New vinyl-1,2,4-triazole derivatives as antimicrobial agents: Synthesis, biological evaluation and molecular docking studies

Article abstract of DOI:10.1016/j.bmcl.2020.127368

1,2,4-Triazole is a very important scaffold in medicinal chemistry due to the wide spectrum of biological activities and mainly antifungal activity of 1,2,4-triazole derivatives. The main mechanism of antifungal action of the latter is inhibition of 14-alpha-demethylase enzyme (CYP51). The current study presents synthesis and evaluation of eight triazole derivatives for their antimicrobial activity. Docking studies to elucidate the mechanism of action were also performed. The designed compounds were synthesized using classical methods of organic synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution method. All tested compounds showed good antibacterial activity with MIC and MBC values ranging from 0.0002 to 0.0069 mM. Compound 2 h appeared to be the most active among all tested with MIC at 0.0002–0.0033 mM and MBC at 0.0004–0.0033 mM followed by compounds 2f and 2g. The most sensitive bacterium appeared to be Xanthomonas campestris while Erwinia amylovora was the most resistant. The evaluation of antifungal activity revealed that all compounds showed good antifungal activity with MIC values ranging from 0.02 mM to 0.52 mM and MFC from 0.03 mM to 0.52 mM better than reference drugs ketoconazole (MIC and MFC values at 0.28–1.88 mM and 0.38 mM to 2.82 mM respectively) and bifonazole (MIC and MFC values at 0.32–0.64 mM and 0.64–0.81 mM). The best antifungal activity is displayed by compound 2 h with MIC at 0.02–0.04 mM and MFC at 0.03–0.06 mM while compound 2a showed the lowest activity. The results showed that these compounds could be lead compounds in search for new potent antimicrobial agents. Docking studies confirmed experimental results.

Full text of DOI:10.1016/j.bmcl.2020.127368

Journal Pre-proofs
New vinyl-1,2,4-triazole derivatives as antimicrobial agents: Synthesis, bio‐
logical evaluation and molecular docking studies
Eugenia Stingaci, Marina Zveaghinteva, Serghei Pogrebnoi, Lucian Lupascu,
Vladimir Valica, Livia Uncu, Anastasia Smetanscaia, Maricica Drumea, Anthi
Petrou, Ana Ciric, Jasmina Glamoclija, Marina Sokovic, Victor Kravtsov,
Athina Geronikaki, Fliur Macaev
PII:
S0960-894X(20)30479-0
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127368
BMCL 127368
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
22 May 2020
16 June 2020
23 June 2020
Please cite this article as: Stingaci, E., Zveaghinteva, M., Pogrebnoi, S., Lupascu, L., Valica, V., Uncu, L.,
Smetanscaia, A., Drumea, M., Petrou, A., Ciric, A., Glamoclija, J., Sokovic, M., Kravtsov, V., Geronikaki, A.,
Macaev, F., New vinyl-1,2,4-triazole derivatives as antimicrobial agents: Synthesis, biological evaluation and
molecular docking studies, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/
j.bmcl.2020.127368
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Graphical Abstract
New vinyl-1,2,4-triazole derivatives as antimicrobial
agents: Synthesis, biological evaluation and molecular
docking studies.
Eugenia Stingacia, Marina Zveaghintevaa, Serghei Pogrebnoia, Lucian Lupascua, Vladimir Valicab, Livia Uncub, Anastasia
Smetanscaiab, Maricica Drumeab, Anthi Petrouc, Ana Ciricd, Jasmina Glamoclijad, Marina Sokovicd, Victor Kravtsove, Athina
Geronikaki*c, Fliur Macaev*a,b
aLaboratory of Organic Synthesis and Biopharmaceuticals, Institute of Chemistry, Chisinau, 3 str. Academiei, Moldova;
bScientific Center for Drug Research, “Nicolae Testemitanu” State University of Medicine and Pharmacy, Chisinau, Moldova;
cDepartment of Pharmacy School of Health, Department of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, 54124,
Greece
dMycological Laboratory, Department of Plant Physiology, Institute for Biological Research, Siniša Stanković, University of
Belgrade, Bulevar Despota Stefana 142, 11000, Belgrade, Serbia.
eLaboratory of Physical Methods of Solid State Investigation ″Tadeusz Malinowski, Institute of Applied Physics, Chisinau, 5 str.
Academiei, Moldova;

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
New vinyl-1,2,4-triazole derivatives as antimicrobial agents: Synthesis, biological
evaluation and molecular docking studies.
Eugenia Stingacia, Marina Zveaghintevaa, Serghei Pogrebnoia, Lucian Lupascua, Vladimir Valicab, Livia Uncub,
Anastasia Smetanscaiab, Maricica Drumeab, Anthi Petrouc, Ana Ciricd, Jasmina Glamoclijad, Marina Sokovicd, Victor
Kravtsove, Athina Geronikaki*c, Fliur Macaev*a,b
aLaboratory of Organic Synthesis and Biopharmaceuticals, Institute of Chemistry, Chisinau, 3 str. Academiei, Moldova;
bScientific Center for Drug Research, “Nicolae Testemitanu” State University of Medicine and Pharmacy, Chisinau, Moldova;
cDepartment of Pharmacy School of Health, Department of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
d.Department of Plant Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia,University of Belgrade, Bulevar
despota Stefana 142, 11000 Belgrade,
eLaboratory of Physical Methods of Solid State Investigation ″Tadeusz Malinowski, Institute of Applied Physics, Chisinau, 5 str. Academiei, Moldova;
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
1,2,4-Triazole is a very important scaffold in medicinal chemistry due to the wide spectrum of
biological activities and mainly antifungal activity of 1,2,4-triazole derivatives. The main
mechanism of antifungal action of the latter is inhibition of 14-alpha-demethylase enzyme
(CYP51). The current study presents synthesis and evaluation of eight triazole derivatives for
their antimicrobial activity. Docking studies to elucidate the mechanism of action were also
performed. The designed compounds were synthesized using classical methods of organic
synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution
method. All tested compounds showed good antibacterial activity with MIC and MBC values
ranging from 0.0002 to 0.0069 mM. Compound 2h appeared to be the most active among all
tested with MIC at 0.0002-0.0033 mM and MBC at 0.0004-0.0033 mM followed by compounds
2f and 2g. The most sensitive bacterium appeared to be Xanthomonas campestris while Erwinia
amylovora was the most resistant. The evaluation of antifungal activity revealed that all
compounds showed good antifungal activity with MIC values ranging from 0.02 mM to 0.52
mM and MFC from 0.03 mM to 0.52 mM better than reference drugs ketoconazole (MIC and
MFC values at 0.28-1.88 mM and 0.38 mM to 2.82 mM respectively) and bifonazole (MIC and
MFC values at 0.32-0.64 mM and 0.64-0.81 mM). The best antifungal activity is displayed by
compound 2h with MIC at 0.02-0.04 mM and MFC at 0.03-0.06 mM while compound 2a
showed the lowest activity. Eight novel triazole derivatives were designed, synthesized and
evaluated for antimicrobial activity. The results showed that these compounds could be lead
compounds in search for new potent antimicrobial agents. Docking studies confirmed
experimental results.
Available online
Keywords:
disubstituted piperazines
pyrano[3,4-c]pyridines
cyclopenta[c]pyridines
alkylation
antibacterial activity
antifungal activity
2009 Elsevier Ltd. All rights reserved.
Four main chemical classes of antimycotics are currently used
in medicine, they are: azoles (imidazoles, triazoles, thiazoles),
echinocandines (caspofungin, micafungin, and anidulafungin),
Recently, a good review on sterol 14-alpha-demethylase
inhibitors has been published by Leaver.1
Majority of the azole antimycotics have high liposolubility
and are not effective orally because of their metabolic
degradation. However, these compounds often appear very useful
in topic formulations due to good skin compatibility and
penetration. Thus, ketoconazole developed by Janssen
Pharmaceutica in 19782 is active per os but still undergoes a
quick metabolism, and it has limited activity against Aspergillus,
fluoropyrimidines
(5-fluorocytosine),
and
polyenes
(amphotericin B, nystatin, and natamycin).
The main mechanism of action of all antifungal azoles
(imidazoles, triazoles, and thiazoles) is inhibition of 14-alpha -
demethylase, a cytochrome P450 enzyme. The inhibition occurs
due to binding of the free nitrogen atom of the azole group to the
iron of heme’s prostetic group in the active site of the enzyme.
Substitution of imidazole moiety with 1,2,4-triazole resulted
in derivatives with increased activity but still susceptible to

metabolism.3 These compounds showed higher activity in vivo
while in vitro tests data indicates a four times lower potency.
antibacterial activity of various 1,2,4-triazole hybrids. Thus,
1,2,4-triazole-quinoline/quinolone hybrids have been proposed as
potential anti-bacterial agents.14 As well, antifungal and
antibacterial activity has been demonstrated for homodrimane
sesquiterpenoids bearing N-substituted 1,2,4-triazole.15
Data indicate that fluconazole representative of the 1,2,4-
triazole derivatives, circulates in plasma in the free form and
eliminated through the kidney in unchanged form. Almost 94%
of fluconazole is absorbed after oral administration and its
bioavailability is not dependent on the gastric pH, while there is
almost no hepatic metabolism. At the same time fluconazole is
known to penetrate the blood-brain barrier and due to good water
solubility it can be administered i.v.4 Another antifungal 1,2,4-
triazole, itraconazole, is largely metabolized by the liver into an
active metabolite. Its hydroxylated analogue, posaconazole, has
bioavailability of 8-47% on empty stomach and it can increase by
400% upon co-administration of fats. It undergoes the first liver
pass metabolism and approximately 77% excreted unmetabolized
with feces.
Here we are presenting another new group of 1,2,4-triazole
derivatives -vynil-1,2,4-triazoles with antifungal and antibacterial
activity.
In the design of new drugs, the data regarding toxicity of
compounds is very important. On the other hand, the in vivo
toxicity testing in animals and in vitro testing in cells are
expensive process. To overcome this many in silico prediction
methods were developed. Thus, the in silico toxicity study can be
used since it is a more rapid and less expensive process than in
vivo toxicity testing in animals and in vitro testing in cell lines.
Besides, it can help to significantly reduce the number of animals
used in the experimental assays. There are several online
programs using in silico models to access toxicity, that predict
average lethal dose, carcinogenicity, mutagenicity etc. In this
work the PROTOX was used.16,17
Fluconazole is primarily active against Candida spp., while
itraconazole have a wider spectrum of activity including activity
against Candida and Aspergillus spp. Posaconazole, being
structurally similar to itraconazole, has been proved to be more
efficient than amphotericin B in the treatment of Aspergillus spp.
Infections.5
The PROTOX program,16 predicts the average lethal dose
(LD50) in rodents. According to this program all chemical
compounds can be classified into six GHS (Globally Harmonized
System of Classification and Labeling of Chemicals, rev. 8)
categories, GHS18 depending on the toxicity of the compounds
and the LD50 values.
The antifungal azoles are widely used in agriculture for crops
protection and animal treatment.6,7 As a result, azole resistance is
6-9
developing at a fast rate
and there is a growing medical need
in development of new azole antifungals that are selective in
ergosterol biosynthesis inhibition and against which the fungi do
not readily develop resistance. Development of new triazoles
with antifungal activity has been reported recently by various
groups,11 however none of these compounds has yet appeared
successful enough to reach any significant clinical development.
Category I: LD50 ≤ 5 mg/kg
Category II: 5 < LD50 ≤ 50 mg/kg
Category III: 50 < LD50 ≤ 300 mg/kg
Category IV: 300 < LD50 ≤ 2000 mg/kg
Category V: 2000 < LD50 ≤ 5000 mg/kg
Category VI: LD50 > 5000 mg/kg
Moreover, as it was shown in our previous studies and by
other research groups, 1,2,4-triazole derivatives also possess
antibacterial activity.11-13 According to Gao et al. 13 1,2,4-Triazole
moiety can influence important physicochemical parameters like
hydrogen bonding, lyposolubility, polarity, that can influence
pharmacodynamics, pharmacokinetics, and toxicity. However,
the core point of the review is that 1,2,4-triazole moiety improves
the activity of the main antibacterial pharmacophore in a hybrid
molecule. More and more works appear to confirm good
All compounds tested were in category IV.
It should be mentioned that the accuracy of prediction increases
as the confidence values rises. In particular, reliable estimates are
considered to be more than 0.025.
Table 1. Prediction of toxicity evaluated with program Protox
Predicted Predicted
№
LD50
Toxicity Hepatotoxicity Carcinogenicity Immunotoxicity Mutagenicity Cytotoxicity
mg/kg
Class
2a
2b
2c
2d
2e
2f
1790
1790
1790
474
4
4
4
4
4
4
4
4
Inactive 0.60
Inactive 0.54
Inactive 0.54
Inactive 0.63
Inactive 0.50
Inactive 0.54
Inactive 0.60
Inactive 0.54
Inactive 0.50
Inactive 0.52
Inactive 0.57
Inactive 0.52
Inactive 0.63
Inactive 0.52
Inactive 0.62
Inactive 0.52
Inactive 0.67
Inactive 0.82
Inactive 0.89
Inactive 0.61
Inactive 0.87
Inactive 0.81
Inactive 0.61
Inactive 0.82
Inactive 0.59 Inactive 0.70
Inactive 0.53 Inactive 0.72
Inactive 0.57 Inactive 0.70
Inactive 0.53 Inactive 0.70
Inactive 0.65 Inactive 0.78
Inactive 0.53 Inactive 0.72
Inactive 0.66 Inactive 0.63
Inactive 0.54 Inactive 0.70
1790
1790
1790
474
2g
2h
Compounds were synthesized according to the synthetic
pathway presented in the Scheme 1. An alkyl-, naphthyl- or
phenacyl triazole (1a–1f) was refluxed with a corresponding
aldehyde in benzene and in the presence of piperidine and acetic
acid as catalysts. The targeted compounds, namely alkyl-,
naphthyl- or phenacyl triazoles (2a – 2h), were easily obtained
with varying yields from 60% up to 70%. The starting materials
(1a-f) were synthesized by the reaction of the corresponding

acylbromides with 1H-1,2,4-triazole. It is important to mention
that in the proposed conditions compound 2h was obtained with a
high level of stereoselectivity. This was confirmed by the
experimental NOESY data. The vinyl proton does not interact
with triazole protons, therefore it can be concluded that the Z-
isomer of the compound is obtained.
Scheme 1. General synthetic pathway for compounds 2a-2h.
All tested compounds showed good antibacterial activity with
MIC and MBC values ranging from 0.0002 to 0.0069 mM. The
antibacterial potency can be presented as follows:
2h>2f>2g>2c>2a>2e>2b>2d. Compound 2h appeared to be the
most active among all tested with MIC at 0.0002-0.0033 mM and
MBC at 0.0004-0.0033 mM followed by compounds 2f and 2g.
Compound 2d showed the lowest antibacterial potency with MIC
and MBC at 0.0027-0.0054 mM respectively. It should be
noticed that sensitivity of bacterial strains towards tested
compounds was in general different. Thus, the antibacterial
potency of compounds against B.subtilis can be presented as
follows: 2h>2f>2g>2c>2b>2e>2d>2a, while against P.
fluorescens as: 2f>2a>2c>2b>2d>2e>2h>2g. The sensitivity of
Erwinia species (Erwinia amylovora, Erwinia carotovora)
towards synthesized compounds appeared to be quite different
from B.subtilis and P.fluorescens and looks like:
2h>2g>2b>2a>2c>2e=2f>2d and 2h>2a>2c=2d>2e=2f>2b>2g,
while the Xanthomonas campestris exhibited completely
against Erwinia carotovora (MIC and MBC at 0.0013mM).
Compound 2h appeared to be 6 times more active against
Erwinia amylovora than ampicillin, while compound 2g was
almost equipotent with ampicillin against Pseudomonas
fluorescens. It should be mentioned that in general compounds
were more potent against Gram negative bacteria.
A structure-activity relationship revealed that the presence of
Me2CHCH2 as R1 and 4-NO2-C6H4 (2h) substituents appeared to
be beneficial for antibacterial activity. The replacement of
Me2CHCH2 (2h) by 4-Cl-C6H4, led to compound 2f with
decreased activity The introduction of second chlorine atom in R1
as well as replacement of 4-NO2-C6H4 in R2 by bulky substituent
3,5(Bu)2-4-OH-C6H2 decreased activity more whereas the
presence of 2-naphtyl group as R1 substituent and 4-
dimethylamino phenyl group as R2 substituent (2d) were
detrimental for antibacterial activity. It seems that there is some
correlation of antibacterial activity with topological polar surface
area (tPSA). Thus, the tPSA of two most active compound 2h
and 2f is 96.94, while the tPSA of the less active compound 2d is
117.07. No correlation was observed between lipophilicity and
antibacterial activity. It seems that electron withdrawing group as
R2 substituent (4-NO2) have positive influence to antibacterial
activity (2h, 2f, 2c) while the presence of electron donating group
(NMe2) as R2 substituent plays negative role.
different
behavior
towards
compounds
tested:
2h>2c>2a>2e=2f>2d>2b>2g. The most sensitive bacterium
appeared to be Xanthomonas campestris while Erwinia
amylovora was the most resistant. Compounds 2f, 2g, 2h showed
very good activity against B.subtilis, Pseudomonas fluorescens,
Erwinia amylovora and Xanthomonas campestris with MIC and
MBC at 0.0008-0.0017mM. Compound 2f was also active
Table 2. Antibacterial activity (MIC/MBC in mM).
N.
Activity
Bacteria Species
B.s.1
P.a.1
E.a.1
0.0017
0.0034
0.0025
0.0025
0.0027
0.0027
0.0027
0.0054
0.0029
0.0029
0.0013
0.0013
0.017
E.c.1
0.0017
0.0017
0.0025
0.0051
0.0027
0.0027
0.0027
0.0027
0,0029
0.0058
0.0013
0.0013
0.0045
0.009
X.c.1
2a
2b
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
0.0069/
0.0069
0.0025
0.0051
0.0027
0.0027
0.0054
0.0054
0,0029
0.0058
0.0013
0.0013
0.017
0.0017
0.0017
0.0025
0.0025
0.0013
0.0027
0.0027
0.0027
0.0029
0.0029
0.0006
0.0013
0.009
0.0017
0.0034
0.0051
0.0051
0.0013
0.0027
0.0027
0.0054
0.0029
0.0029
0.0013
0.0013
0.017
2c
2d
2e
2f
2g
0.017
0.009
0.017
0.017
2h
0.0008
0.0008
0.0002
0.0002
0.0003
0.0003
0.0033
0.0033
0.0086
0.0086
0.0005
0.0005
0.0004
0.0008
0.00025
0.0005
0.00015
0.0003
0.0004
0.0008
0.0001
0.0002
0.00025
0.0005
0.0008
0.0008
0.0002
0.0002
0.0001
0.0001
Am2
Ch2

B.s.- Bacillus subtilis, P.a. - Pseudomonas fluorescens, E.a. -Erwinia amylovora, E.c. - Erwinia carotovora, X.c. - Xanthomonas campestris, Am.- Ampicillin, Ch.
– Chloramphenicole
The antifungal activity was evaluated against eight different
fungal species: Aspergillus fumigatus, A. versicolor, A.
ochramensis, A. niger, Trichoderma viride, Penicillium
funiculosum, P. ochrochloron, P. verrucosum var. cyclopium.
Minimum inhibitory concentration (MIC) and minimum
fungicidal concentration (MFC) have been determined for each
compound against all eight fungal strains (Table 3).
mM and 0.64-0.81 mM). The order of compounds can be
presented as followed: 2h>2g>2f>2d>2c>2e>2b>2a. The best
antifungal activity as in case of antibacrterial is displayed by
compound 2h with MIC at 0.02-0.04 mM and MFC at 0.03-0.06
mM while compound 2a showed the lowest activity. It should be
mentioned that fungi in the contrary with bacteria showed almost
the same sensitivity towards compounds tested with very small
differences. Thus, the antifungal potency of compounds against A
fumigatus can be presented as follows: 2h>2g>2f>2e>2d>-
2c>2b>2a, while against A.niger: 2h>2g>2e>2f>2c>2d>2a>2b
and the P.v.c as: 2h>2f>2d>2g>2c>2e>2b>2a. Almost all fungi
appeared to be not sensitive to compound 2a except of A. niger,
which showed no sensitivity to compound 2b. The most sensitive
fungal appeared to be T.viride, while P.v c was the most resistant
one. Compounds 2e-2h exhibited very good activity against
T.viride with MIC at 0.03-0.08 mM and MFC at 0.06-0.10mM,
while 2d against A. ochraceus and T.viride with MIC at 0.07 mM
and MFC 0.14 mM. Compound 2c displayed good activity (MIC
0.10 mM and MFC 0.20 mM) against A.versicolor, A. ochraceus
and T.viride. Ketoconazole exhibited antifungal potential at 0.38-
1.88 mM and MFC at 0.57-2.82 mM, while bifonazole showed
MIC at 0.32-0.64 mM and MFC at 0.64-0.81 mM. It should be
mentioned that all tested compounds appeared to be more potent
against fungi than reference drugs.
A. fumigatus is the most common representative of the genus
Aspergillus that causes opportunistic infection, aspergillosis, in
patients with immunodefficiency such as organ transplant
patients, AIDS, and leukemia.19 A. versicolor dwells in humid
indoor environments and on food products and produces
hepatotoxic and carcinogenic mycotoxin – sterigmatocystin.20 A.
niger causes black mold on apricots, grapes, peanuts, tomatoes,
and onions. There is a much lower possibility for this fungus to
cause human disease than for any other Aspergillus species. A.
ochraceus is also a mold often contaminating food products and
producing mycotoxins ochratoxin A and citrinin. Its spores can
cause asthma and other lung diseases in humans.21
Trichoderma viride is a fungus used as biofungicide in
agriculture whose growth is regulated by such agricultural
pathogens as Armillaria, Pythium, and Rhizoctonia.22
Penicillium funiculosum is involved in seed-borne fungal
infections of plants and is used in biotechnology for production
of different metabolites. Penicillium ochrochloron is a non-
pathogenic fungus which is used as a producer of chitinolytic
The study of structure - activity relationships revealed that like
in the case of antibacterial activity the presence of Me2CHCH2 as
R1 and 4-NO2-C6H4 substituents appeared to be beneficial for
antifungal activity. The replacement of Me2CHCH2 (2h) by 2,4-
Cl- C6H3 and 4-NO2-C6H4 in R2 by 3,5(Bu)2-4-OH-C6H2 led to
the compound 2g with decreased activity, while replacement of
Me2CHCH2 with 4-Cl- C6H4 (2f) had induced lower activity than
that of 2h. Activity decreased more with the presence of 2-
naphtyl group as R1 substituent and 4-dimethylamino phenyl
group as R2 substituent (2d), while the presence of phenyl group
as R1 and 3-hydroxy phenyl as R2 substituent appeared to be
deleterious for the antifungal activity.
enzymes.23
Penicillium verrucosum var. cyclopium is a
psychrophilic fungus causing food infestations and which growth
is regulated in order to reduce the food spoilage with
characteristic mycotoxins, i.e. immunosuppressive and
teratogenic ochratoxin A.
The results of antifungal activity of synthesized compounds
(2a-2h) are presented in Table 2. The evaluation results revealed
that all compounds showed good antifungal activity with MIC
values ranging from 0.02 mM to 0.52 mM and MFC from 0.03
mM to 0.52 mM better than reference drugs ketoconazole (MIC
and MFC values at 0.28-1.88 mM and 0.38 mM to 2.82 mM
respectively) and bifonazole (MIC and MFC values at 0.32-0.64
In the case of antifungal activity, correlation was not observed
nor with lipophilicity neither with tPSA.
Table 3. Antifungal activity of compounds in mM.
Fungi Species
N
Activity
A.fum.1 A.v. 1 A.o. 1 A.n. 1 T.v.1 P.f. 1 P.o.1 P.v.c.1
2a
MIC
MFC
0.38
0.52
0.26
0.52
0.19
0.52
0.52
0.10
0.19 0.26
0.26 0.52
0.26
0.52
0.38
0.52
2b
MIC
MFC
0.25
0.51
0.25
0.51
0.13
0.25
0.25
0.51
0.09 0.18
0.13 0.25
0.13
0.25
0.25
0.51
2c
2d
2e
2f
MIC
MFC
0.20
0.41
0.10
0.20
0.10
0.20
0.15
0.20
0.10 0.15
0.20 0.20
0.10
0.20
0.20
0.41
MIC
MFC
0.14
0.27
0.14
0.27
0.07
0.14
0.14
0.27
0.07 0.19
0.14 0.27
0.14
0.27
0.14
0.27
MIC
MFC
0.16
0.22
0.08
0.22
0.10
0.22
0.16
0.22
0.05 0.22
0.10 0.44
0.16
0.44
0.22
0.44
MIC
MFC
0.10
0.19
0.10
0.19
0.07
0.10
0.14
0.19
0.07 0.14
0.10 0.19
0.10
0.19
0.14
0.19
2g
2h
MIC
MFC
0.08
0.16
0.08
0.16
0.06
0.16
0.08
0.16
0.03 0.12
0.08 0.16
0.08
0.16
0.16
0.32
MIC
MFC
0.02
0.03
0.04
0.06
0.02
0.03
0.02
0.03
0.03 0.04
0.06 0.06
0.03
0.06
0.04
0.06

0.38
0.94
0.48
0.64
0.38
0.94
0.32
0.64
0.28
0.38
0.48
0.64
0.38
0.94
0.48
0.64
1.88 0.38
2.82 0.94
0.48 0.64
0.64 0.81
1.88
2.82
0.64
0.81
0.38
0.57
0.32
0.64
MIC
MFC
Ktz2
Bfz2
MIC
MFC
A.fum. - Aspergillus fumigatus, A.v.- Aspergillus versicolor, A.o. -Aspergillus ochraceus, A.n. -Aspergillus niger, T.v.- Trichoderma viride, P.f.- Penicillium
funiculosum, P.o.- Penicillium ochrochloron, P.v.c.- Penicillium verrucosum var. cyclopium.
2 Ktz. – Ketoconazole, Bfz. – Bifonazole
Compound 2h crystallizes in the triclinic P-1 space group with
unit cell parameters a=5.2451(5), b=11.9553(12),
Figure 1. View of the molecule 2h with partial numbering scheme, thermal
ellipsoids are shown with the 50% probabilities.
c=13.5334(12)Å, α=112.990(9), β=97.520(8), γ=95.950(8)º,
The crystal structure reveals the disorder of isobutyl group
over two positions with probability 0.809(5)/0.191(5) indicating
their liability.
V=763.29(13) Å3. The structure of molecule is shown on the Fig.
1.
The triazole fragment reside in cis-position to nitrobenzene
moiety and trans- to carbonyl group (o1 – c1= 1.212(3) å) in
respect to double c2 - c3= 1.333(3) å and single c1 - c2= 1.498(3)
å bonds, respectively. the torsion angles n1-c2-c3-c10 and n1-c2-
c1-o1 equal -1.8(4) and 164.9(3)º. the dihedral angle between
planar triazole and nitrobenzene moiety equals 66.28(6)º. two c3-
As we do not know the mechanism of action of the compounds,
molecular docking studies have been performed at the active sites
of E. coli MurB (PDB code: 2Q85), E. coli DNA GyrB (PDB
code: 1KZN) and Thymidylate kinase (PDB code: 4HOF) as
antibacterial targets. The results showed that E. coli DNA GyrB
24-kDa domain in complex with clorobiocin is the most suitable
enzyme where binding scores were reliable with biological
activity (Table 4.).
2
h·o1=3.386å interactions result in r2 (10) supramolecular synthon
and unite centersymmetry related molecules in dimer.
It should be mentioned that all discussion regarding docking is
only a presumption.
Table 4. Molecular docking binding affinities.
Est. binding energy (kcal/mol)
I-H
Gyrase
Residues
Gyrase
Thymidylate
kinase
4QGG
Comp.
E. coli MurB
Gyrase
1KZN
Gyrase
2Q85
2a
2b
2c
2d
2e
2f
-8.32
-7.52
-7.80
-6.61
-5.29
-8.17
-5.78
-8.56
-6.21
-3.28
-
-8.72
-7.63
-7.70
-7.02
-6.28
-9.44
-5.23
-10.93
-28.37
-26.15
-27.10
-25.18
-22.54
-28.17
-19.44
-30.51
2
1
1
1
-
Gly63, Thr132
Asn32
Asn32
-
Asp59
-4.40
-3.21
-1.27
-5.12
-
2
-
Arg62, Gly63
2g
2h
-
3
Arg62, Arg103
Clorobioc
in
-
-
-8.69
-27.54
3
Asn32, Gly63
interactions with the residues Ala33, Asp59, Val57, Met133,
Most of the studied compounds showed similar important
interactions as it was observed for the reference drug
clorobiocin such as the H-bonding interaction with the
residues Asn32 and Gly63 (Figure 3). This is, possibly, the
reason of the high inhibitory action of these compounds.
The docking pose of the most active compound 2h showed 3
favorable hydrogen bonds. Two of them between the oxygen
atom of the –NO2 substituent and the hydrogens of the side chain
of Arg103 (distance 2.60 and 2.94 Å), and another one between
the oxygen atom of the –NO2 group and the hydrogen of the side
chain of Arg62 (distance 2.98 Å). The benzene ring showed
hydrophobic and pi interactions with Glu36 and Ile64, while the
two methyl groups formed plenty of pi and van der Waals
Val134, Val29, Cln58 and Thr132 (Figure 1).

compound of fungal cell membranes preventing fungal
growth,24,25 all the synthesized compounds and reference drug
were docked to lanosterol 14-alpha-demethylase of C. albicans.
Table 5. Molecular docking binding affinities
Binding
affinity score
CYP51 of C.
albicans
Est. binding
energy(kcal/mo
l)
CYP51 of C.
albicans
Residues
CYP51 of C.
albicans
N/N
I-H
PDB ID: 5V5Z
PDB ID:
5V5Z
PDB ID: 5V5Z
Figure 2. Docked conformation of the most active compound 2h in E. coli
2a
2b
2c
2d
2e
2f
-76.11
-7.52
-6.56
-7.19
-8.54
-8.77
-20.15
-21.03
-21.88
-22.51
-23.71
-25.48
-
-
DNA GyrB.
1
1
1
1
1
Tyr132
Tyr118
Tyr118
Tyr132
Tyr132
Interestingly, compound 2h has better structural flexibility
that allows binding deeper in the active center of enzyme than
clorobiocin. This is probably the reason why compound 2h
showed such a high inhibitory action comparable to that of
Ampicillin and Chloramphenicol (Figure 3, 4).
HEM601
(ionizable)
2g
2h
-9.85
-11.07
-8.23
-27.54
-31.53
-22.47
-
-
HEM601
(Fe binding)
ketocon
azole
1
Tyr64
Docking results revealed that all the synthesized compounds
may bind to CYP51Ca in a way that it is similar to the binding of
ketoconazole. Compound 2h takes place inside the enzyme
alongside to heme group, interacting with the Fe of the heme
group of CYP51Ca and the pyridine ring of the compound.
Moreover, hydrophobic interactions between Thr311, Phe225,
Met508, Val209, Leu276, Thr311 and the methyl groups of the
compound 2h were detected. Interaction with the heme group
was also observed with the benzene ring of ketoconazole which
forms positive ionizable interactions (figure 2 and 3). However,
compound 2h formed more stable complex of ligand with
enzyme indicating its interaction with the Fe. This is probably the
reason why compound 2h have better antifungal activity than
ketoconazole.
Figure 3. Docked conformation of clorobiocin in E. coli DNA GyrB.
Figure 5. Docked conformation of ketoconazole in lanosterol 14-alpha-
demethylase of C. albicans (CYP51ca).
Figure 4. Docked conformation of the most active compound 2h (blue) and
clorobiocin (yellow) in E. coli DNA GyrB.
Since it is known that azoles are competitive inhibitors of
lanosterol 14-alpha-demethylase (a cytochrome P-450 enzyme),
and thus block the biosynthesis of ergosterol, which is a key

Demethylase in the Human Pathogen Trypanosoma
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[7] Perlin DS, Rautemaa-Richardson R, Alastruey-
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Resistance: Prevalence, Mechanisms, and Management.
The Lancet Infectious Diseases 2017;17:e383–e392.
[8] Seyedmousavi S, Wiederhold NP, Ebel F, Hedayati
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Veterinary Practice and Emergence of Resistance. In:
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[9] Klix MB, Verreet JA, Beyer M. Comparison of the
Declining Triazole Sensitivity of Gibberella Zeae and
Increased Sensitivity Achieved by Advances in Triazole
Fungicide Development. Crop Prot. 2007;26:683–690.
[10] Chowdhary A, Sharma C, Meis JF. Azole-Resistant
Aspergillosis: Epidemiology, Molecular Mechanisms,
and Treatment. J. Infect. Dis. 2017;216:S436–S444.
[11] Stana A, Enache A, Vodnar DC, Nastasǎ C, Benedec D,
Ionuţ I, Login C, Marc G, Oniga O, Tiperciuc B. New
Thiazolyl-Triazole Schiff Bases: Synthesis and
Evaluation of the Anti-Candida Potential. Molecules
2016;21:1595.
[12] Ezabadi IR, Camoutsis C, Zoumpoulakis P, Glamoc J,
Geronikaki A, Sokovic M. Antibacterial Agentsꢀ:
Synthesis , Biological Evaluation , Lipophilicity , and
Conformational Studies. 2008;16:1150–1161.
[13] Sztanke K, Tuzimski T, Rzymowska J, Pasternak K,
Kandefer-Szerszeń M. Synthesis, Determination of the
Lipophilicity, Anticancer and Antimicrobial Properties
of Some Fused 1,2,4-Triazole Derivatives. Eur. J. Med.
Chem. 2008;43:404–419.
Figure 6. Docked conformation of compound 2h in lanosterol 14-alpha-
demethylase of C. albicans (CYP51ca).
Eight novel triazole derivatives were designed, synthesized
and evaluated for antimicrobial activity.. The study revealed that
new triazole derivatives bearing a variety of substituents possess
antibacterial and antifungal activities. All tested compounds
exhibited good ability to inhibit bacteria and fungi. In some
cases, the antibacterial activity was higher than the commercial
antimicrobial agents used as reference drugs, while tested
compounds appeared to be more potent than ketoconazole and
bifonazole.
Docking studies demonstrated that DNA GyrB inhibition ,
probably, may explain the anti-bacterial action of compounds,
while inhibition of lanosterol 14-alpha-demethylase (a
cytochrome P-450 enzyme), as was expected, probably,is
involved in the mechanism of antifungal activity. Thus, these
compounds could serve the role of lead compounds in search for
new potent antimicrobial agents
Acknowledgments
E.S., M.Z., S.P., L.L., F.M. are grateful for the funding of this
research under the Moldovan State Program projects
20.80009.5007.17
S.P., V.V., L.U., F.M., A.S. and M.D. are grateful for the
generous support from Moldovan State Program projects
20.80009.8007.14
[14] Gao F, Wang T, Xiao J, Huang G. Antibacterial
Activity Study of 1,2,4-Triazole Derivatives. European
Journal of Medicinal Chemistry 2019;274–281.
[15] Zhang J, Wang S, Ba Y, Xu Z. 1,2,4-Triazole-
Quinoline/Quinolone Hybrids as Potential Anti-
Bacterial Agents. European Journal of Medicinal
Chemistry 2019; 1–8.
Conflicts of interest
[16] ProTox-II - Prediction Of Toxicity Of Chemicals.
http://tox.charite.de/protox_II/ (Accessed Sep 2, 2019).
[17] Banerjee P, Eckert AO, Schrey AK, Preissner R.
ProTox-II: A Webserver for the Prediction of Toxicity
of Chemicals. Nucleic Acids Res. 2018;46:W257–
W263.
E.S., M.Z., S.P., L.L. and F.M have received funding from the
Moldovan State Program project 20.80009.5007.17.
S.P., V.V., L.U., F.M., A.S. and M.D. have received funding
from the Moldovan State Program project 20.80009.8007.14
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.
Table 1. Prediction of toxicity evaluated with program Protox
Predi Predi
cted
cted
Hepatot Carcinog Immunot Mutage Cytoto
Table 2. Antibacterial activity (MIC/MBC in mM).
№ LD50 Toxic
oxicity
enicity
oxicity
nicity
xicity
mg/k
g
ity
Class
N.
Activity
Bacteria Species
B.s.1
P.a.1
E.a.1
0.0017
0.0034
0.0025
0.0025
0.0027
0.0027
0.0027
0.0054
0.0029
0.0029
0.0013
0.0013
0.017
E.c.1
0.0017
0.0017
0.0025
0.0051
0.0027
0.0027
0.0027
0.0027
0,0029
0.0058
0.0013
0.0013
0.0045
0.009
X.c.1
2
a
Inactive
0.60
Inactive
0.50
Inactive
0.67
Inactive Inactiv
0.59 e 0.70
1790
1790
1790
474
4
4
4
4
4
4
4
4
2a
2b
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
0.0069/
0.0069
0.0025
0.0051
0.0027
0.0027
0.0054
0.0054
0,0029
0.0058
0.0013
0.0013
0.017
0.0017
0.0017
0.0025
0.0025
0.0013
0.0027
0.0027
0.0027
0.0029
0.0029
0.0006
0.0013
0.009
0.0017
0.0034
0.0051
0.0051
0.0013
0.0027
0.0027
0.0054
0.0029
0.0029
0.0013
0.0013
0.017
2
b
Inactive
0.54
Inactive
0.52
Inactive
0.82
Inactive Inactiv
0.53 e 0.72
2c
2
c
Inactive
0.54
Inactive
0.57
Inactive
0.89
Inactive Inactiv
0.57 e 0.70
2d
2e
2
d
Inactive
0.63
Inactive
0.52
Inactive
0.61
Inactive Inactiv
0.53 e 0.70
2f
2
e
Inactive
0.50
Inactive
0.63
Inactive
0.87
Inactive Inactiv
0.65 e 0.78
1790
1790
1790
474
2g
0.017
0.009
0.017
0.017
2h
0.0008
0.0008
0.0002
0.0002
0.0003
0.0003
0.0033
0.0033
0.0086
0.0086
0.0005
0.0005
0.0004
0.0008
0.00025
0.0005
0.00015
0.0003
0.0004
0.0008
0.0001
0.0002
0.00025
0.0005
0.0008
0.0008
0.0002
0.0002
0.0001
0.0001
2
f
Inactive
0.54
Inactive
0.52
Inactive
0.81
Inactive Inactiv
0.53 e 0.72
Am2
Ch2
2
g
Inactive
0.60
Inactive
0.62
Inactive
0.61
Inactive Inactiv
0.66 e 0.63
B.s.- Bacillus subtilis, P.a. - Pseudomonas fluorescens, E.a. -Erwinia
2
h
Inactive
0.54
Inactive
0.52
Inactive
0.82
Inactive Inactiv
amylovora, E.c. - Erwinia carotovora, X.c. - Xanthomonas campestris, Am.-
Ampicillin, Ch. – Chloramphenic
0.54
e 0.70
0.2
5
0.5
1
0.1
0
0.2
0
0.1
3
0.2
5
0.1
0
0.2
0
0.2
5
0.5
1
0.1
5
0.2
0
0.0
9
0.1
3
0.1
0
0.2
0
0.1
8
0.2
5
0.1
5
0.2
0
0.1
3
0.2
5
0.1
0
0.2
0
2b
2c
MIC
MFC
0.25
0.51
0.25
0.51
Table 3. Antifungal activity of compounds in mM.
MIC
MFC
0.20
0.41
0.20
0.41
Fungi Species
Activit
N
y
A.fum
A.v A.o A.n T.v. P.f. P.o. P.v.c.
0.1
4
0.2
7
0.0
8
0.0
7
0.1
4
0.1
0
0.1
4
0.2
7
0.1
6
0.0
7
0.1
4
0.0
5
0.1
9
0.2
7
0.2
2
0.1
4
0.2
7
0.1
6
1
1
1
1
1
1
1
1
.
.
.
.
2d
2e
MIC
MFC
0.14
0.27
0.14
0.27
0.2
6
0.5
2
0.1
9
0.5
2
0.5
2
0.1
0
0.1
9
0.2
6
0.2
6
0.5
2
0.2
6
0.5
2
2a
MIC
MFC
0.38
0.52
0.38
0.52
MIC
MFC
0.16
0.22
0.22
0.44

0.2
2
0.1
0
0.1
9
0.0
8
0.1
6
0.0
4
0.0
6
0.3
0.2
2
0.0
7
0.1
0
0.0
6
0.1
6
0.0
2
0.0
3
0.2
0.2
2
0.1
4
0.1
9
0.0
8
0.1
6
0.0
2
0.0
3
0.3
0.1
0
0.0
7
0.1
0
0.0
3
0.0
8
0.0
3
0.0
6
1.8
0.4
4
0.1
4
0.1
9
0.1
2
0.1
6
0.0
4
0.0
6
0.3
0.4
4
0.1
0
0.1
9
0.0
8
0.1
6
0.0
3
0.0
6
1.8
2a
2b
2c
2d
2e
2f
-76.11
-7.52
-6.56
-7.19
-8.54
-8.77
-20.15
-21.03
-21.88
-22.51
-23.71
-25.48
-
-
1
1
1
1
1
Tyr132
Tyr118
Tyr118
Tyr132
Tyr132
2f
2g
2h
MIC
MFC
0.10
0.19
0.14
0.19
MIC
MFC
0.08
0.16
0.16
0.32
MIC
MFC
0.02
0.03
0.04
0.06
HEM601
(ionizable)
2g
2h
-9.85
-11.07
-8.23
-27.54
-31.53
-22.47
-
-
HEM601
(Fe binding)
0.38
0.94
8
0.9
4
8
0.3
8
8
0.9
4
8
2.8
2
8
0.9
4
8
2.8
2
0.38
0.57
Ktz MIC
2
MFC
ketocon
azole
1
Tyr64
0.3
2
0.4
8
0.4
8
0.4
8
0.6
4
0.6
4
0.48
0.64
0.32
0.64
Bfz MIC
2
MFC
0.6
4
0.6
4
0.6
4
0.6
4
0.8
1
0.8
1
A.fum. - Aspergillus fumigatus, A.v.- Aspergillus versicolor, A.o. -Aspergillus
ochraceus, A.n. -Aspergillus niger, T.v.- Trichoderma viride, P.f.- Penicillium
funiculosum, P.o.- Penicillium ochrochloron, P.v.c.- Penicillium verrucosum
var. cyclopium.
2 Ktz. – Ketoconazole, Bfz. – Bifonazole
Table 4. Molecular docking binding affinities.
Est. binding energy (kcal/mol)
I-H
Gyrase
Residues
Gyrase
Thymidylate
kinase
4QGG
E. coli MurB
Gyrase
1KZN
Gyrase
2Q85
-8.32
-7.52
-7.80
-6.61
-5.29
-8.17
-5.78
-8.56
-6.21
-3.28
-
-8.72
-7.63
-7.70
-7.02
-6.28
-9.44
-5.23
-10.93
-28.37
-26.15
-27.10
-25.18
-22.54
-28.17
-19.44
-30.51
2
1
1
1
-
Gly63, Thr132
Asn32
Scheme 1. General synthetic pathway for compounds 2a-2h.
Asn32
-
Asp59
-4.40
-3.21
-1.27
-5.12
-
Graphical Abstract
2
-
Arg62, Gly63
-
3
Arg62, Arg103
-
-
-8.69
-27.54
3
Asn32, Gly63
Table 5. Molecular docking binding affinities
Est. binding
Binding
energy(kcal/mo
affinity score
l)
Residues
CYP51 of C.
albicans
N/N
CYP51 of C.
albicans
PDB ID:
5V5Z
I-H
CYP51 of C.
albicans
PDB ID: 5V5Z
PDB ID: 5V5Z

Declaration of interests
New vinyl-1,2,4-triazole derivatives as
antimicrobial agents: Synthesis, biological
evaluation and molecular docking studies.
Leave this area blank for abstract info.
Eugenia Stingacia, Marina Zveaghintevaa, Serghei Pogrebnoia, Lucian Lupascua, Vladimir Valicab,
Livia Uncub, Anastasia Smetanscaiab, Maricica Drumeab, Anthi Petrouc, Ana Ciricd, Jasmina
Glamoclijad, Marina Sokovicd, Victor Kravtsove, Athina Geronikaki*c, Fliur Macaev*a,b
aLaboratory of Organic Synthesis and Biopharmaceuticals, Institute of Chemistry, Chisinau, 3 str. Academiei, Moldova;
bScientific Center for Drug Research, “Nicolae Testemitanu” State University of Medicine and Pharmacy, Chisinau, Moldova;
cDepartment of Pharmacy School of Health, Department of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
dMycological Laboratory, Department of Plant Physiology, Institute for Biological Research, Siniša Stanković, University of Belgrade, Bulevar Despota
Stefana 142, 11000, Belgrade, Serbia.
eLaboratory of Physical Methods of Solid State Investigation ″Tadeusz Malinowski, Institute of Applied Physics, Chisinau, 5 str. Academiei, Moldova;
X☐ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests: