Amphiphilic silicone-bridged bis-triazoles as effective, selective metal ligands and biologically active agents in lipophilic environment

Article abstract of DOI:10.1016/j.molliq.2019.111560

Pairs of different substituted 3-mercapto-1,2,4-triazole units are coupled, through thioether bridges, to organic-inorganic substrates consisting in short hydrophobic silicone segment. A library of six compounds are isolated as crystalline solids and structurally characterized by X-ray single crystal diffraction, elemental, spectral and thermal analysis. The flexibility of the silicone spacer makes the small molecular compounds exhibit glass transition in the negative domain. The metal binding capacity is evaluated by quantum mechanics calculations, the results being in line with experimental data obtained by UV–vis spectroscopy titration. The results indicate that the prepared compounds can act as ligands for metal ions with high selectivity for Cu²⁺, an element of interest in biological processes, forming 1:1 stable mononuclear complexes with an association constant up to 8.87 × 10³ M^?1. The presence of the highly hydrophobic silicone spacer makes the behavior of bis-triazoles obtained more sensitive to the nature of the environment. The preliminary bioassay indicates lipophilic medium more suitable for biocide action of silicone-bridged bis-triazoles, which in some cases far exceeds that of reference. The mechanism of enzyme inhibition is demonstrated by molecular docking, and the results indicate that, in all docked complexes, the ligands are directly coordinated to the heme ferric iron.

Full text of DOI:10.1016/j.molliq.2019.111560

Journal of Molecular Liquids 294 (2019) 111560
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Amphiphilic silicone-bridged bis-triazoles as effective, selective metal
ligands and biologically active agents in lipophilic environment
Georgiana-Oana Turcan-Trofin a, Mirela-Fernanda Zaltariov a, Gheorghe Roman a, Sergiu Shova a,
Nicoleta Vornicu b, Mihaela Balan-Porcarasu a, Dragos Lucian Isac a, Andrei Neamtu c,a, Maria Cazacu a,
⁎
a
Department of Inorganic Polymers, “Petru Poni” Institute of Macromolecular Chemistry, Aleea Gr. Ghica Voda 41 A, Iasi 700487, Romania
Metropolitan Center of Research T.A.B.O.R, The Metropolitanate of Moldavia and Bukovina, Iasi, Romania
b
c
Regional Institute of Oncology (IRO), TRANSCEND Research Center, str. General Henry Mathias Berthlot nr. 2-4, Iasi, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 April 2019
Received in revised form 6 July 2019
Accepted 10 August 2019
Available online 12 August 2019
Pairs of different substituted 3-mercapto-1,2,4-triazole units are coupled, through thioether bridges, to organic-
inorganic substrates consisting in short hydrophobic silicone segment. A library of six compounds are isolated as
crystalline solids and structurally characterized by X-ray single crystal diffraction, elemental, spectral and ther-
mal analysis. The flexibility of the silicone spacer makes the small molecular compounds exhibit glass transition
in the negative domain. The metal binding capacity is evaluated by quantum mechanics calculations, the results
being in line with experimental data obtained by UV–vis spectroscopy titration. The results indicate that the pre-
pared compounds can act as ligands for metal ions with high selectivity for Cu2+, an element of interest in bio-
logical processes, forming 1:1 stable mononuclear complexes with an association constant up to 8.87
× 103 M−1. The presence of the highly hydrophobic silicone spacer makes the behavior of bis-triazoles obtained
more sensitive to the nature of the environment. The preliminary bioassay indicates lipophilic medium more
suitable for biocide action of silicone-bridged bis-triazoles, which in some cases far exceeds that of reference.
The mechanism of enzyme inhibition is demonstrated by molecular docking, and the results indicate that, in
all docked complexes, the ligands are directly coordinated to the heme ferric iron.
Keywords:
Amphiphile ligands
Triazoles on silicone substrate
Chemosensors
Biologically active ligands
Self-assembly
© 2019 Elsevier B.V. All rights reserved.
1. Introduction
technical interest such as liquid crystals [5], surfactants [6–8], anti-
foaming and textile finishing agents [4], but only limited information
Methyl-substituted disiloxanes as well as oligomeric siloxanes, pos-
sess intrinsic structural features (high flexibility and hydrophobicity
conferred by Si\\O bond characteristics and by the presence of methyl
groups attached to silicon atoms) and represent platforms available
for chemical modification at the active sites with the view to obtain
compounds with particular properties [1–3]. Several silanes and
disiloxanes with terminal reactive groups are commercially available,
and others can be easily obtained from appropriately substituted silanes
through a hydrolysis-condensation sequence. In general, the reactive
groups in disiloxanes are either Si\\H functions or various organic
groups (vinyl, chloro-, cyano-, carboxy-, glycidoxy-alkyl, etc.), which
can be further modified by reactions specific to silicon (hydrosilylation)
or organic (nucleophilic substitution, condensation, addition, etc.)
chemistry, respectively. However, the conjugation of silicones with
more polar species is often a challenge due to opposite polarities and
differences in solubility and reactivity [4]. For example, the modification
of siloxanes has been mainly performed to obtain compounds of
is available so far for the applications of silicon-containing compounds
as ligands, most of which has been reported by the authors of this
work [9–19]. In addition, siloxanes have been employed as scaffolds in
medicinal chemistry. Thus, several types of functional
oligodimethylsiloxanes with a polar substituent (methylpyridinium,
quaternary amino, phosphoramide, carboxyl, 1-alkyl-3-β-D-
glucopyranosyl) at one chain end showed high transdermal penetration
without irritation owing to the bulkiness and the physiological inert-
ness of the siloxane backbone. Furthermore, it has been showed that
the disiloxane compounds might limit inflammation even if it pene-
trated into the skin, because it remains in the stratum corneum due to
its high lipophilicity, and no transfer into the epidermis occurs [20]. It
is reported the application of 1-alkyl-3-β-D-glucopyranosyl-1,1,3,3-
tetramethyldisiloxane and its oligomers as skin penetration enhancers
[21].
The
first
imidazolophanes
having
bis(methylene)
tetramethyldisiloxane spacers, which have been obtained by the reac-
tion of 1,3-bis(iodomethyl)-1,1,3,3-tetramethyldisiloxane with imidaz-
oles, have been reported to be useful as antibiotic and antitumor drugs,
but also as building blocks for receptors and sensors, ionic liquids or mo-
lecular containers and catalysts [22]. A series of silanols, siloxanes or
⁎
Corresponding author.
E-mail address: mcazacu@icmpp.ro (M. Cazacu).
https://doi.org/10.1016/j.molliq.2019.111560
0167-7322/© 2019 Elsevier B.V. All rights reserved.

2
G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
silanol-siloxanes having nucleobases attached through hydrocarbon
chains with variable lengths has been synthesized, and one of these
compounds inhibited HIV-1 replication in cell culture [23]. Also, another
compound containing a 1,3-bis(methyl)tetramethyldisiloxane motif,
namely 4-[(3-methoxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-
aza-2,6-disilacyclohexane hydrochloride, has been tested as skeletal
muscle relaxant [24]. In the recent years, a project implemented by Har-
vard University aimed at the development and application of
disiloxanes as a new class of hard anion-binding organocatalysts able
to deliver medicinally important compounds in a new and highly spe-
cific way, an application that could help in the development and pro-
duction of new compounds to fight cancer and other diseases [25].
Morpholino-disiloxane (ALIS-409) and piperazino-disiloxane (ALIS-
421) have been developed as inhibitors of multidrug resistance of vari-
ous types of cancer cells [26]. However, despite the aforementioned re-
cent progress, there is still only scarce information on the biological
activity of oligosiloxanes.
tetramethyldisiloxanes and presenting their characterization was pub-
lished [44]. In our approach, bis(chloromethyl)dimethylsilane and 1,3-
bis(chloromethyl)tetramethyldisiloxane were used as substrates and
three mercaptotriazole derivatives were used as reagents in reactions
leading to thioethers. Thioethers themselves constitute a class of valu-
able and significant compounds that are useful in heterocyclic synthesis,
medicine, biochemistry, agriculture, industry, etc. [45,46]. The associa-
tion of siloxanes with triazoles through a thioether bond represents a
novel strategy for the creation of bis-triazole conjugates whose biologi-
cal activity was subsequently assessed and interpreted from the per-
spective of the presence and the nature of the siloxane or silane
spacer. The mechanism of enzyme inhibition has been demonstrated
by molecular docking. The metal binding capacity was also evaluated
both experimentally and theoretically by quantum mechanics.
2. Experimental
Heterocyclic compounds play an important role in our lives through
their significance in all major life processes, their usefulness as scaffolds
in the development of drugs, or as building blocks in materials with a
wide range of applications. Within the broad field of heterocyclic com-
pounds, 1,2,4-triazoles are a well-represented class of nitrogen-
containing polyheteroatomic compounds with five-membered rings,
which exhibit a broad spectrum of biological activities [27–37], while
having low toxicity and good pharmacokinetic and pharmacodynamic
profiles. Furthermore, in an approach towards the development of
novel compounds based on different pharmacophores, it has been
found that the presence of two or more pharmacological moieties in a
molecule enhances the performance of the hybrid compound, which
may bind to several active sites, and consequently exhibit higher bioac-
tivity and therapeutic effect. Thus, derivatives of 1,2,3- and 1,2,4-
triazoles were attached to methylene or ethylene bridges with a view
to create a study base for the effect of the length of this bridge on the bi-
ological activity [38]. The presence of two triazole rings in the molecule
could give the resulting compounds improved solubility in water, in-
creased targeting capacity and higher bioactivity [39]. Despite the rela-
tively low number of studies, the results obtained so far in this line of
research validate the working hypothesis and constitute a motivation
for further investigations.
In addition to biological activity, 1,2,4-triazoles have a remarkable
potential for metal binding, as they form a wide variety of complexes
that may differ in coordination number, geometry, or the number of
metal ions in the coordinating unit. The presence in the structure of
the three hard nitrogen donors that can easily coordinate the metal is
responsible for the complex formation ability of 1,2,4-triazoles. Due to
the position of these nitrogen atoms in the heterocyclic ring, 1,2,4-
triazoles can also coordinate together [40,41] to afford complexes that
could be of biological and medicinal interest [42]. Taking into account
the above-mentioned considerations for 1,2,4-triazoles and silicones, it
has been deemed interesting to connect multiple 1,2,4-triazole units
using silicone spacers with the view to enhance the biological and
metal bonding effects of the triazole moiety, and to generate novel
properties due to the particular nature of the silicone segment (e.g.,
high flexibility, hydrophobicity, low surface energy). Additionally, sev-
eral flexible bis-triazole ligands based on organic spacers have been
shown to be valuable candidates for building coordination polymers
with different architectures [43], and this is most likely to be true for
bis-triazole ligands derived from siloxane spacers as well.
2.1. Materials
1,3-Bis(chloromethyl)-1,1,3,3-tetramethyldisiloxane (assay 99%, bp
204.5–205 °C, linear formula ClCH2Si(CH3)2OSi(CH3)2CH2Cl, MW
231.27, d25 1.05 g/mL), and bis(chloromethyl)dimethylsilane (assay
97%, bp 159–160 °C, linear formula (CH3)2Si(CH2Cl)2, MW 157.11, d25
1.075 g/mL), acetohydrazide (90%, molecular formula C2H6N2O, MW
74.08, mp 58–68 °C), phenyl isothiocyanate (98%, molecular formula
C7H5NS, MW 135.19), anhydrous potassium carbonate (K2CO3, powder,
99.99%, MW 138.21), copper(II) chloride dihydrate (CuCl2·2H2O 99.9%,
MW 170.48) and N,N-dimethylformamide (DMF, p.a. 99.8%) were pur-
chased from Sigma Aldrich. 3-Mercapto-1,2,4-triazole (N98.0%(GC)(T),
molecular formula C2H3N3S, MW 101.13, mp 218.0–223.0 °C) and 3-
mercapto-4-methyl-1,2,4-triazole (N98.0%(T), molecular formula
C3H5N3S, MW 115.15, mp 165.0–169.0 °C) were purchased from TCI EU-
ROPE N.V. and used as such. Abs. ethanol (p.a.), acetone (p.a.) chloro-
form (p.a.) and ethyl acetate (p.a.) were obtained from Chemical
Company (Iaşi, Romania). Methanol (Emplura Grade, 98%) was pro-
vided by Merck Millipore.
3-Mercapto-4-phenyl-5-methyl-1,2,4-triazole 1 (molecular formula
C9H9N3S, MW 191.256) was prepared in a two-step reaction sequence
comprising the addition of acethydrazide to phenyl isothiocyanate,
followed by the ring closure of the resulting 2-acetyl-N-
phenylhydrazine-1-carbothioamide in the presence of KOH, as de-
scribed in the Experimental section.
The microorganisms required for the biological evaluation
(Aspergillus niger, Penicillium frequentans, Penicillium fumigatus,
Alternaria alternate, Fusarium, Pseudomonas aeruginosa and Bacillus
polymyxa) were provided by American Type Culture Collection
(ATCC), USA. Sabouraud agar medium with dextrose (4%, SDA) and
Standard
I nutrient agar medium were obtained from Merck
(Schwalbach Hesse, Germany). Reference compounds caspafugin and
kanamycin were from Liofilchem (Roseto degli Abruzzi, Italy).
2.2. Measurements
Fourier transform infrared (FT-IR) spectra were recorded using a
Bruker Vertex 70 FT-IR spectrometer. The experiments were performed
in the transmission mode in the range 400–4000 cm−1 at room temper-
ature with a resolution of 2 cm−1 and accumulation of 32 scans. NMR
spectra were recorded on a Bruker Avance NEO 400 MHz Spectrometer
equipped with a 5 mm BBFO direct detection probe and z-gradients. The
spectra were recorded in DMSO d6 at room temperature, and the chem-
ical shifts are reported as δ values (ppm) using the solvent residual peak
(2.51 for 1H and 39.5 for 13C) as reference. Carbon, hydrogen, nitrogen
and sulfur content were determined on a Perkin–Elmer CHNS 2400 II el-
emental analyser. Differential scanning calorimetry (DSC) measure-
ments were performed on a DSC 200 F3 Maia (Netzsch, Germany) in
the range − 150 ÷ 200 °C applying a heating and cooling rate of 10
Therefore, the present paper aims at derivatizing selected silanes
and siloxanes in a telechelic manner with different 1,2,4-triazole deriv-
atives to give the corresponding bis-triazoles. To the best of our knowl-
edge, only a small number of similar structures have been mentioned so
far in literature reports dealing mostly with medicinal or biological ap-
plications. Siloxane derivatives of triazoles have been not reported
until 2016, when a study describing their preparation through the alkyl-
ation
of
triazoles
with
1,3-bis(iodomethyl)-1,1,3,3-

G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
3
°C/min. About 10 mg of sample were heated in pressed and punched
2.3. Computational calculations
aluminum crucibles using nitrogen as flowing inert purge gas at a flow
rate of 100 mL/min. Melting points were taken on a MEL-TEMP capillary
melting point apparatus and are uncorrected. UV–Vis absorption spec-
tra measurements were carried out in methanol solution on a Specord
200 spectrophotometer.
Two theoretical approaches have been combined to describe the
mechanism of binding between the ligands (triazole derivatives) and
the receptor (enzyme, 14α-Demethylase, Aspergillus fumigatus). The
first theoretical procedure was based on quantum mechanics (QM) cal-
culations and the second was the molecular docking. The QM calcula-
tions were employed to predict the structures, the dipole moment as
well as the metal binding ability. The QM computations were based on
ab initio method predicting the structure of metal chelating complexes.
The Hartree-Fock (HF) functional was used with LanL2DZ basis set. All
electronic calculations were carried out with Gaussian G09 program
[50].
2.2.1. X-ray crystallography
X-ray diffraction measurements for compounds 1, 2 and 4 were car-
ried out with an Oxford-Diffraction XCALIBUR E CCD diffractometer
equipped with graphite-monochromated MoKα radiation. Single crys-
tals were positioned at 40 mm from the detector and 392, and 395
frames were measured each for 30, and 70 s over 1° scan width for 2,
and 4, respectively. Intensity data for 5, 6 and 7 were collected with Ox-
ford Diffraction SuperNova diffractometer using hi-flux micro-focus
Nova CuKα (or MoKα radiation). The single crystal was positioned at
49 mm from the detector and 457, 430 and 463 frames were measured
each for 50, 30 and 30 s over 1° scan width for 5, 6 and 7, respectively.
The unit cell determination and data integration were carried out
using the CrysAlis package of Oxford Diffraction [47]. The structures
were solved by direct methods using Olex2 [48] software with the
SHELXS structure solution program and refined by full-matrix least-
squares on F2 with SHELXL-97 [49] using an anisotropic model for
non hydrogen atoms. All H atoms were introduced in idealised positions
(dCH = 0.96 Å) using the riding model. The positional parameters for H-
atoms attached to O or N were verified by the geometric parameters of
the possible hydrogen bonds. The molecular plots were obtained using
the Olex2 program. The crystallographic data and refinement details
are quoted in Table 1, while bond lengths are summarized in Table S1.
CCDC-1847845 (1) CCDC-1846905 (2), CCDC-1846906 (4), CCDC-
1846907 (5), CCDC–1846908 (6) and CCDC-1846909 (7) contain the
supplementary crystallographic data for this contribution. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or
deposit@ccdc.ca.ac.uk).
The dipole moment of triazole derivatives and their metal binding
capacity were also evaluated with HF/Lan2DZ level of theory. The bind-
ing energy of metal-ligand complex (ML) was computed on equilibrium
geometries by the following formula:
ꢀ ꢀ
ꢁ
ꢁ
E
bindM−L ¼ EðM−L complexÞ− E M2þ þ EðLÞ
where E(M-L complex) would be the energy of the whole metal com-
plex, E(M2+) is the energy of the metal cation, E(L) is the energy of the
ligands silicone bis-triazoles ligand without metal (L(7)).
The molecular docking was performed with AutoDock 4.2 software
package [51]. The number of docking trials was set to 1000 poses,
while ligand structure was kept flexible in order to obtain more confor-
mations with low energies. The molecular docking simulations were re-
peated to confirm that the results are reproducible. The initial ligands
structures were obtained from crystallographic data. The 14α-
Demethylase (Aspergillus fumigatus) was selected as the target enzyme
and was taken from the Protein Data Bank (PDB) code 6CR2 [52]. The
ligand-enzyme complex with the lowest Kd was selected as the most
probable binding mode for each compound. Because the parametriza-
tion for Si atom is missing from AutoDock, the empirical parameters
for this atom were taken over from carbon (which it is isoelectronic
Table 1
Crystal data and details of data collection.
Compound
1
2
4
5
6
7
Empirical formula
Fw
C9H9N3S
191.25
C24H32N6OS2Si2
540.86
C10H20N6OS2Si2
360.62
C23.5H33.5N6.5O1.5S2Si
523.28
C10H18N6S2Si
314.51
C8H14N6S2Si
286.46
T [K]
294
293
200
293
293
293(2)
Crystal system
Space group
a [Å]
b [Å]
c [Å]
Triclinic
P-1
Triclinic
P-1
Triclinic
P-1
Orthorhombic
Pmn21
21.445(4)
10.1967(17)
6.6078(14)
90.00
90.00
90.00
1444.9(5)
2
1.203
Orthorhombic
Pnam
11.8768(12)
6.8522(5)
19.8637(19)
90.00
90.00
90.00
1616.5(3)
4
1.292
Trigonal
R-3
27.3748(16)
27.3748(16)
9.8198(6)
90.00
90.00
120.00
6372.9(7)
18
1.344
6.8845(7)
7.3728(8)
10.3138(9)
96.909(8)
93.589(8)
107.554(10)
492.79(9)
2
9.2110(11)
12.3774(14)
14.0350(16)
73.983(10)
74.816(10)
71.495(10)
1431.5(3)
2
8.0129(5)
8.9536(7)
13.9206(12)
79.051(7)
84.366(6)
70.593(7)
924.16(12)
2
α [°]
β [°]
γ [°]
V [Å3]
Z
ρ
calcd [g cm−3
]
1.289
0.284
1.255
0.298
1.296
0.425
μ [mm−1
]
0.255
0.400
4.145
Crystal size [mm]
Radiation
0.30 × 0.30 × 0.02
0.30 × 0.20 × 0.05
0.20 × 0.06 × 0.02
0.30 × 0.15 × 0.03
0.20 × 0.05 × 0.02
0.25 × 0.01 × 0.01
MoKα (λ = 0.71073) MoKα (λ = 0.71073) MoKα (λ = 0.71073) MoKα (λ = 0.71073) MoKα (λ = 0.71073) CuKα (λ = 1.54184)
2Θ range
4 to 48.814
3068
1613 [Rint = 0.0356]
1613/0/119
0.0891
3.08 to 50.04
9658
5029 [Rint = 0.0422]
5029/0/322
0.0734
0.1556
1.064
0.33/−0.21
2.98 to 50.04
6374
3270 [Rint = 0.0349]
3270/0/194
0.0549
0.1142
1.062
0.31/−0.33
6.46 to 50.06
10,204
2597 [Rint = 0.0708]
2597/8/166
0.0691
0.1952
1.028
0.44/−0.35
6.28 to 50.06
10,430
1467 [Rint = 0.0458]
1467/0/94
0.0584
0.1653
1.030
0.30/−0.24
21.8 to 141
4630
2625 [Rint = 0.0399]
2625/0/160
0.0467
0.1045
1.031
0.23/−0.23
Reflections collected
Independent reflections
Data/restraints/parameters
a
R1
b
wR2
0.2470
1.102
GOFc
Largest diff. peak/hole/e Å−3 0.68/−0.26
a
R1 = Σ||Fo|−|Fc||/Σ|Fo|.
b
wR2 = {Σ[w(F2o−F2c)2]/Σ[w(Fo2)2]}1/2
.
c
GOF = {Σ[w(F2o−Fc2)2]/(n−p)}1/2, where n is the number of reflections and p is the total number of parameters refined.

4
G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
with Si atom), except the charges (Gasteiger) and the van der Waals pa-
rameters, which were computed in accordance with the AutoDock 4.2
methodology.
954w, 906w, 842vs, 808vs, 754w, 694m, 648m, 532w. 1H NMR
(DMSO-d6, 400.13 MHz,): δ (ppm) 8.55 (s, 2H, CH from triazole), 3.56
(s, 6H, N-CH3 overlapped with the residual peak of water from solvent),
2.47 (s, 4H, S-CH2-Si), 0.20 (s, 12H, Si-CH3). 13C NMR (DMSO-d6,
100.6 MHz,): δ (ppm) 150.7 (C\\S from triazole), 146.0 (CH from tri-
azole), 30.6 (N-CH3), 18.1 (S-CH2-Si), −0.1 (Si-CH3). Anal. Calcd. for
2.4. Synthesis
2.4.1. 3-Mercapto-4-phenyl-5-methyl-1,2,4-triazole, 1
C12H24N6OS2Si2 (M = 388.659 g/mol),%: C, 37.08; H, 6.22; N, 21.62; S,
To a solution of acethydrazide (814 mg, 10 mmole, 90% purity) in
abs. ethanol (10 mL), phenyl isothiocyanate (1.35 g, 10 mmole) was
added. The mixture was heated at reflux temperature for 1 h, it was
allowed to cool at room temperature, and then it was refrigerated for
3 h. The crystalline material was filtered, sequentially washed with
cold isopropanol (2 × 5 mL) and hexanes (1 × 10 mL), and air-dried.
The resulting 2-acetyl-N-phenylhydrazine-1-carbothioamide (1.96 g,
9.38 mmole) was added to a solution of KOH (741 mg, 11.25 mmole,
85% purity) in water (30 mL), and the mixture was heated at reflux tem-
perature for 3 h. The cold reaction mixture was filtered, and then the fil-
trate was treated dropwise under efficient stirring with 10% HCl until
pH 2. The solid material was filtered, washed thoroughly with water,
air-dried and recrystallized to give colorless crystals (1.415 g, 79%),
mp 214–215 °C (ethanol). IR spectrum (KBr pellet), νmax: 3099s,
3051s, 2916s, 2906s, 2758m, 2729s, 1582m, 1501vs. 1H NMR,
(400.13 MHz, δ (ppm), DMSO-d6): 13.65 (s, 1H, NH), 7.59–7.42 (m,
5H, aromatic protons), 2.09 (s, 3H, CH3). 13C NMR, (100.6 MHz, δ
(ppm), DMSO-d6): 167.4 (C=S), 149.1 (C-CH3), 133.8 (C\\N), 129.3,
128.1 (aromatic carbon atoms), 11.7 (CH3). Anal. Calcd. for C9H9N3S
(M = 191.25 g/mol), %: C, 56.52; H, 4.74; N, 21.97; S, 16.77. Found: C,
56.34; H, 4.52; N, 21.85; S, 16.87.
16.50. Found: C, 37.34; H, 6.27; N, 21.78; S, 16.76.
2.4.4. 1,3-Bis{[(4H-1,2,4-triazol-3-yl)thio]methyl}-1,1,3,3-
tetramethyldisiloxane, 4
A solution of 1,3-bis(chloromethyl)tetramethyldisiloxane (0.18 g,
0.78 mmole) in acetone (2.5 mL) was added to the solution of 3-
mercapto-1,2,4-triazole (0.16 g, 1.56 mmole) in acetone (4.5 mL). An-
hydrous K2CO3 (0.24 g, 1.72 mmole) was then added, and the mixture
was heated at reflux temperature for 5 h. After the inorganic salts
were filtered off, compound 4 was isolated from the filtrate and purified
in a manner similar to the one described for compound 3. Yield 0.23 g
(79%). Tm 110 °C (DSC peak), Tg −15 °C. UV–vis (methanol, 4.62
× 10−5 M): λmax (ε, M−1 cm−1) 236 (14653). IR (KBr): νmax 3103w,
2958m, 2902m, 1645w, 1521w, 1458s, 1396w, 1338m, 1257vs,
1182m, 1136w, 1066vs, 898w, 839vs, 806vs, 756w, 707w, 497w. 1H
NMR (DMSO-d6, 400.13 MHz,): δ (ppm) 13.93 (s, 2H, NH), 8.34 (s, 2H,
CH from triazole), 2.42 (s, 4H, S-CH2-Si), 0.18 (s, 12H, Si-CH3). 13C
NMR (DMSO-d6, 100.6 MHz,): δ (ppm) 158.2 (C\\S from triazole),
146.5 (CH from triazole), 17.2 (S-CH2-Si), −0.1 (Si-CH3). Anal. Calcd.
for C10H20N6OS2Si2 (M = 360.606 g/mol), %: C, 33.31; H, 5.59; N,
23.31; S, 17.78. Found: C, 33.45; H, 5.83; N, 23.45; S, 17.32.
2.4.2. 1,1,3,3-Tetramethyl-1,3-bis{[(5-methyl-4-phenyl-4H-1,2,4-triazol-
3-yl)thio]methyl}disiloxane, 2
2.4.5.
methyl}silane, 5
Dimethylbis{[(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)thio]
A solution of 1,3-bis(chloromethyl)tetramethyldisiloxane (0.18 g,
0.78 mmole) in acetone (2.5 mL) was added to the solution of 3-
mercapto-4-phenyl-5-methyl-1,2,4-triazole 1 (0.30 g, 1.56 mmole) in
acetone (4.5 mL). Anhydrous K2CO3 (0.24 g, 1.72 mmole) was then
added, and the mixture was heated at reflux temperature for 5 h.
Then, the inorganic salts were filtered off, and crystals of compound 2
gradually separated from the filtrate as acetone slowly evaporated.
The crystals were filtered, washed with methanol and dried. Yield
0.35 g (83%). Tm 131 °C (DSC peak), Tg 2 °C. UV–vis (methanol, 3.8
× 10−5 M): λmax (ε, M−1 cm−1) 248 (16563). IR (KBr): νmax 3059w,
2960m, 2904w, 2374w, 1595m, 1533m, 1498s, 1433s, 1384s, 1317m,
1257s, 1134w, 1060vs, 839vs, 808vs, 727w, 694s, 555m. 1H NMR
(DMSO-d6, 400.13 MHz,): δ (ppm) 7.61–7.42 (m, 10H, aromatic pro-
tons), 2.35 (s, 4H, S-CH2-Si), 2.19 (s, 6H, triazole-CH3), 0.06 (s, 12H, Si-
CH3). 13C NMR (DMSO-d6, 100.6 MHz,): δ (ppm) 152.3 (C-CH3), 151.0
(C\\S from triazole), 133.2 (C\\N from phenyl), 129.9–127.0 (5 aro-
matic carbons), 17.6 (S-CH2-Si), 10.8 (triazole-CH3), −0.2 (Si-CH3).
Anal. Calcd. for C24H32N6OS2Si2 (M = 540.86 g/mol), %: C, 53.30; H,
5.96; N, 15.54; S, 11.86. Found: C, 53.55; H, 5.99; N, 15.50; S, 11.91.
A solution of bis(chloromethyl)dimethylsilane (0.12 g, 0.78 mmole)
in acetone (2.5 mL) was added to the solution of 3-mercapto-4-phenyl-
5-methyl-1,2,4-triazole 1 (0.30 g, 1.56 mmole) in acetone (4.5 mL). An-
hydrous K2CO3 (0.24 g, 1.72 mmole) was then added, and the mixture
was heated at reflux temperature for 5 h. The inorganic salts were fil-
tered off, and then the filtrate was allowed to slowly evaporate. The
resulting residue was dissolved in a warm mixture of ethyl acetate:
DMF (2.5 mL, 1:10 v/v), then the solution was brought to room temper-
ature. The product crystallized in a few hours, and it was filtered off, rap-
idly washed with a small volume of ethyl acetate and dried. Yield 0.29 g
(81%). Tm 136 °C (DSC peak), Tg −17 °C. UV–vis (methanol, 5.8
× 10−5 M): λmax (ε, M−1 cm−1) 256 (19406). IR (KBr): νmax 3055w,
2955 m, 2903 m, 2747w, 1709vs, 1589s, 1533m, 1499vs, 1423s, 1319s,
1256s, 1045s, 916w, 841s, 772s, 729m, 694s, 609w, 557m, 500w. 1H
NMR (DMSO-d6, 400.13 MHz,): δ (ppm) 7.60–7.42 (m, 10H, aromatic
protons), 2.43 (s, 4H, S-CH2-Si), 2.18 (s, 6H, triazole-CH3), 0.06 (s, 6H,
Si-CH3). 13C NMR (DMSO-d6, 100.6 MHz,): δ (ppm) 152.9 (C-CH3),
151.3 (C\\S from triazole), 133.7 (C\\N from phenyl), 129.9–127.0
(5C, aromatic carbons), 15.4 (S-CH2-Si), 11.3 (triazole-CH3), −3.5 (Si-
CH3). Anal. Calcd. for C47H67N13O3S4Si2 (M = 1046.58 g/mol), %: C,
53.94; H, 6.45; N, 17.40; S, 12.26. Found: C, 54.41; H, 6.70; N, 17.75; S,
12.65.
2.4.3. 1,1,3,3-Tetramethyl-1,3-bis{[(4-methyl-4H-1,2,4-triazol-3-yl)thio]
methyl}disiloxane, 3
A solution of 1,3-bis(chloromethyl)tetramethyldisiloxane (0.18 g,
0.78 mmole) in acetone (2.5 mL) was added to the solution of 3-
mercapto-4-methyl-1,2,4-triazole (0.18 g, 1.56 mmole) in acetone
(4.5 mL). Anhydrous K2CO3 (0.24 g, 1.72 mmole) was then added, and
the mixture was heated at reflux temperature for 5 h. Afterwards, the
inorganic salts were filtered off, and the filtrate was allowed to slowly
evaporate to afford a residue which was dissolved in chloroform. The
resulting solution was repeatedly extracted with water (3 × 10 mL),
dried over anh. Na2SO4, and allowed to slowly evaporate to give a crys-
talline material. Yield 0.22 g (72%). Tm 104 °C (DSC peak), Tg −30 °C.
UV–vis (methanol, 4.28 × 10−5 M): λmax (ε, M−1 cm−1) 249 (9539).
IR (KBr): νmax 3109w, 3012vw, 2956m, 2904w, 1649w, 1562vw,
1512s, 1473m, 1421s, 1365m, 1257vd, 1201m, 116m, 1132w, 1066vs,
2.4.6. Dimethylbis{[(4-methyl-4H-1,2,4-triazol-3-yl)thio]methyl}silane, 6
A solution of bis(chloromethyl)dimethylsilane (0.12 g, 0.78 mmole)
in acetone (2.5 mL) was added to the solution of 3-mercapto-4-methyl-
1,2,4-triazole (0.18 g, 1.56 mmole) in acetone (4.5 mL). Anhydrous
K2CO3 (0.24 g, 1.72 mmole) was then added, and the mixture was
heated at reflux temperature for 5 h. The inorganic salts were filtered
off, and the filtrate was processed in a manner similar to the one de-
scribed for compound 5 to give bis-triazole 6. Yield 0.21 g (85%). Tm
146 °C (DSC peak), Tg −18 °C. UV–vis (methanol, 5.29 × 10−5 M):
λmax (ε, M−1 cm−1) 250 (19024). IR (KBr): νmax 3859w, 3742w,
3627w, 3564w, 3096m, 3007m, 2957m, 2908w, 2355w, 1653w,
1558w, 1528s, 1472s, 1418s, 1362s, 1254s, 1213s, 1159m, 1067s,

G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
5
991w, 955w, 833vs, 725m, 690m, 648m, 432w. 1H NMR (DMSO-d6,
3. Results and discussion
400.13 MHz,): δ (ppm) 8.53 (s, 2H, CH from triazole), 3.57 (s, 6H, N-
CH3), 2.55 (s, 4H, S-CH2-Si), 0.18 (s, 6H, Si-CH3). 13C NMR (DMSO-d6,
100.6 MHz,): δ (ppm) 150.4 (C\\S from triazole), 146.1 (CH from tri-
azole), 30.6 (N-CH3), 15.6 (S-CH2-Si), −4.1 (Si-CH3). Anal. Calcd. for
3.1. Synthesis of bis-triazoles and structural analysis
Alkylation of thiols with alkyl halides is a well-known method for
the formation of thioethers. This paper reports the S-alkylation of
three mercaptotriazoles, namely 3-mercapto-1,2,4-triazole, 3-
mercapto-4-methyl-1,2,4-triazole, and 3-mercapto-4-phenyl-5-
methyl-1,2,4-triazole with two silicon-containing alkylating agents,
namely 1,3-bis(chloromethyl)-1,1,3,3-tetramethyldisiloxane and bis
(chloromethyl)dimethylsilane (Scheme 1). While all other reagents
were purchased from the market, 3-mercapto-4-phenyl-5-methyl-
1,2,4-triazole was synthesized and characterized in the laboratory
(Figs. S1–S4). The thioalkylation reactions were conducted in the pres-
ence of K2CO3 in acetone at reflux temperature. Acetone, rather than
DMF (another solvent recommended for such reactions [54]), was the
solvent we chose owing to its good miscibility with siloxanes/silicones.
The progress of the S-alkylation reaction was monitored by IR spec-
troscopy. Thus, the decrease in intensity and, finally, the disappearance
of the absorption band corresponding to the S\\H bond in
mercaptotriazole at around 2620 cm−1, corroborated with the disap-
pearance of the absorption band for the C\\Cl bond in chloromethyl-
terminated silicones at approximately 750 cm−1, was indicative for
the gradual advance of the reaction to completion. In the same manner,
the increase in intensity of the S\\C band around 550–560 cm−1 was
suggestive for the formation of thioethers 2–7. Additional evidence for
the conversion of mercaptotriazole into the corresponding thioether is
the modification of the IR absorption pattern for C\\H stretch band of
the triazole ring or, for compounds 1 and 2, from the phenyl ring. In
the case of the starting mercaptotriazoles, this pattern consists of two
bands around 3000–3100 cm−1 (3051 and 3100 cm−1 in the case of
3-mercapto-4-phenyl-5-methyl-1,2,4-triazole, 3117 and 3165 cm−1 in
the case of 3-mercapto-4-methyl-1,2,4-triazole, 3084 and 3144 cm−1
in the case of 3-mercapto-1,2,4-triazole) that correspond to the two tau-
tomeric forms (thiol and thione) of this particular type of compounds.
The aromatic C\\H stretch appears as a single band for the correspond-
ing thioethers lacking the possibility of tautomerism (3046, 3109, 3103,
3055, 3115, and 3117 cm−1 in the case of compound 2, 3, 4, 5, 6, and 7,
respectively) (for more, see ESI). Once the reaction was complete, the
inorganic salts were filtered off, and the reaction product was isolated
from the filtrate by different procedures, depending on the structure
of the product. Thus, compound 2 was separated directly in crystalline
form from the filtrate by slow evaporation of the solvent, while in
other cases (compounds 3 and 4), the isolation of the product consisted
in the evaporation of acetone, followed by repeated extractions with
water of the solution of the resulting residue in chloroform in order to
completely remove the inorganic salts. A crystalline product separated
from the chloroform solution after slow evaporation of the solvent. Si-
lane derivatives 5–7 crystallize well from ethyl acetate in the presence
of a few drops of DMF. The yields range from good to excellent, and pu-
rity of the separated products was high, as shown by the results of the
elemental analysis (vide supra). The chemical shift of the peaks in the
1H and 13C NMR spectra, along with the integral ratios of the peaks
from the 1H NMR spectra, confirm that the proposed structures for com-
pounds 2–7 are correct. Also, the correlation between the triazole car-
bon attached to sulfur (151–158 ppm) and the protons in the
methylene group adjacent to sulfur (2.35–2.55 ppm) in the H,C-HMBC
spectra for compounds 2–7 indicates that the reactions took place
with the formation of a novel covalent bond between the sulfur atom
in mercaptotriazoles and the terminal carbon atom in the silicones
used as starting materials (Figs. S5–S22).
C10H18N6S2Si (314.505 g/mol), %: C, 38.19; H, 5.77; N, 26.72; S, 20.39.
Found: C, 38.52; H, 5.43; N, 27.01; S, 20.72.
2.4.7. Bis{[(4H-1,2,4-triazol-3-yl)thio}methyl}dimethylsilane, 7
A solution of bis(chloromethyl)dimethylsilane (0.12 g, 0.78 mmole)
in acetone (2.5 mL) was added to the solution of 3-mercapto-1,2,4-tri-
azole (0.16 g, 1.56 mmole) in acetone (4.5 mL). Anhydrous K2CO3
(0.24 g, 1.72 mmole) was then added, and the mixture was heated at re-
flux temperature for 5 h. The inorganic salts were filtered off to give a
filtrate that was processed in a manner similar to the one described
above for compound 5 to afford bis-triazole 7. Yield 0.18 g (82%). Tm
167 °C (DSC peak), Tg −7 °C. UV–vis (methanol, 3.49 × 10−5 M): λmax
(ε, M−1 cm−1): 243 (16143). IR (KBr): νmax 3851vw, 3782vw, 3638w,
3574w, 3117s, 2944m, 2904m, 1659w, 1516m, 1464s, 1404m, 1344vs,
1256vs, 1178m, 1134w, 1051m, 1005w, 966w, 845vs, 760w, 698m,
636w, 500w, 407vw. 1H NMR (DMSO-d6, 400.13 MHz,): δ (ppm) 8.29
(s, 2H, CH from triazole), 7.38 (s, 2H, NH), 2.48 (s, 4H, S-CH2-Si), 0.15
(s, 6H, Si-CH3). 13C NMR (DMSO-d6, 100.6 MHz,): δ (ppm) 157.8 (C\\S
from triazole), 146.9 (CH from triazole), 14.7 (S-CH2-Si), −3.9 (Si-
CH3). Anal. Calcd. for C8H14N6S2Si (286.452 g/mol), %: 33.54; H, 4.93;
N, 29.34; S, 22.39. Found: C, 33.89; H, 5.20; N, 28.98; S, 22.77.
2.5. Assessment of metal binding capacity
In order to investigate the complex formation ability of the newly
synthesized compounds, stock solutions of bis-triazole derivatives 2–7
(0.1 mM) in methanol and CuCl2·2H2O (1 mM) in methanol were pre-
pared. In titration experiments, increasing volumes (containing up to 10
equivalents of CuCl2·2H2O) of diluted metal ion solution in methanol
were sequentially added into the solution of the bis-triazole derivatives.
The samples were mixed at room temperature prior to each UV–vis
measurement. Spectra were recorded in the 200–400 nm spectral
range at room temperature.
2.6. Assessment of antimicrobial activity
Antibacterial and fungicidal activity was evaluated by performing
in vitro tests against pure culture of five fungi species, one Gram-
negative and one Gram-positive bacteria. Antimicrobial evaluation
was performed by the MIC test strip method according to standard pro-
cedures [53]. Cultivation was performed by using a mixture of 1:1 mi-
croorganism suspension and solution of the compound to be tested
that were placed on the solid medium. When the MIC Test Strip is ap-
plied onto an inoculated agar surface, the preformed exponential gradi-
ent of antimicrobial agent is immediately transferred to the agar matrix.
After 48 h of incubation a symmetrical inhibition ellipse centered along
the strip was formed. The MIC value is read directly from the scale as
μg/mL at the point where the edge of the inhibition ellipse of intersects
with the MIC test strip. Observations on the results were made by visual
analysis and microscopy, using a Novex stereomicroscope Ap-8
Euromex (Olympus Europa Holding GmbH, Hamburg, Germany) and
Olympus SZY 160 microscope (Olympus Corporation, Shinjuku, Tokyo,
Japan). MIC Test Strip is a quantitative assay for determining the Mini-
mum Inhibitory Concentration MIC of antimicrobial agents against mi-
croorganisms and for detecting the resistance mechanisms [53]. It
should be noted that Sabouraud agar medium with dextrose (4%,
SDA) was used for fungi, while a Standard I nutrient agar medium was
used for bacteria.
DSC scans in the temperature range of −150 ÷ 200 °C, which have
been performed for all the newly synthesized compounds, revealed a
melting endotherm (Tm) along with a clear, second order transition
assigned to the glass transition (Tg). In the case of bis-triazoles 2–7,
the observed glass transitions could be tentatively explained, on one

6
G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
N N
N N
N N
K2CO3
S
Si
Si
S
R2
O
R2
2
+ Cl
Si
Si
Cl
R2
SH
acetone, 60 oC
-2 KCl
O
N
N
N
n
n
R1
R1
R1
R1=-C6H5; R2= -CH3 (5)
R1= -CH3; R2= -H (6)
R1= -H; R2= -H (7)
R1=-C6H5; R2= -CH3 (2)
R1= -CH3; R2= -H (3)
R1= -H; R2= -H (4)
n=0,
n=1,
Scheme 1. Alkylation reaction of 3-mercapto-1,2,4-triazole derivatives with 1,3-bis(chloromethyl)-1,1,3,3-tetramethyldisiloxane and bis(chloromethyl)dimethylsilane leading to
compounds 2–7.
hand, by the presence of the seven-atom long spacer between the tri-
azole rings for the siloxane derivatives 2–4 and of the five atom bridges
for silanes 5–7, and, on the other hand, by the crystal packing of these
compounds (vide infra) in extended structures (one-, two- or three-
dimensional) either through hydrogen bonds (case of the compounds
4, 6 and 7) or intermolecular π-π stacking (compound 5). However, Tg
glass transition also occurs in the case of compound 2, whose crystal
structure has been found to be composed of discrete molecules that in-
teract poorly. Consequently, it seems that the presence of the spacer is
the main cause for the detected glass transitions, a conclusion that is
supported by the observation that, with the exception of value recorded
for compound 2, all the values of Tg are negative, ranging between −7
and −30 °C, and this is specific for highly flexible silicones. Low Tg
values are associated with an increased difficulty in obtaining crystalline
materials, as was the case for compound 3 (Tg −30 °C), for which it was
not possible to isolate a suitable crystal for an accurate structural analy-
sis. As expected, melting temperatures are lower than those of the
starting triazoles, and range from 104 °C (compound 3) to 167 °C (com-
pound 7). It is noteworthy that silane derivatives have higher melting
temperatures than their siloxane counterparts.
dimeric supramolecular units (Fig. 2) formed via hydrogen bonding be-
tween N\\H group of triazole system as donor and sulfur atom of adja-
cent molecule, as acceptor of proton.
In compounds 2 and 4, the central part of the molecules is formed by
a tetramethyldisiloxane fragment (Fig. 3) showing close geometric pa-
rameters. The average Si\\O distance and Si-O-Si angles are of 1.626
(4) Å, 1.624(3) Å and 152.5(2)°, 155.7(2)°, for 2 and 4, respectively.
Due to high flexibility of the spacer, such compounds could adopt either
trans or cis conformations as it was found in the case of ethane or pro-
pane spacers [55]. According to X-ray crystallography, molecule 2 has
a trans-oid configuration (Fig. 3a), while 4 has a cis-oid configuration,
which is stabilized by the intramolecular stacking interaction between
triazole rings at 3.56 Å of centroid-to-centroid distance (Fig. 3b). In
the case of compound 2, the π-π triazole interaction is not possible
due to the presence of phenyl substituents, which are not in the same
plane as the triazole rings. Obviously, the adoption of a particular con-
formation affects the packaging in the crystalline structure. The crystal
structure of compound 2 can be characterized as the packing of discrete,
weakly interacting molecules. In opposition to this, the crystal packing
for compound 4 shows the presence of one-dimensional supramolecu-
lar chains due to fragments that are potential proton donors or proton
acceptors. A view of the main crystal structure motif in the crystal 4,
consolidated by N-H—N hydrogen-bonds is depicted in Fig. 4.
3.1.1. Crystallographic analysis
The results of X-ray diffraction study of the precursor 1 and the com-
pounds 2–7 are shown in Figs. 1–7, while bond distances and angles are
listed in Table S1. All the studied compounds have a molecular crystal
structure, which is built up from the corresponding neutral molecules
without any co-crystallized solvent molecules except the compound 5,
which crystalizes with DMF and H2O molecules in 1:0.5:1 ratio.
As shown in Fig. 1, in the crystal state the molecule 1 exhibit essen-
tially non-planar configuration with the dihedral angle between triazole
and phenyl rings at 75.7(3)°. The crystal structure is built from the
In an effort to elucidate the crystal structure of compound 3, its crys-
tallization from a large variety of mixed solvents has been repeatedly
attempted. Unfortunately, all the experiments gave only a bunch of
small-sized polycrystalline products unsuitable for single-crystal X-ray
diffraction studies. All of the tested crystals were weakly diffracting with
quite low resolution, and the reciprocal space has clearly showed the
Fig. 1. X-ray molecular structure of 1 with atom labeling and thermal ellipsoids at 50%
probability.
Fig. 2. Dimeric associate in the crystal structure 1. H-bond parameters: N2-H—S1 [N2\\H
0.86 Å, H—S1 2.42 Å, H—S1(1 –x, 2 – y, 1 - -z) 3.274(4) Å, ∠ N2HS1 173.6°.

G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
7
Fig. 3. X-ray molecular structure of compounds 2 (a) and 4 (b) with atom labeling scheme and thermal ellipsoids at 540% probability. Centroid-to-centroid contact is shown in orange-
dashed line.
presence of an aggregate of several crystalline grains. Nevertheless, the
structure could be solved and the electron density of the molecule was
well defined, allowing the determination of the atomic connectivity. The
model of the structure was refined with anisotropic temperature factors
for all non hydrogen atoms (see Fig. S23 and exp_532.res file SI). The
model proposed on the basis of these attempts is supported by the results
of complementary analysis (elemental, IR, NMR). The structure of this
compound was also designed and optimized towards reached to equilib-
rium structure (Fig. S24), level of theory for optimization procedure being
that described in Computational calculations section.
b and c, respectively. The bond lengths and angles are summarized in
Table S1.
In the crystals of 5 and 6, the packing of the neutral molecules shows
the presence of two-dimensional supramolecular network, as depicted
in Fig. 6a and b, respectively. In the case of compound 5, 2D layers are
formed due to the intermolecular π-π stacking between centro-
symmetrically related triazole rings at 3.447 Å (Fig. 6a). In the crystal
of 6, the formation of the wave-like 2D network is driven by C-H—N in-
termolecular hydrogen bonding (Fig. 6b). A partial view of the crystal
structure of 7 along c crystallographic axis is shown in Fig. 7. In this
case, the packing diagram can be characterized as a three-dimensional
supramolecular motif, based on the hydrogen bonding involving N\\H
The asymmetric parts of the crystal structures of compounds 5, 6
and 7, containing the dimethylsilane fragment are depicted in Fig. 5a,
Fig. 4. One-dimensional supramolecular architecture in the crystal structure 4. H-bonds parameters: N1-H—N2 [N1\\H 0.86 Å, H—N1 2.01 Å, N1—N2(1 - x, -y, 1 – z) 2.855(4) Å, ∠N1HN2
167.5°]; N2-H—N5 [N2\\H 0.86 Å, H—N5 2.02 Å, N2—N5(-x, 1 -y, 1 – z) 2.856(4) Å, ∠N2HN5 162.7°].

8
G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
a
b
c
Fig. 5. X-ray molecular structure for: a - compound 5; b - compound 6; c – compound 7, with atom labeling and thermal ellipsoids at 50% probability. Symmetry code i) 1 – x, y, z.
groups as donors and nitrogen atoms as acceptors from two distinct tri-
azole rings (Fig. 7).
assigned to the LMCT (dπ(Cu(II)) → π*(L)), confirming the coordination
of Cu2+ ion by the triazole ring.
Under the same conditions, the sensing properties of bis-triazoles 2–
7 were also tested towards Zn2+ and Mn2+ but no change in the absorp-
tion maximum or the appearance of a novel band was noticed after se-
quential addition of increasing volumes of solutions containing either
Zn2+ or Mn2+ to the solution of bis-triazoles. Therefore, bis-triazoles
2–7 demonstrate a high selectivity towards Cu2+ in methanolic solu-
tion. A similar tendency of Cu(II) and Zn(II) towards different ligands
has been noted previously, when Cu2+ was strongly complexed by or-
ganic ligands, while a substantial part of Zn2+ remained as free Zn2+
in the water of an eutrophic lake [58]. This is not surprising, since Cu2
3.2. Assessment of metal bonding capacity
3.2.1. UV–vis titration
In a recent study, 1,3-bis[5-(2-hydroxyphenyl)-4-phenyl-1,2,4-tri-
azole-3-yl-thio]propane has been shown to act as a fluorescence sensor
for the detection of Zn2+, Cu2+ and Ni2+ [56]. The ability to form com-
plexes with transition metal ions and potentially act as sensors was also
investigated for our compounds. According to the Irving-Wiliam's [57],
the divalent 3d metals are placed in the following order after the stabil-
ity constant: Mn b Co b NibCuNZn, which has been confirmed for a great
variety of ligands. For evaluation of sensing properties of bis-triazole 2–
7 we considered Mn2+ ion, the last in the series, and Cu2+ and Zn2+, the
first in the Irving-William's order. The absorption spectra of the triazole
derivatives 2–7 recorded in methanol solution (Fig. 8) reveal a maxi-
binds to most ligands at least 100 times stronger than Zn2+ does
+
[59]. With many ligands, copper(II) complexes are more stable than
their zinc(II) counterparts, but increasing ligand rigidity has been
shown to improve selectivity towards Zn(II) [60]. The structural flexibil-
ity of our triazole derivatives could explain the selectivity for Cu(II)
complex formation. Addition of Cu2+ changed the color of the solution
from colorless to greenish due to the formation of the Cu(II) complex,
while the addition of Zn2+ or Mn2+ to the triazole solution did not
cause any change in color. The color and the stability of the Cu(II) com-
plex in solution was monitored in time, and there was no change in the
absorption maxima or the color of the solution after one week.
⁎
mum at 240–257 nm, assigned to the π-π transitions in the triazole
ring. Initially, the cation binding ability was studied by monitoring the
changes in the absorption spectra during the titration of triazole deriv-
atives with a solution of CuCl2 in methanol. Addition of different vol-
umes of 0.1 mM CuCl2 solutions (0.05 to 2 mL) red shifted the band
assigned to the triazole ring by 12–20 nm. The new band has been

G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
9
a
b
Fig. 6. View of two-dimensional supramolecular architecture in the crystal structure 5 (a) and 6 (b). Centroid-to-centroid distances and H-bonds are drawn in dashed orange and black
lines, respectively. Non-relevant H-atoms are not shown. H-bond parameters: C2-H—N2 [C2\\H 0.93 Å, H—N2 2.501 Å, C2-H—N2(1.5 – x, y – 0.5, 1 – x) 3.406(3) Å, ∠C2HN2 164.4°].

10
G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
Fig. 7. Crystal structure packing of compound 7, viewed along c crystallographic axis. The methyl groups of the silane fragments are not shown for clarity. H-bonds parameters: N3-H—N5
[N3\\H 0.86 Å, H—N5 1.98 Å, N3—N5(5/3 - y, 1/3 + x - y, z – 2/3) 2.835(3) Å, ∠N3HN5 173.0°]; N6-H—N1 [N6\\H 0.86 Å, H—N1 1.93 Å, N6—N1(1/3 + y, 2/3 –x + y, 2/3 – z) 2.815(4) Å,
∠N3HN1 172.5°].
The binding energies were computed taking into account the coordi-
248 nm (2), 249 nm (3), 240 nm (4), 257 nm (5), 250 nm (6),
243 nm (7) were extrapolated, which indicate a 1:1 (L:M) stoichiome-
try for all the complexes (Fig. 9).
nation possibility of compound 7 (as a ligand L(7)) to metal ions studied
experimentally (Cu2+, Zn2+, Mn2+) and two other metals (Co2+, Ni2+
)
in the Irving-Wiliam's series [57]. The theoretical results predict that the
complexation of Cu(II) (see Table 2) is more favored, which is consistent
with experimental results.
The stoichiometry was also determined by Job's method [61] in the
case of compound 2. In this study, the total concentration (2.5
× 10−5 M) of the triazole derivatives and metal ion was kept constant,
while the molar ratio metal ion/ligand was changed from 0 to 1. The
Job's plot data are shown in Table S2.
3.2.2. Stoichiometry
From the UV–vis titration experiments, the stoichiometric ratio of
each triazole derivatives to Cu2+ and the binding constant of the com-
plex (K) were calculated. The [Cu2+]/[L] ratios were 4.69 (2), 4.37 (3),
5.5 (4), 4.8 (5), 5.0 (6) and 4.9 (7) when the plots of the absorbance at
The plotted data (Fig. S25) show that the absorbance of the complex
reached a maximum when the molar ratio between Cu2+ and triazole
derivative 2 is approximately 0.5, which is indicative of a 1:1 complex
formation.
Fig. 8. Changes in the UV–vis spectra of triazole derivatives 2–7 during titration with a solution of CuCl2. [Cu2+] mol/L: 1.75 × 10−6, 3.5 × 10−6, 5.4 × 10−6, 7.5 × 10−6, 9.6 × 10−6, 1.1
× 10−5, 1.36 × 10−5, 1.56 × 10−5, 1.74 × 10−5, 1.9 × 10−5, 2.1 × 10−5, 2.24 × 10−5, 2.58 × 10−5, 2.74 × 10−5, 2.89 × 10−5, 3.06 × 10−5, 3.25 × 10−5, 3.4 × 10−5, 3.61 × 10−5, 3.79
× 10−5, 4.13 × 10−5, 4.3 × 10−5, 4.51 × 10−5, 4.68 × 10−5, 4.86 × 10−5, 5.04 × 10−5, 5.22 × 10−5, 5.39 × 10−5, 5.54 × 10−5, 5.71 × 10−5, 5.89 × 10−5, 5.96 × 10−5, 1.1 × 10−5, 6.27
× 10−5, 6.33 × 10−5, 6.63 × 10−5, 6.8 × 10−5, 7.5 × 10−5, 8.2 × 10−5, 9.5 × 10−5, 1.04 × 10−4
.

G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
11
Table 2
represents the stability constant of the complex (Fig. S26). The values
for the binding stability determined by this approach for the six bis-
triazoles are presented in Table 3.
Binding energies of M-L complexes for compound 7 as ligand,
L(7).
The highest value of the binding constant (8.87 × 103 M−1) was ob-
tained for the complex formation between triazole derivative 2 and Cu2
+. According to data showed in Table 3, it seems that the presence of the
phenyl and methyl moieties as electron donating groups in the triazole
ring (compounds 2, 3, 5 and 6) has a positive effect on the complexing
properties of the ligands. It can also be observed that, systematically,
the values for the siloxane derivatives are slightly higher than those of
the silane counterparts. The greater conformational flexibility of the for-
mer could be an explanation for this.
Complex
E
bind (kcal/mol)
Cu2+L(7)
Zn2+L(7)
Mn2+L(7)
Co2+L(7)
Ni2+L(7)
0
287.87
128.74
54.85
261.60
3.2.3. Copper binding constant determination
Owing to the great biological and environmental importance, a large
number of ligands for recognition and sensing of metal ions has been
designed and synthesized. Ligands containing triazole rings have
attracted tremendous interest as versatile ligands with a variety of coor-
dination modes to transition metal centers because of the versatile
chemistry and the various donor sites of triazoles.
3.3. Assessment of antimicrobial activity
Triazole derivatives are often used in anti-infectious therapies, with
triazole-based fluconazole being the first-choice antifungal agent, due
to its excellent safety, favorable pharmacokinetic characteristics and a
broad spectrum of biological activity. A large number of other triazole
antifungals are used clinically: voriconazole, itraconazole and
posaconazole. Due to lower electron density, the triazole has a lower co-
ordination capacity and therefore lower toxicity, as compared with im-
idazole isostere [39].
The binding ability of the synthesized bis-triazoles to Cu2+ was in-
vestigated by determining the binding constant using the Benesi-
Hildebrand equation [62]:
ꢂ
ꢂ
ꢃ
½Lꢀ
1
εk
1
¼
Þ þ
ΔA
Ks½Mꢀεk
The newly synthesized here bis-triazole compounds containing dif-
ferently substituted 1,2,4-triazole rings bridged through 1,3-bis(methy-
lene)tetramethyldisiloxane or bis(chloromethyl)dimethylsilane
moieties have been evaluated as antibacterials and antifungals using
in vitro testing against pure cultures of five fungi species (Aspergillus
niger, Penicillium frequentans, Penicillium fumigatus, Alternaria alternate,
Fusarium) and against selected Gram-negative (Pseudomonas
aeruginosa) and Gram-positive (Bacillus polymyxa) bacteria. The
where [L], [M] and εk are the concentrations of the ligand (triazole de-
rivative), concentrations of Cu2+ and molar absorption coefficient,
respectively;
ΔA = A−A0, [A] is the absorbance at each molar ratio of Cu2+ to li-
gand, and A0 is the absorbance in the absence of Cu2+
.
By plotting 1/ΔA as a function of the 1/[Cu2+], where [Cu2+] is the
concentration of copper(II) salt, one gets a straight line, whose slope
Fig. 9. Plots of the UV–vis absorbance of triazole derivatives 2–7 as a function of Cu2+ concentration.

12
G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
Table 3
The analysis of the results in Table S3 shows that none of the starting
materials used in the synthesis of compounds 2–7 exhibit significant an-
timicrobial activity. However, some of the investigated bis-triazoles 2–7
are very potent antimicrobial candidates, and their activity is compara-
ble or even higher than that of reference compounds caspofungin and
kanamicin. The cause of this manifestation could be one or all of these
elements: the presence of two triazole cycles in a single molecule,
Binding constant, K, for 1:1 complex formation of the triazole derivative with Cu2+ in
methanol solution at 25 °C.
Compound
2
3
4
5
6
7
K×10−3 (M−1
)
8.87
8.73
7.72
8.56
8.39
7.66
minimum inhibitory concentration (MIC) values obtained for com-
pounds 2–7 are summarized in Table S3, and the results are suggestively
presented in a concise graphic form in Fig. 10a,b.
their
coupling
by
the
flexible,
highly
hydrophobic
tetramethyldisiloxane spacer and the presence of thioether bridges.
The antimicrobial activity of these compounds becomes more potent
Fig. 10. Comparative representation of antifungal (a) and antibacterial (b) activities (as MIC values) of bis-triazoles 2–7 as 1.5 wt% solutions in methanol (M) and chloroform (C).

G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
13
with the increasing concentration of the sample, and is definitely de-
pendent on the nature of the solvent in which the tested compound is
dissolved. Thus, the results obtained for samples of a particular com-
pound dissolved in chloroform are consistently better than the results
obtained for the same compound in methanol. Blank tests have shown
that chloroform itself exerts a higher antimicrobial activity than metha-
nol. However, the higher activity found for some of the compounds in
the bis-triazoles series 2–7 in chloroform can not only be attributed to
chloroform's own antimicrobial activity. The best biological activity in
the series of tested compounds has been recorded for compound 7 at
a concentration of 1.5 wt% in chloroform, when this compound was
more active than the reference compounds. The MIC values for this
compound are 0.006 μg/mL for all fungi, compared to 0.3 μg/mL for
caspofungin. Meanwhile, the MIC values are 0.064 μg/mL for both bacte-
rium species, compared to 3.5 μg/mL for reference kanamycin. In con-
trast, the antimicrobial activity of compound 7 in methanolic solutions
is significantly lower, with MIC values of 0.75 μg/mL for fungi and 64
μg/mL for bacteria. Evaluation of compounds 3 and 5 also provided
good results against bacteria (MIC values of 0.094 and 0.25 μg/mL, re-
spectively) and fungi (MIC values of 0.098 and 0.012 μg/mL, respec-
tively) when used as a 1.5 wt% solution in chloroform. Compound 2
shows an antimicrobial activity that is similar or comparable to that of
the reference drugs.
Previous studies conducted with sixteen 3-mercapto-1,2,4-triazole
derivatives support the hypothesis of a correlation between dipole mo-
ment values and antibacterial activity [63]. Therefore, the values of the
dipole moment have been calculated for compounds 2–7 with HF/
Lan2DZ and the obtained values are graphically represented in Fig. 11.
As can be seen, in 2–4 compounds series with siloxane spacers, the di-
pole moment increases from the 3-mercapto-4-phenyl-5-methyl-
1,2,4-triazole derivative to the 3-mercapto-4-methyl-1,2,4-triazole
and 3-mercapto-1,2,4-triazole. In contrast, in the silane series, this hier-
archy is disturbed by compound 6 derived from 3-mercapto-4-methyl-
1,2,4-triazole, which has a dipole moment somewhat higher than com-
pound 7, which is derived from to 3-mercapto-1,2,4-triazole. As a result,
these values alone cannot explain the highest antibacterial activity of
compound 7, for example. Conformational factors may be responsible
for this.
thioether function. The co-existence in a structure of both hydrophilic
and hydrophobic fragments is characteristic for surfactants. Because
our compounds can be assimilated to surfactants, the hydrophilic-
lyophilic balance (HLB) was calculated using the Griffin [65,66] and Da-
vies [67] formula:
HLB ¼ ð%by weight hydrophilic partÞ=5
The obtained HLB values shown graphically in Fig. 11 lie between
3.73 and 7.06, which are characteristic for hydrophobic compounds
that include insoluble in water to water-dispersible materials. The HLB
values are in an increasing order in each of the two series based on silox-
ane (2 b 3 b 4) and silane (5 b 6 b 7) spacer. Compound 7, which is the
most potent candidate in our library, has the highest HLB value (7.06), a
correlation that is consistent with the behavior reported in ref. [65]. For
the other active compounds, namely 3, 5 and 2, the antibacterial activity
decreases with decreasing the HLB values. Nevertheless, the biologically
poorly active or inactive compounds 4 and 6 also have high HLB values
(5.60 and 6.43, respectively), but this lack of activity could be tentatively
associated with the influence of the substituents (implicitly their steric
effect) from the triazole ring. None of our compounds exhibited a signif-
icant antimicrobial activity in methanol, whereas they were very potent
when the samples for biological evaluation were prepared in chloro-
form. This would indicate that solvent-directed conformation and self-
assembly factors are responsible for the observed biological activity. A
tentative explanation for this behavior could be provided by the results
of DLS (Fig. S27) which, in case of methanol solutions, reveals mostly
the existence of molecular species having sub-nanometric hydrody-
namic diameter values, while in the chloroform, the compounds exist
mostly as aggregates of hundreds of nanometers. Understandably, the
aggregates in chloroform would be organized with the non-polar
tetramethyldisiloxane moiety on the outside, in close contact with the
solvent. This arrangement imparts an even more hydrophobic character
to these aggregates, and a higher availability for adsorption onto the
outer surface of bacteria, in a manner similar to that of alkylimidazolium
and alkylpyridinium compounds [68]. It is already accepted that more
lipophilic entities can more easily penetrate the cell membrane due to
their interaction with fatty acid fragments of the lipid bilayer [64]. It
could also be hypothesized that the poor interaction of triazole tails
with low polarity solvents allows them to be readily available to interact
with the microorganisms (e.g., to coordinate with the heme iron in
CYP51), thus inhibiting their growth [69]. The MIC values obtained for
the biocidal activity of the compounds described in this paper are better
than those reported for triazoles with a more complex structure
In a different study, the structure-activity relationship analysis and
computational studies suggested that the most active compounds are
those having low lipophilicity and high intrinsic solubility [64].
Compounds 2–7 accommodate in their structure the slightly polar and
hydrophilic triazole moiety and the highly hydrophobic
tetramethyldisiloxane or dimethylsilane segment, linked through a
Fig. 11. Comparative graphical representation of the dipole moment (μ) values calculated using HF/Lan2DZ level of theory and the hydrophilic-lyophilic balance (HLB) of compounds 2–7.

14
G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
[38,70,71]. Another advantage presented by our compounds is that the
siloxane bridge is not a risk factor for drug administration and metabo-
lism [72]. It is well-known that silicones are found in many pharmaceu-
tical formulations, generally called Dimethicone or Simethicone, for
which no mutagenic, irritating, or acutely toxic effects have been
disclosed so far [73].
inhibited by the compounds presented in this study. This is a crucial en-
zyme for fungal survival, being involved in ergosterol biosynthesis, an
important fungal cell membrane component. Therefore, this particular
enzyme has become a therapeutic target for many azole-containing
anti-fungal agents [74]. The results of theoretical computations based
on molecular docking are reflected in Fig. 12.
In silico results show both hydrophobic and hydrophilic interactions
between ligands and receptor, as well as π-π stacking interactions in the
stabilization of docking complexes, but the hydrophobic interactions
are predominant. Interestingly, all docked complexes show the
triazole-based ligands directly coordinating the heme ferric iron (resi-
due 601A) with nitrogen atom, where Fe atom plays the role as acceptor
3.3.1. Molecular docking
Molecular docking calculations were run to predict the inhibitory ef-
ficiency of our compounds and to identify the atomic scale interactions
responsible for binding. Sterol 14α-Demethylase from Aspergillus
fumigatus was selected as a possible biologic effector, which could be
Fig. 12. Molecular representation of the best binding modes for the six studied compounds as resulted from the docking calculations (ball and stick models). Secondary structure elements
lining the 14α-Demethylase (CYP51) active sites are represented as ribbons. The heme group and residues important for binding are depicted as sticks. Iron was represented as an orange
sphere.

G.-O. Turcan-Trofin et al. / Journal of Molecular Liquids 294 (2019) 111560
15
Table 4
angles (°), Job's data and plot for compound 2, data plotting for copper
complex stability constant determination of the compound 2, DLS mea-
surement results, antimicrobial activity tests results, copper complex
stability data. Supplementary data to this article can be found online
at https://doi.org/10.1016/j.molliq.2019.111560.
Calculated dissociation constants (Kd) for the complexes of
the six triazoles-based ligands with the active site of 14α-
Demethylase (CYP51) enzyme.
Compound
Kd (μM)
2
3
4
5
6
7
4.58 × 10−4
0.428
2.52
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