve the
reactants, including hydrazide 1a. The reaction mixture
must be heated to at least 50°C to improve the hydrazide
solubility and the progress of reaction. The reaction did not
occur in the absence of a base even at higher temperature.
The reaction did not progress in the presence of different
amounts (1.0, 1.5, and 2.0 mmol) of KOH at temperatures
up to 100°C. No product was obtained in the presence of
1 mmol of K2CO3 at 50°C. The reaction progress was
checked at 60°C when 1–2.5 mmol of K2CO3 was used as
base (Table 1, entries 1–4). The lowest reaction time and
the highest product yield were obtained in the presence of
Environmental problems due to the use of most organic
solvents make it necessary to find green alternatives. One
of the main purposes of green chemistry is to design and
483

Chemistry of Heterocyclic Compounds 2020, 56(4), 482–487
Scheme 2. A possible mechanism for the formation of 1,2,4-triazoles 3a–k in the presence of K2CO3
solubility of reactants, especially hydrazides, increases
Table 1. Optimization of reaction conditions in the synthesis
of 3,5-diphenyl-1H-1,2,4-triazole (3a)*
nucleophilicity of hydrazides through formation of strong
hydrogen bonds, facilitates NH3 removal process to form
intermediate amidrazones A, as well as elimination of H2O
during the intramolecular cyclocondensation.
Amount of K2CO3,
Entry
Temperature, °C Time, h
Yield, %
mmol
1
2
3
4
5
6
1.0
1.5
2.0
2.5
2.0
2.0
60
60
67
58
48
48
48
48
71
76
86
80
84
83
Finally, 1,2,4-triazole derivatives 3a–k were prepared
under the optimized conditions (twofold excess of K2CO3,
60°C) (Scheme 1). 1,2,4-Triazoles 3b,j,k have not been
described before. The chemical structure of all synthesized
60
60
1
80
products was characterized and confirmed by FT-IR, H and
1
13C NMR spectroscopies and elemental analysis. In H NMR
100
spectra at ambient temperature, signals of NH groups of
triazole rings appeared as singlets or broad singlets at 9.45–
14.23 ppm. In 13C NMR spectra, two signals were detected
in the range 155.3–164.9 ppm attributed to the C-3 and C-5
carbon atoms of triazole rings 3b–k. In IR spectra, the NH
stretching vibrations were observed at ~3400 cm–1.
In vitro antimicrobial properties of all synthesized 1,2,4-
triazoles were studied against some important pathogenic
fungi and Gram-positive and Gram-negative bacteria, as
shown in Tables 2 and 3. The results were compared to the
data for the antibiotic ampicillin and the antifungal drug
clotrimazole.
* For all entries, benzhydrazide (1a) (1.0 mmol), benzamidine hydro-
chloride (2) (1.0 mmol), H2O (2 ml).
2 mmol of K2CO3 at 60°C (entry 3). Increasing the
temperature did not improve the yields (entries 5, 6).
1,2,4-Triazole 3a was not produced in the presence of
only OH– ions. Aqueous solutions of K2CO3 also contain
–
–
other anions such as CO3 and HCO3 . It seems that they
play a key role in the reaction as a buffering system, as
shown in Scheme 2. An excess of K2CO3 is required for pH
regulation along the progress of the reaction. K2CO3 as a
base neutralizes benzamidine hydrochloride, improves the
Table 2. Antibacterial activity of 1,2,4-triazoles 3a–k expressed as minimum inhibitory concentration (MIC), in μg·ml–1,
and minimum bactericidal concentration (MBC), in μg·ml–1
Test compound
Reference
Ampicillin
Bacteria
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
256
256
256
1024
2048
2048
1024
1024
256
1024
2048
1024
2048
1024
2048
32
64
64
64
–*
–
16
64
–
–
–
–
1024
2048
–
–
32
2048
2048
2048
2048
256
1024
2048
2048
1024
2048
512
1024
16
32
128
512
256
256
1024
1024
2048
2048
–
128
512
–
256
1024
64
1024
2048
1024
2048
2048
2048
2048
2048
256
1024
1024
2048
2048
2048
1024
1024
256
2048
2048
1024
2048
256
256
1024
16
64
32
32
–
–
1024
1024
512
512
–
0.063
0.063
8
8
8
8
4
4
0.031
0.063
16
32
0.25
4
1
2
2
2
Pseudomonas aeruginosa
Salmonella enterica
subsp. enterica
–
64
2048
2048
2048
2048
1024
1024
–
–
–
–
16
256
1024
256
1024
1024
2048
32
Escherichia coli
256
–
2048
2048
64
1024
2048
1024
2048
–
Klebsiella pneumoniae
Shigella dysenteriae
Acinetobacter baumannii
Bacillus cereus
–
1024
1024
512
512
64
256
512
–
1024
256
64
256
256
16
2048
2048
256
1024
256
256
512
512
256
1024
1024
1024
1024
1024
1024
1024
256
32
–
–
1024
2048
256
1024
256
1024
512
512
128
256
512
1024
512
512
64
2048
2048
512
512
512
512
–
64
64
64
64
512
1024
128
128
1024
1024
2048
2048
2048
2048
32
Staphylococcus epidermidis
Listeria monocytogenes
Streptococcus pyogenes
256
256
512
1024
1024
64
1024
1024
1024
2048
256
512
1024
1024
1024
1024
1024
2
2
1024
32
256
64
–
* – No noticeable antibacterial effect at concentration 2048 μg·ml–1.
484

Chemistry of Heterocyclic Compounds 2020, 56(4), 482–487
Table 3. Antifungal activity of 1,2,4-triazoles 3a–k expressed as minimum inhibitory concentration (MIC), in μg·ml–1,
and minimum fungicidal concentration (MFC), in μg·ml–1
Test compound
Reference
Fungi
Clotrimazole
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
MIC
MFC
MIC
MFC
MIC
MFC
256
1024
2048
2048
16
512
512
64
64
512
512
1024
2048
16
64
–*
–
–
–
–
–
–
16
32
32
32
16
32
128
128
16
512
512
2048
2048
128
1024
1024
512
512
32
–
–
–
–
–
–
1024
2048
32
64
512
512
32
32
256
512
256
512
Aspergillus fumigatus
Fusarium oxysporum
Candida albicans
256
1024
1024
2048
256
1024
1024
2048
64
–
32
512
64
* – No noticeable antibacterial effect at concentration of 2048 μg·ml–1.
According to the results presented in Table 2, products
3a,b,d,g,h,i were effective against all tested bacteria. All
synthesized triazoles could inhibit the growth of Gram-
negative Shigella dysenteriae and Gram-positive Staphylo-
coccus epidermidis and Listeria monocytogenes. The best
antibacterial activities were observed for triazole 3j
containing 3-(5-chlorothiophen-2-yl) and 5-phenyl substi-
tuents, however, it was completely ineffective against the
studied fungi. 1,2,4-Triazole 3j was the only chlorine-
containing compound among the prepared derivatives.
All fungal strains were inhibited by compounds
3a,b,g,h,i,k (Table 3). 3-(5-Phenyl-1H-1,2,4-triazol-3-yl)-
naphthalen-2-ol (3g) was recorded as possessing the
highest antifungal potency. As expected from literature
data,5 compounds 3a–k were more successful in blocking
fungal than bacterial strains.
In this study, a new modified procedure was proposed
for the preparation of 3,5-disubstituted 1,2,4-triazoles. The
use of green, easy available and inexpensive solvent and
base, simple workup and purification, and acceptable yields
are the advantages of the designed method. The efficiency
of this eco-friendly system can be evaluated in other
heterocyclic synthesis from starting materials, such as
hydrazines or hydrazides. Inhibitory potentials of synthe-
sized products were proved against a broad spectrum of
bacterial and fungal pathogens. Chlorinated aryls or
sulfurated heterocycles at positions 3 and 5 of the triazole
ring may improve antimicrobial effects.
Synthesis of 1,2,4-triazoles 3a–k (General method).
A suspension of aryl hydrazide 1a–k (1.0 mmol), benz-
amidine hydrochloride (2) (0.157 g, 1.0 mmol), and K2CO3
(0.276 g, 2.0 mmol) in double-distilled H2O (2 ml,
conductivity 1.76 µS·cm–1) was vigorously stirred at 60°C
for 18–48 h. The progress of the reaction was monitored by
TLC. The reaction mixture was cooled in an ice bath and
subsequently neutralized with 1.0 M HCl solution. The
precipitate was filtered off, washed with cold H2O (5 ml)
and EtOH (5 ml), and dried in an oven to afford 1,2,4-
triazoles 3a–k without the need for additional purification.
3,5-Diphenyl-1H-1,2,4-triazole (3a). Reaction time 48 h.
Yield 190 mg (86%), mp 188–190°C (mp 190–192°C35).
1
IR spectrum, ν, cm–1: 3414 (NH), 1617 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 7.41–7.50 (6H, m, H-3,4,5 Ph);
8.07 (4H, d, J = 6.8, H-2,6 Ph); 14.23 (1H, s, NH).
13C NMR spectrum, δ, ppm: 126.3; 129.2; 129.5; 130.5;
159.1. Found, %: C 76.03; H 4.99; N 18.98. C14H11N3.
Calculated, %: C 76.00; H 5.01; N 18.99.
4-(5-Phenyl-1H-1,2,4-triazol-3-yl)phenol (3b). Reaction
time 45 h. Yield 216 mg (91%), mp 265–267°C. IR spectrum,
1
ν, cm–1: 3418 (NH), 3342 (OH), 1620 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 6.87 (2H, d, J = 8.1, H-3,5 Ar);
7.44–7.48 (3H, m, H-3,4,5 Ph); 7.87 (2H, d, J = 8.1, H-2,6 Ar);
8.04 (2H, d, J = 6.2, H-2,6 Ph); 10.16 (1H, br. s, OH);
14.13 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 116.0;
126.3; 128.1; 128.6; 129.2; 129.6; 130.0; 159.3; 164.9;
160.8. Found, %: C 70.85; H 4.66; N 17.75. C14H11N3O.
Calculated, %: C 70.87; H 4.67; N 17.71.
3-(4-tert-Butylphenyl)-5-phenyl-1H-1,2,4-triazole (3c).36
Reaction time 41 h. Yield 269 mg (97%), mp 177–179°C.
Experimental
FT-IR spectra were recorded on a Bruker Tensor-27
1
1
FT-IR spectrometer in thin layer. H and 13C NMR spectra
IR spectrum, ν, cm–1: 3414 (NH), 1644 (C=N). H NMR
were recorded on a Bruker FT-NMR Ultra Shield-400 spectro-
spectrum, δ, ppm (J, Hz): 1.28 (9H, s, 3CH3); 7.40–7.50 (5H,
m, H-3,5 Ar, H-3,4,5 Ph); 8.06 (2H, d, J = 8.1, H-2,6 Ar); 8.14
(2H, d, J = 7.0, H-2,6 Ph); 14.13 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 31.4; 34.8; 125.9; 126.3; 126.4; 129.1;
129.5; 130.6; 131.6; 152.3; 158.5; 159.2. Found, %:
C 77.90; H 6.93; N 15.17. C18H19N3. Calculated, %: C 77.95;
H 6.90; N 15.15.
meter (400 and 100 MHz, respectively) using DMSO-d6
1
residual solvent peak as internal standard (for H nuclei
δ 2.48 ppm, for 13C nuclei δ 39.9 ppm). Elemental analyses
for C, H, N, and S atoms were performed on a Termo
Finnigan Flash EA microanalyzer. Melting points are uncor-
rected and were determined using a Kruss-type KSP1N
melting point apparatus. The progress of the reactions was
monitored by aluminum TLC plates precoated with silica
gel with fluorescent indicator F254, different mixtures of
MeOH and CH2Cl2 were used as the mobile phase.
All solvents and reagents were commercially purchased
from Sigma-Aldrich and Merck and used without further
purification.
3-(4-Nitrophenyl)-5-phenyl-1H-1,2,4-triazole (3d).
Reaction time 18 h. Yield 253 mg (95%), mp 248–250°C
(mp 246–247°C27). IR spectrum, ν, cm–1: 3415 (NH), 1621
1
(C=N), 1551 (N–O). H NMR spectrum, δ, ppm (J, Hz):
7.43–7.46 (3H, m, H-3,4,5 Ph); 7.85 (2H, d, J = 7.7, H-2,6 Ph);
8.30–8.09 (4H, m, H Ar); 14.06 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 124.5; 126.4; 127.2; 129.3; 130.6; 133.7;
485

Chemistry of Heterocyclic Compounds 2020, 56(4), 482–487
138.5; 147.2; 159.3; 162.2. Found, %: C 63.19; H 3.79;
262°C. IR spectrum, ν, cm–1: 3416 (NH), 1635 (C=N), 823
(C–S–C). 1H NMR spectrum, δ, ppm: 7.16 (1H, s,
H-4 Het); 7.47–7.50 (4H, m, H-3 Het, H-3,4,5 Ph); 8.02
(2H, d, J = 6.2, H-2,6 Ph); 14.15 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm (J, Hz): 125.8; 126.5; 127.1; 128.3; 128.5;
129.4; 130.3; 132.5; 155.3; 157.5. Found, %: C 55.08;
H 3.10; N 16.03; S 12.21. C12H8ClN3S. Calculated, %:
C 55.07; H 3.08; N 16.06; S 12.25.
N 21.02. C14H10N4O2. Calculated, %: C 63.15; H 3.79;
N 21.04.
3-(3-Methoxyphenyl)-5-phenyl-1H-1,2,4-triazole (3e).
Reaction time 18 h. Yield 231 mg (92%), mp 184–186°C
(mp 178–180°C35). IR spectrum, ν, cm–1: 3419 (NH), 1623
1
(C=N). H NMR spectrum, δ, ppm (J, Hz): 3.81 (3H, s,
CH3); 7.01 (1H, d, J = 7.7, H-4 Ar); 7.38–7.49 (4H, m, H-2 Ar,
H-3,4,5 Ph); 7.66–7.71 (2H, m, H-5,6 Ar); 8.11 (2H, d,
J = 6.8, H-2,6 Ph); 9.85 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 55.5; 111.5; 115.7; 118.8; 126.4; 129.2;
129.8; 130.0; 130.4; 131.2; 158.6; 158.9; 160.0. Found, %:
C 71.73; H 5.19; N 16.68. C15H13N3O. Calculated, %:
C 71.70; H 5.21; N 16.72.
4-Methyl-5-(5-phenyl-1H-1,2,4-triazol-3-yl)-1,2,3-thia-
diazole (3k). Reaction time 46 h. Yield 231 mg (95%),
mp 258–259°C. IR spectrum, ν, cm–1: 3418 (NH), 1621
1
(C=N). H NMR spectrum, δ, ppm (J, Hz): 2.96 (3H, s, CH3);
7.50–7.52 (3H, m, H-3,4,5 Ph); 7.97–8.00 (2H, m, H-2,6
Ph); 14.17 (1H, br. s, NH). 13C NMR spectrum, δ, ppm:
14.1; 126.7; 129.5; 131.1; 141.1; 153.9; 156.4; 156.6; 162.1.
Found, %: C 54.35; H 3.70; N 28.80; S 13.15. C11H9N5S.
Calculated, %: C 54.31; H 3.73; N 28.79; S 13.17.
3-(3-Bromophenyl)-5-phenyl-1H-1,2,4-triazole (3f).37
Reaction time 40 h. Yield 255 mg (85%), mp 210–212°C.
1
IR spectrum, ν, cm–1: 3417 (NH), 1643 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 7.45–7.50 (5H, m, H-2,5 Ar,
3,4,5 Ph); 7.62 (1H, d, J = 7.3, H-4 Ar); 8.06 (2H, d,
J = 6.7, H-2,6 Ph); 8.22 (1H, s, H-6 Ar); 10.64 (1H, br. s,
NH). 13C NMR spectrum, δ, ppm: 122.5 125.3; 126.5;
128.8; 129.4; 130.3; 131.5; 132.0; 132.5; 133.1; 158.3;
158.7. Found, %: C 56.04; H 3.35; N 13.97. C14H10BrN3.
Calculated, %: C 56.02; H 3.36; N 14.00.
Biological evaluation. Mueller–Hinton broth, Mueller–
Hinton agar, RPMI 1640 medium (Roswell Park Memorial
Institute 1640) buffered to pH 7.0 with morpholine propane
sulfonic acid, ampicillin, and clotrimazole were obtained
from HiMedia and Sigma-Aldrich companies. Appropriate
concentration of microbial suspensions was prepared with a
Jenway 6405 UV/Vis spectrophotometer. Gram-positive
bacterial strains including Streptococcus pyogenes (PTCC
1447), Staphylococcus epidermidis (PTCC 1435), Listeria
monocytogenes (PTCC 1297), Bacillus cereus (PTCC 1665),
Gram-negative bacterial strains including Pseudomonas
aeruginosa (PTCC 1310), Salmonella enterica subsp.
enterica (PTCC 1709), Shigella dysenteriae (PTCC 1188),
Klebsiella pneumoniae (PTCC 1290), Acinetobacter
baumannii (PTCC 1855), Escherichia coli (PTCC 1399),
molds including Aspergillus fumigatus (PTCC 5009) and
Fusarium oxysporum (PTCC 5115) and yeast Candida
albicans (PTCC 5027) were obtained from the Persian
Type Culture Collection (PTCC), Karaj, Iran. Anti-
microbial susceptibility tests were performed according to
published procedures.40 The reported results are taken as
the mean of three independent experiments.
3-(5-Phenyl-1H-1,2,4-triazol-3-yl)naphthalen-2-ol (3g).
Reaction time 38 h. Yield 270 mg (94%), mp 247–249°C
(mp 244–246°C38). IR spectrum, ν, cm–1: 3414 (NH), 3339
1
(OH), 1622 (C=N). H NMR spectrum, δ, ppm (J, Hz):
7.03–7.10 (2H, m, H-6,7 Ar); 7.24–7.30 (1H, m, H-1 Ar);
7.44–7.48 (3H, m, H-3,4,5 Ph); 7.50–7.54 (2H, m,
H-5,8 Ar); 7.71 (1H, d, J = 8.0, H-4 Ar); 7.88–7.90 (2H, m,
H-2,6 Ph); 8.51 (1H, s, OH); 14.10 (1H, br. s, NH).
13C NMR spectrum, δ, ppm: 110.9; 121.3; 123.1; 125.2;
125.4; 127.0; 127.1; 128.7; 128.9; 129.7; 130.4; 133.7;
136.8; 151.4; 161.6; 165.1. Found, %: C 75.24; H 4.60;
N 14.61. C18H13N3O. Calculated, %: C 75.25; H 4.56;
N 14.63.
4-(5-Phenyl-1H-1,2,4-triazol-3-yl)pyridine (3h). Reaction
time 28 h. Yield 189 mg (85%), mp 242–243°C (mp 241–
242°C32). IR spectrum, ν, cm–1: 3418 (NH), 1619 (C=N).
1H NMR spectrum, δ, ppm (J, Hz): 7.48–7.54 (3H, m,
H-3,4,5 Ph); 7.70 (2H, d, J = 4.7, H-3,5 Py); 7.99 (2H, d,
J = 4.7, H-2,6 Py); 8.07 (2H, d, J = 7.3, H-2,6 Ph); 14.08
(1H, br. s, NH). 13C NMR spectrum, δ, ppm: 120.5; 126.6;
128.2; 129.4; 130.6; 137.6; 150.8; 157.6; 158.5. Found, %:
C 70.21; H 4.53; N 25.26. C13H10N4. Calculated, %:
C 70.25; H 4.54; N 25.21.
This study was funded by the University of Zabol (grant
No. UOZ-GR-9618-10).
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