Synthesis, antibacterial, and antifungal activities of imidazo[2,1-c][1,2, 4]triazoles and 1,2,4-triazolo[4,3-a]pyrimidinones

Article abstract of DOI:10.1080/00397911.2013.804576

A straightforward method has been developed for the synthesis of 1-phenyl-imidazo [2,1-c][1,2,4]triazole derivatives 5a-j and 1-phenyl-[1,2,4]triazolo[4,3-a]pyrimidinones derivatives 6a-g starting from 5-amino-1-phenyl[1,2,4]triazole and p-toluenesulfonic acid (PTSA). This methodology affords a number of 1-phenyl-imidazo [2,1-c][1,2,4]triazoles 5a-j and 1-phenyl-[1,2,4]triazolo[4,3-a]pyrimidinones 6a-g in reasonable yields and short reaction times. The structures of all new compounds were elucidated using infrared, ¹H and ¹³C NMR, and high-resolution mass spectrometry. Some of the newly synthesized compounds were screened for their antimicrobial activity. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.804576

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Synthesis, Antibacterial, and
Antifungal Activities of Imidazo[2,1-c]
[1,2,4]triazoles and 1,2,4-Triazolo[4,3-
a]pyrimidinones
Monia Aouali a , Fatma Allouche a , Imen Zouari b , Dhekra Mhalla b ,
Mohamed Trigui b & Fakher Chabchoub a
a Laboratoire de Chimie Appliquée: Hétérocycles, Corps Gras et
Polymères , Faculté des Sciences de Sfax, Université de Sfax , Sfax ,
Tunisia
b Biopesticides Team (LPIP) , Center of Biotechnology of Sfax,
University of Sfax , Sfax , Tunisia
Published online: 20 Feb 2014.
To cite this article: Monia Aouali , Fatma Allouche , Imen Zouari , Dhekra Mhalla , Mohamed Trigui
& Fakher Chabchoub (2014) Synthesis, Antibacterial, and Antifungal Activities of Imidazo[2,1-
c][1,2,4]triazoles and 1,2,4-Triazolo[4,3-a]pyrimidinones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:6, 748-756, DOI:
10.1080/00397911.2013.804576
To link to this article: http://dx.doi.org/10.1080/00397911.2013.804576
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Synthetic Communications1, 44: 748–756, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.804576
SYNTHESIS, ANTIBACTERIAL, AND ANTIFUNGAL
ACTIVITIES OF IMIDAZO[2,1-c][1,2,4]TRIAZOLES
AND 1,2,4-TRIAZOLO[4,3-a]PYRIMIDINONES
Monia Aouali,1 Fatma Allouche,1 Imen Zouari,2
Dhekra Mhalla,2 Mohamed Trigui,2 and Fakher Chabchoub1
1
´
´ ´
`
Laboratoire de Chimie Appliquee: Heterocycles, Corps Gras et Polymeres,
´
´
Faculte des Sciences de Sfax, Universite de Sfax, Sfax, Tunisia
2Biopesticides Team (LPIP), Center of Biotechnology of Sfax,
University of Sfax, Sfax, Tunisia
GRAPHICAL ABSTRACT
Abstract A straightforward method has been developed for the synthesis of 1-phenyl-imidazo
[2,1-c][1,2,4]triazole derivatives 5a–j and 1-phenyl-[1,2,4]triazolo[4,3-a]pyrimidinones
derivatives 6a–g starting from 5-amino-1-phenyl[1,2,4]triazole and p-toluenesulfonic acid
(PTSA). This methodology affords a number of 1-phenyl-imidazo [2,1-c][1,2,4]triazoles
Received April 7, 2013.
Address correspondence to Fatma Allouche, Laboratoire de Chimie Appliquee: Heterocycles,
´ ´ ´
Corps Gras et Polymeres, Faculte des Sciences de Sfax, Universite de Sfax, 3018 Sfax, Tunisia. E-mail:
`
fatma.mallek_allouch@yahoo.fr
´
´
748

TRIAZOLOPYRIMIDINE
749
5a–j and 1-phenyl-[1,2,4]triazolo[4,3-a]pyrimidinones 6a–g in reasonable yields and short
reaction times. The structures of all new compounds were elucidated using infrared, 1H and
13C NMR, and high-resolution mass spectrometry. Some of the newly synthesized
compounds were screened for their antimicrobial activity.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords 5-Amino-1-phenyl[1,2,4]triazole; antimicrobial activity; imidazo[2,1-c][1,2,4]-
triazole; triazolo[4,3-a] pyrimidinones
INTRODUCTION
There exist a number of [1,2,4]triazoles having a wide range of pharmacological
activities, some of them are applied in medicine: alprazolam (tranquilizer), estazolam
(hypnotic, sedative, tranquilizer), rilmazafon (hypnotic, anxiolytic, used in the case
of neurotic insomnia), benatradin (diuretic), trapidil (hypotensive), trazodon (antide-
pressant, anxiolytic), etoperidone (antidepressant), nefazodone (antidepressant,
5-HT2A antagonist), anastrozole, letrozole, vorozole (antineoplastics, nonsteroidal
competitive aromatase inhibitors), ribavirin (the potent antiviral N-nucleoside), flu-
conazole, itraconazole, and terconazole (the powerful azole antifungal agents).[1] It
follows from the literature survey that, depending on the type of substituent, the
derivatives of [1,2,4]triazole have a high potential for biological activity, possessing
a wide range of antimicrobial[2] and antitumor[3] properties. The other ones show
anti-inflammatory,[4] antihypertensive,[5] anticonvulsant and antiviral,[6] and anal-
gesic[7] activities. Previous studies by Sztanke et al.[8] concerning bridgehead nitro-
gen–heterocyclic compounds obtained by fusion of the 1-hydroimidazole and
[1,2,4]triazole nuclei have identified compounds containing a group at position 3
and aryl substituent at position 7 with significant antibacterial activity. This hetero-
bicycle was strongly active against Staphylococcus aureus ATCC 25923, with a mini-
mum inhibition concentration (MIC) value of 31.7 mM and showed superior
antibacterial activity to ampicillin.[8a] On the other hand, some derivatives having
the same heterocyclic skeleton are bioactive molecules[9] and imidazo-fused hetero-
cycles, revealing promising anticancer activities.[10] It seemed worthwhile to synthe-
size some novel biheterocyclic derivatives containing the imidazotriazole and
triazolopyrimidine nuclei as possible compounds of high biological potency. In a
second study, bridgehead nitrogen–heterocyclic compounds obtained by fusion of
the 1,5-dihydro pyrimidine and [1,2,4]triazole lead to 1,2,4-triazolo[4,3-a]pyrimidine
carboxylate derivatives. The synthesis and biological activities of these compounds
have been interesting topics in the fields of medicinal and agricultural chemistry
for many years.[11] Some triazolopyrimidine derivatives are known as cardiovascular
vasodilators,[11a] dual thrombin=factor Xa inhibitors[11b], and human adenosine A2a
and A3 receptor ligands.[11c,d]
The present work describes an interesting approach to substituted imidazotria-
zoles and triazolopyrimidinones derivatives having antifungal and antibacterial
activities. In particular, we were interested in the synthesis of para-toluenesulfonic
acid (PTSA)–catalyzed 1-phenyl-imidazo[2,1-c][1,2,4] triazoles 5 and 1-phenyl[1,2,4]
triazolo[4,3-a] pyrimidinones 6 from easily accessible 5-amino-1-phenyl[1,2,4]triazole.

750
M. AOUALI ET AL.
Table 1. Yields of the compounds according to the catalyst
Catalyst
R1
R2
Yield (%)
Compound
PTSA
CH3COOH
Sc(OTf)3
CH3
CH3
CH3
H
H
H
83
63
72
5a
5a
5a
RESULTS AND DISCUSSION
Chemistry
The 5-amino-1-phenyl [1,2,4] triazoles derivatives 1a–c were synthesized
according to the literature.[12]
The general synthetic procedure employed for 1-phenyl-imidazo[2,1-
c][1,2,4]triazole 5 involves the reaction of appropriate 5-amino-1-phenyl[1,2,4]tria-
zole 1 with a-bromocetophenone 2 in the presence of a catalytic amount of PTSA
(5 mol%) in refluxing ethanol. 1-Phenyl imidazo[2,1-c][1,2,4]triazole derivatives 5
were isolated as stable compounds in good yields. Three amino triazoles and differ-
ent para-substituted bromoacetophenones have been tested successfully (Table 1).
We show the different imidazo[2,1-c][1,2,4]triazole derivatives 5 obtained by
the condensation. We examined this reaction with a variety of Brønsted acid
(CH3CO2H) and Lewis acids (PTSA and Sc(OTf)3). The reactions were run by mix-
ing 5-amino-1-phenyl[1,2,4]triazole 1 and a-bromacetophenone 2 in an appropriate
solvent, adding the acid catalyst, and monitoring the reaction progress by thin-layer
chromatography (TLC). To our delight, in all the cases studied, the anticipated pro-
duct 5a was formed. While substantial formation of this product was achieved using
a catalytic amount of acid, PTSA was found to be superior in terms of both the
purity of the product mixtures and the isolated yield.
We tried to prove the mechanism of the reaction by carrying out the reaction
using a Dean–Stark apparatus and we found water. This proves that the reaction
occurs when a primary amino group intercepts a bromine atom, liberating HBr,
followed by intracyclization and elimination of a water molecule to give 1-phenyl-
imidazo[2,1-c][1,2,4]triazole 5a–j. Bromoacetophenone proved to be more efficient,
for example, in the synthesis of 5a and 5h, the yields were 83% and 71%, respectively,
for using methyl and benzyl amino triazole, and for the other imidazotriazoles
synthesized from 3-benzyl-5-amino[1,2,4] triazole the yields are lower. From these
results, we conclude that the electronic nature of the substituent on the bromoaceto-
phenone has a significant role on the reaction outcome. The correct identity of com-
1
pound as imidazo[2,1-c][1,2,4]triazole was confirmed by H NMR, 13C NMR, and
high-resolution mass spectrometry (HRMS).(Scheme 1, Table 2).
As starting materials we use 5-amino-1-phenyl[1,2,4]triazole derivatives 1a–c.
First, it was subjected to condensation with dimethyl or diethyl acetylene dicarbox-
ylate 3, in the presence of a catalytic amount of PTSA (5 mol%). The mixture was
refluxed overnight in ethanol to produce 1,2,4-triazolo[4,3-a]pyrimidines carboxy-
lates 6a–d, obtained after chromatographic purification. The structure and yields
of the products formed are independent of the nature of the substituent at aminotria-
zole. Triazolo[4,3-a]pyrimidines carboxylate 6a–d were isolated in 62 to 67% yield.

TRIAZOLOPYRIMIDINE
751
Scheme 1.
The reaction mechanism has been explicitly discussed when studying the conden-
sation of imidazolecarboxamides and dithioesters with diethyl acetylene dicarboxy-
late.[13] Second, it is known that the synthesis of triazolopyrimidines is generally
performed by condensation of amino triazoles with b-keto esters in glacial acetic acid
under reflux.[14] Therefore, we investigated the reaction of 5-amino-1-phenyl[1,2,4]-
triazole derivatives 1 with ethyl-2-chloro-3-oxobutanoate 4 in the presence of a cata-
lytic amount of PTSA (5 mol%) to probe the possibility of synthesis of biheterocyclic
compounds.
The spectroscopic analysis revealed that compounds 6e–g, isolated from the
reaction, were formed when initially heating compounds 1 and 4 to reflux in xylene.
Upon further heating, the enaminoester intermediate gradually disappeared. These
latter compounds are usually not isolatable because of rapid cyclization into
[1,2,4]triazolo[4,3-a]pyrimidin-5-ones 6e–g. Following isolation and recrystallization
from ethanol, 6e–g are obtained in 65% yield (Scheme 2, Table 3).
Table 2. Synthesis of 1-phenyl-imidazo[2,1-c][1,2,4]triazoles 5a–j recrystallized from ethanol
Compounds
R1
R2
Yield (%)
Mp (ꢀC)
5a
5b
5c
5d
5e
5f
CH3
CH3
H
83
63
57
70
62
65
60
71
53
53
170
179
177
170
206
210
226
206
208
205
4-CH3
4-Cl
CH3
CH3
4-OCH3
4-CH3
4-Cl
C2H5
C2H5
C2H5
5g
5h
5i
4-OCH3
H
C6H5-CH2
C6H5-CH2
C6H5-CH2
4-CH3
4-OCH3
5j

752
M. AOUALI ET AL.
Scheme 2.
Antimicrobial Activity
The in vitro antimicrobial activity was qualitatively assessed by the determi-
nation of the inhibition zone diameters. The antibacterial and antifungal potency
of the compounds under similar conditions were compared with gentamicin and
amphotericin B, which served as positive controls for bacteria and fungi, respect-
ively. Among the tested compounds, 5d showed a wide range of antimicrobial
activity against Gram-positive and Gram-negative bacteria and fungi (Table 4). Nine
out of the 11 tested strains were inhibited by 5d. It inhibit the growth of clinically
important Gram-negative bacteria such as E. coli and food spoilage bacteria such
as Salmonella enterica (food isolate) and the Gram-positive bacteria L. monocyto-
genes (food isolate) with inhibition zones of 14, 11, and 14 mm, respectively. The
compound 5 h showed a high antibacterial activity against the Gram-positive bac-
teria S. aureus with an inhibition zone of 22 mm, slightly less than the inhibition zone
of gentamicin (25 mm). However, 5a, 5b, 4c, and 5j failed to show any antibacterial
activity at the tested concentration. The Gram-positive bacteria were more suscep-
tible to the antimicrobial properties of synthesized compounds than Gram-negative
ones. These differences could be attributed in part to the great complexity of the
double membrane-containing cell envelope in Gram-negative bacteria compared to
the single membrane structure of positive ones.[15] The strong antibacterial activity
Table 3. Synthesis of 1-phenyl-[1,2,4] triazolo[4,3-a] pyrimidinones 6a–g
Compounds
R1
R3
Yield (%)
Mp (ꢀC)
6a
6b
6c
6d
6e
6f
CH3
C2H5
C2H5
CH3
CH3
C2H5
CH3
—
67
66
62
65
66
65
62
180
139
149
178
160
159
164
C6H5-CH2
CH3
C6H5-CH2
C2H5
—
—
6g

TRIAZOLOPYRIMIDINE
753
Table 4. Antibacterial and antifungal activities of 5c, d, h and reference drugs against fungi and food-
borne and spoiling bacteria using the agar well diffusion method
Inhibition zone diameter (mm)a
Strain
5c
5d
5h
Reference compound
Bacterial strains
Gram positive
Gentamicinb
Bacillus cereus ATCC 14579
Staphylococcus aureus ATCC 25923
Enterococcus faecalis ATCC 29212
Listeria monocytogenes (food isolate 2132)
Gram negative
0
0
0
0
11
12
11
14
7
22
0
20
25
12
15
11
Salmonella enterica (food isolate)
Escherichia coli ATCC 25922
Fungal strains
0
0
11
14
0
0
18
21
Amphotericin Bc
Aspergillus niger CTM 10099
Fusarium oxysporum CTM10402
Botrytis cinerea CTM10410
Pythiumsp LPAP032
0
11
0
0
11
11
0
0
0
0
0
0
15
14
12.5
Nt
14
0
Alternaria alternata CTM 10230
0
8
aDiameter of inhibition zones of synthesized compounds including diameter of well, 6 mm.
bThe used concentation of gentamicin was 10 mg=well.
cThe used concentation of amphotericin B was 20 mg=well.
of the synthesized compound 5d indicated that methoxy-substituent might mediate
greater potency than methyl or chloride substituents against bacteria. These results
indicate that moderate lipophilicity is needed to exert antibacterial activity and to
disrupt the permeability barrier of cell membrane[16]
.
Contamination by fungal strains such as Fusarium oxysporum and Botrytis
cinerea and their respective mycotoxins is considered as a challenge for agriculture
and food industries. As with the antibacterial activity, we evaluated antifungal
activity by means of inhibition zone diameters compared to the positive control,
amphotericin B. Among the tested synthesized compounds, 5d exhibited antifungal
activity with inhibition zone of 11 mm against F. oxysporum and B. cinerea. The
compound 5c showed activity against only F. oxysporum. These results suggest that,
as in the case of antibacterial activity, the methoxy-substituent at the 4-position
influences strongly both the antifungal spectrum and degree of activity.
CONCLUSION
In conclusion we designed a simple synthesis of substituted new 1-phenyl-
imidazo[2,1-c][1,2,4]triazoles 5a–j and 1-phenyl-[1,2,4]triazolo[4,3-a] pyrimidinones
6a–g in good yields. The synthesized compounds were tested for their antibacterial
and antifungal activities. Results showed that the compound 5d exhibited strong
antibacterial and moderate antifungal activities. Taking into account the significant
antibacterial and antifungal activities of the presented compounds, the research in
this field will be continued.

754
M. AOUALI ET AL.
EXPERIMENTAL
Melting points were measured on an Electrothermal apparatus. Progress of the
reactions was monitored with thin-layer chromatography (TLC) using aluminium
sheets with silica gel 60 F254 from Merck. Spectra infrared (IR) were recorded on
a Perkin-Elmer Paragon FT-IR spectrometer covering field 400–4000 cmÀ1. The
spectra of 1H NMR and 13C NMR were recorded in solution in CDCl3 or in
dimethylsulfoxide (DMSO-d6) on a Bruker spectrometer (1H at 400 MHz, 13C at
100 MHz). The chemical shifts are expressed in parts per million (ppm) using
tetramethylsilane (TMS) as internal reference. The multiplicities of the signals are
indicated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quad-
ruplet; and m, multiplet, and coupling constants are expressed in hertz.
5-Amino-1-phenyl[1,2,4]triazole 1a–c were prepared from the corresponding
cyanamide and phenyle hydrazonates according to the literature[12] by gently
refluxing in methanol.
a-Bromoacetophenone 2, dimethyl acetylenedicarboxylate 3, ethyl-2-chloro-3-
oxobutanoate 4, PTSA, Sc(OTf)3, CH3COOH, and solvents used in this work were
obtained from Aldrich and Fluka and were used without further purification.
General Procedure for the Synthesis of Substituted Imidazo
[2,1-c][1,2,4]triazoles 5a–j
p-TsOH Á H2O (5 mol%) was added to a mixture of 5-amino-1-phenyl[1,2,4]
triazole 1 (1 mmol)[12] and a-bromacetophenone 2 (1 mmol) in 3 mL of ethanol. It
was refluxed for 12 h. After completion of the reaction, as indicated by TLC
(EtOAc–hexane, 90:10), the precipitated solid was separated by filtration, washed
with ethanol, and crystallized from a suitable solvent to obtain the pure product.
General Procedure for the Synthesis of Substituted [1,2,4]Triazolo
[4,3-a]pyrimidine Carboxylate 6a–d
p-TsOH Á H2O (5 mol %) was added to a mixture of 5-amino[1,2,4]triazole 1
(1 mmol) and dimethyl or diethyl acethylenedicarboxylate 3 (1 mmol) in 3 mL of
ethanol. It was refluxed for 12 h. After completion of the reaction, as indicated by
TLC (EtOAc–hexane, 90:10), the deposited solid was filtered, washed with ether,
and recrystallized from an appropriate organic solvent to give the triazolo[4,3-a]pyr-
imidine carboxylate derivatives.
General Procedure for the Synthesis of Substituted [1,2,4]Triazolo
[4,3-a]pyrimidinones 6e–g
PTSA (5 mol %) was added to a mixture of 5-amino[1,2,4] triazole 1 (1 mmol)
and ethyl-2-chloro-3-oxobutanoate 4, (1 mmol) in 3 mL of xylene and refluxed for
12 h. After completion of the reaction, as indicated by TLC (EtOAc–hexane,
90:10), The deposited solid was filtered, washed with ether, and recrystallized from
an appropriate organic solvent to give the triazolo[4,3-a]pyrimidinones derivatives
6e–g.

TRIAZOLOPYRIMIDINE
755
Antimicrobial Test
Six bacterial and five fungal strains were used in this study. The tested patho-
genic bacteria were Bacillus cereus ATCC 14579, Staphylococcus aureus ATCC
25923, Enterococcus faecalis ATCC 29212, Listeria monocytogenes (food isolate
2132), Esherichia coli ATCC 25922, and Salmonella enterica (food isolate 824).
The tested fungi were Aspergillus niger CTM 10099, Fusarium oxysporum
CTM10402, Botrytis cinerea CTM10410, Pythium sp. LPAP032, and Alternaria
alternata CTM 10230. The bacterial strains were cultivated in Muller–Hinton agar
(MH) (Oxoid Ltd, UK) at 37 ꢀC except for Bacillus species, which were incubated
at 30 ꢀC. The fungi were cultured on potato dextrose agar medium (PDA) and incu-
bated at 28 ꢀC. Working cultures were prepared by inoculating a loopful of each
tested bacteria in 3 ml of MH and were incubated at 37 ꢀC for 12 h. For the test, final
inoculum concentration of 107 CFU=ml of bacteria was used. Fungal spore suspen-
sions were collected from the surface of such fungal colonies by gently scraping with
a loop and suspended in 10 ml potato dextrose broth (PDB). Each suspension was
mixed vigorously by vortexing for 15–20 min. The spore suspension stock was
diluted to obtain a concentration of 106 spores=ml (measured by Thoma blade).
Antibacterial and antifungal tests were performed using agar well diffusion
method as described by Guven et al.[17] One hundred ml of freshly prepared cell sus-
¨
pension adjusted to 107 CFU=ml for bacteria and 106 spores=ml for fungi were
inoculated onto the surface of agar plates. Thereafter, wells with 6 mm in diameter
were punched in the inoculated agar medium with sterile Pasteur pipettes and the
molecules were added to each well. Negative control consisted of DMSO, which
was used to dissolve the compounds. Gentamicin (10 mg=wells) was used as positive
control for bacteria while amphotericin B (20 mg=well) was used as positive control
for fungal strains. The plate was allowed to stand for 2 h at 4 ꢀC to permit the dif-
fusion of the molecule followed by incubation at 37 ꢀC for 24 h for bacterial strains
and 72 h for fungi at 28 ꢀC. The antimicrobial activity was evaluated by measuring
the inhibition zones (clear zone around the well) against the tested microorganisms.
All tests were repeated three times.
SUPPLEMENTARY DATA
Supplementary data (experimental details, characterization data, and copies of
1H and 13C NMR) associated with this article can be found in the online version.
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