Copper(I) halide complexes of N-methylbenzothiazole-2-thione: Synthesis, structure, luminescence, antibacterial activity and interaction with DNA

Article abstract of DOI:10.1016/j.jinorgbio.2013.01.001

The reactions of copper(I) halides, CuX (X = Cl, Br, I) with N-methylbenzothiazole-2-thione (mbtt), independent of the molar ration chosen (1:2 or 1:3), led to the formation of dinuclear complexes of the formula [CuX(mbtt)₂]₂, whereas the reactions of CuX and mbtt in the presence of two equivalents of triphenylphosphine (PPh₃) afforded mononuclear mixed-ligand complexes of the formula [CuX(PPh₃) ₂(mbtt)]. The molecular structure of a representative compound from each of the two above types of complexes, namely [CuCl(mbtt)₂] ₂ and [CuI(PPh₃)₂(mbtt)] have been established by single-crystal X-ray diffraction. The new complexes are strongly emissive both in the solid state and in solution. The complexes were also screened for antibacterial activity and their ability to interact with native calf thymus DNA (CT-DNA) in vitro. Both types of complexes showed significant activities against all the bacteria tested as compared to that of standard antibiotic ampicillin, however, the three mixed-ligand complexes including triphenylphosphane as ligand exhibited perceptibly stronger antibacterial activity than the three homoleptic ones possessing only the mbtt ligand. DNA electrophoretic mobility experiments showed that all complexes bind to CT-ds DNA resulting in high molecular weight complexes ending in DNA degradation.

Full text of DOI:10.1016/j.jinorgbio.2013.01.001

Journal of Inorganic Biochemistry 121 (2013) 121–128
Contents lists available at SciVerse ScienceDirect
Journal of Inorganic Biochemistry
journal homepage: www.elsevier.com/locate/jinorgbio
Copper(I) halide complexes of N-methylbenzothiazole-2-thione: Synthesis, structure,
luminescence, antibacterial activity and interaction with DNA
a,
M.A. Tsiaggali a, E.G. Andreadou b, A.G. Hatzidimitriou a, A.A. Pantazaki b, , P. Aslanidis
⁎
⁎
a
Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, GR-541 24 Thessaloniki, Greece
b
Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, GR-541 24 Thessaloniki, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions of copper(I) halides, CuX (X=Cl, Br, I) with N-methylbenzothiazole-2-thione (mbtt), independent
of the molar ration chosen (1:2 or 1:3), led to the formation of dinuclear complexes of the formula [CuX(mbtt)2]2,
whereas the reactions of CuX and mbtt in the presence of two equivalents of triphenylphosphine (PPh3) afforded
mononuclear mixed-ligand complexes of the formula [CuX(PPh3)2(mbtt)]. The molecular structure of a repre-
sentative compound from each of the two above types of complexes, namely [CuCl(mbtt)2]2 and [CuI(PPh3)2
(mbtt)] have been established by single-crystal X-ray diffraction. The new complexes are strongly emissive
both in the solid state and in solution. The complexes were also screened for antibacterial activity and their ability
to interact with native calf thymus DNA (CT-DNA) in vitro. Both types of complexes showed significant activities
against all the bacteria tested as compared to that of standard antibiotic ampicillin, however, the three mixed-
ligand complexes including triphenylphosphane as ligand exhibited perceptibly stronger antibacterial activity
than the three homoleptic ones possessing only the mbtt ligand. DNA electrophoretic mobility experiments
showed that all complexes bind to CT-ds DNA resulting in high molecular weight complexes ending in DNA
degradation.
Received 1 November 2012
Received in revised form 31 December 2012
Accepted 1 January 2013
Available online 9 January 2013
Keywords:
Copper(I)
N-methylbenzothiazole-2-thione
Luminescence
Crystal structures
Antimicrobial activity
DNA interaction
© 2013 Elsevier Inc. All rights reserved.
1. Introduction
the ligand's characteristics and the structural diversity observed [5].
Further, in view of the fact that many emissive first row transition
The coordination chemistry of heterocyclic thiones has been a
very attractive area of study for the last three decades not only from
a pure academic point of view but also because of some important
applications arising from the relevance of these compounds to biolog-
ical systems [1,2]. In fact, due to the close structural resemblance
to thioamides, heterocyclic thiones are regarded as a very promising
starting point for biological studies and several imidazole-, thiazole-,
thiadiazole-, oxazole-, uracil- and hydantoin-based thioamide deriva-
tives as well as their transition metal complexes have been tested
towards pharmacological activities, such as antiviral, antibacterial or
antifungal.
Thione ligands are broadly employed in synthesis of complexes
of closed-shell d10 metal ions, mainly CuI and AgI, and a vast amount
of compounds with an extraordinary variety of molecular structures
have been obtained, displaying the versatility of this class of com-
pounds in adopting monodentate, chelating and bridging modes of
coordination [3,4]. Within this field of research, we have long been
engaged in the investigation of molecular architectures realized by
thione-ligated copper(I) complexes bearing tertiary aryl-phosphanes as
bulky auxiliary ligands, aiming to gain insight into the interplay between
metal complexes are particularly attractive, being increasingly consid-
ered as potential alternatives to the currently used third-row noble
metal complexes in a wide range of applications [6–15], we recently
turned our attention to the photophysical properties of these compounds.
In particular, exploring the photochemistry of mixed-ligand copper(I)
complexes incorporating neutral heterocyclic thiones or thiolates in the
coordination sphere we reported on Cu(I) compounds which emission
energies proved to be tunable by modifying the ligands as well as intro-
ducing electron-donating or -accepting substituents to the heterocyclic
rings [16,17].
The biochemical action of copper both as an essential trace metal
bound to several proteins and as a constituent of exogenously admin-
istered compounds in humans, mainly in the form of complexes than
can interact with biomolecules is well known. Current interest in cop-
per complexes focuses among others on their potential use as antimi-
crobial, antiviral, anti-inflammatory and antitumor agents, however,
the copper-based compounds tested so far are almost exclusively
copper(II) complexes, whereas respective studies on the copper(I)
ones are very rare and essentially limited to derivatives of ligands
capable of stabilizing the low oxidation of the metal ion in aqueous
media [18,19].
Further, interactions of metal complexes with DNA may be either
coordination-type interactions or non-coordination-type interactions. In
coordination-type interaction the labile part of the complex is replaced
⁎
Corresponding authors. Tel.: +30 310 997694; fax: +30 310 997738.
E-mail addresses: natasa@chem.auth.gr (A.A. Pantazaki), aslanidi@chem.auth.gr
(P. Aslanidis).
0162-0134/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jinorgbio.2013.01.001

122
M.A. Tsiaggali et al. / Journal of Inorganic Biochemistry 121 (2013) 121–128
by a nitrogen base of DNA such as guanine via its N7 donor atom. On the
other hand, the non-coordinative DNA interactions include intercalative,
electrostatic and groove binding of cationic metal complexes outside
the DNA helix, the major or minor groove. Intercalation involves the
partial insertion of aromatic heterocyclic rings between the DNA base
pairs [20–24]. The most known antitumor drug, cis-platin, binds to
DNA through interstrand cross-linkage between neighboring guanine
residues bound covalently through purine nitrogen atoms [25], thus
affecting replication, transcription and DNA repair. A profound under-
standing of the DNA-binding properties of metal complexes is driven
by numerous motivations, which include chemotherapeutic approaches,
study of nucleic acid conformations, drug design, and new tools for nano-
technology [26–29]. A number of copper(II) complexes have been used
as candidates for mediation of strand scission of duplex DNA character-
ized as chemical nucleases [30–32] and as probes of DNA structure in
solution [33–35]. Double-strand breaks in duplex DNA are thought to
be more significant sources of cell lethality than are single strand breaks,
as they appear to be less readily repaired by DNA repair mechanisms
[36–39]. Coordination compounds of copper have been extensively
used in metal ion mediated DNA cleavage and derivatives of monovalent
copper are frequently involved in such studies [40–45].
Among the numerous molecules containing the thioamide moiety,
N-methylbenzothiazole-2-thione (Scheme 1), hereafter abbreviated as
mbtt, has received some attention in the past, mainly as donor-
component in dihalogen and interhalogen charge transfer adducts
[46–49], its coordination chemistry, however, is unexpectedly rare,
being limited to some antimony(III) halide [50] and tellurium(IV) chlo-
ride [51] compounds, and even a single report on the reaction with
copper(II) salts [52], and to the best of our knowledge, there are no struc-
turally characterized copper(I) compounds bearing mbtt reported so far.
In this work we report the synthesis and characterization of copper(I)
halide complexes from type [CuX(mbtt)2]2 and [CuX(mbtt)(PPh3)2]
(mbtt=N-methylbenzothiazole-2-thione) and the structural character-
ization of one representative compound of each type. Further we inves-
tigate the luminescence properties of the new compounds as well as
the antibacterial activity and their interaction with calf thymus-
double-stranded DNA (CT-dsDNA).
2.2. Crystal structure determination
Single crystals of [CuCl(mbtt)2]2 (1) and [CuI(mbtt)(PPh3)2] (6)
suitable for crystal structure analysis were obtained by slow evapora-
tion of their mother liquids at room temperature. For the structure
determination single crystals of the compounds were mounted on a
Bruker Kappa APEX II diffractometer equipped with a triumph mono-
chromator. For compound 1 a total of 1132 frames were collected. The
total exposure time was 1.57 h. The integration of the data using a
monoclinic unit cell yielded a total of 16,487 reflections to a maxi-
mum θ angle of 25.06° (0.84 Å resolution). The final cell constants
are based upon the refinement of the XYZ-centroids of 9956 reflec-
tions above 20 σ(I) with 4.637°b2θb50.16°. Data were corrected for
absorption effects using the multi-scan method (SADABS) [53]. The
ratio of minimum to maximum apparent transmission was 0.813.
For compound 6 a total of 2944 frames were collected. The total expo-
sure time was 4.09 h. The frames were integrated with the Bruker
SAINT software package [54] using a narrow-frame algorithm. The
integration of the data using a monoclinic unit cell yielded a total of
33,163 reflections to a maximum θ angle of 25.31° (0.83 Å resolution),
of which 7055 were independent (average redundancy 4.701). The
final cell constants are based upon the refinement of the XYZ-centroids
of 9923 reflections above 20 σ(I) with 4.924°b2θb50.32°.
Data were corrected for absorption effects using the multi-scan
method (SADABS). The ratio of minimum to maximum apparent trans-
mission was 0.613. The structures were solved using SUPERFLIP pack-
age [55] and refined by full-matrix least-squares method on F2 using
the CRYSTALS package version 14.00 [56]. All non hydrogen atoms
have been refined anisotropically. All hydrogen atoms were found at
expected positions and refined using soft constraints. By the end of
the refinement they were positioned using riding constraints. The crys-
tal data and some details of the data collection and structure refinement
for both compounds are given in Table 1. Illustrations were generated
by CAMERON [57].
2.3. General procedure for the synthesis of complexes 1–3
A suspension of 0.5 mmol of copper(I) halide (49.5 mg for CuCl,
72 mg for CuBr, 95 mg for CuI) in 50 mL of dry acetonitrile was
stirred for two hours at 50 °C. The resulting clear solution was filtered
2. Experimental section
2.1. Materials and instrumentation
Table 1
Crystal data and structure refinement details for compounds 1 and 6.
Commercially available copper(I) halides (Merck) were used as
received while N-methylbenzothiazole-2-thione (Aldrich) was re-
crystallized from hot ethanol prior to its use. All the solvents were
purified by respective suitable methods and allowed to stand over
molecular sieves. Infra-red spectra in the region of 4000–200 cm−1
were obtained in KBr discs with a Nicolet FT-IR 6700 spectropho-
tometer, while a Shimadzu 160A spectrophotometer and a Hitachi
F-7000 fluorescence spectrometer were used to obtain the electron-
ic absorption (UV–visible, UV–vis) and emission/excitation spectra
respectively.
Compound
1
6
Empirical formula
Formula weight
Crystal system
Temperature
C
32 H28 Cl2 Cu2 N4 S8
C44 H37 Cu1 I1 N1 P2 S2
896.31
Monoclinic
295 K
923.13
Monoclinic
295 K
Radiation
Mo Kα
Mo Kα
Space group
P 21/c
P 21/c
Unit cell dimensions
a=8.6150(2)Å
b=11.7747(3)Å
c=17.7247(5)Å
α=90°
a=13.0939(4)Å
b=10.6413(4)Å
c=28.5908(10)Å
α =90°
β =97.871(2)°
γ=90°
β =92.6240(10)°
γ =90°
Volume
Z
1781.04(8)Å3
2
3979.6(2)Å3
4
Absorption coefficient (μ)
Reflections collected
Independent reflections
1.846 mm−1
16,487
1.542 mm−1
33,156
3155
7056
Completeness up to theta(max) 99.0%
96.8%
Data/restraints/parameters
3004/0/217
1.014
5789/0/460
0.990
Goodness-of-fit on F2
Final R indices [I>2σ(I)]
R1 =0.0315,
wR1=0.0879
R2 =0.0325,
wR2=0.0898
R1=0.0586,
wR1=0.0840
R2=0.0733,
wR2=0.0854
R indices (all data)
Largest diff. peak and hole
0.70 e Å−3, −0.37 Å−3 0.82 e Å−3, −1.26 Å−3
Scheme 1. The heterocyclic thione N-methylbenzothiazole-2-thione (mbtt) used as ligand.

M.A. Tsiaggali et al. / Journal of Inorganic Biochemistry 121 (2013) 121–128
123
of and then treated with a solution of N-methylbenzothiazole-2-
2.5. Materials and methods for biological tests
2.5.1. Materials
thione (181 mg, 1 mmol) dissolved in a small amount (~20 mL) of
ethanol or methanol and the new reaction mixture was stirred for
additional two hours at 50 °C. Slow evaporation of the clear solution
at ambient afforded a microcrystalline solid, which was filtered off
and dried in vacuo.
Agarose was purchased from BRL. Tryptone and yeast extract were
purchased from Oxoid (Unipath Ltd., Hampshire, UK). All other
chemicals were obtained from Sigma. Nucleic acids: Native DNA
(dsDNA) type I, highly polymerized from calf thymus gland was pur-
chased from Sigma (D-1501). The intercalative dye ethidium bromide
(EthBr), were purchased from Sigma. Experiments were carried out
in 50 mM Tris–Cl pH 7.5 buffer solutions to control the acidity of
the reaction systems. All plastics and glassware used in the biological
experiments were autoclaved for 30 min at 120 °C and 130 kPa.
Heat-resistant solutions were similarly treated, while heat-sensitive
reagents were sterilized by filter.
2.3.1. [CuCl(mbtt)2]2 (1)
Yellow crystals (115 mg, 50%), m.p. 164 °C; Anal. Calc. for C32H28
N4Cu2Cl2S8: C, 41.64; H, 3.06; N, 6.07. Found: C, 41.46; H, 3.03; N,
6.03%. IR (cm−1): 3074m, 3043m, 2919w, 1579m, 1464s, 1419s,
1348vs, 1317vs, 1263s, 1139vs, 1094vs, 978vs, 752vs, 694s, 510s.
UV–vis (λmax, log ε): 228 (4.78), 236 (4.75), 323 (4.97).
The DNA stock solution (1 mg/ml) was prepared at 0–4 °C by dis-
solving the commercially purchased calf thymus DNA in buffer A
[50 mM Tris ((hydroxymethyl)aminomethane)–HCl buffer (pH 7.5)]
as solvent. Stock solutions of the complexes were prepared at a final
concentration of 5 mM by dissolving the complexes in 5%DMSO-
water.
2.3.2. [CuBr(mbtt)2]2 (2)
Yellow crystals (121 mg, 48%), m.p. 178 °C; Anal. Calc. for C32H28
N4Cu2Br2S8: C, 37.98; H, 2.79; N, 5.54. Found: C, 37.96; H, 2.82; N,
5.52%. IR (cm−1): 3154s, 2930w, 1682vs, 1556vs, 1464s, 1391s,
1230vs, 1207vs, 1160s, 1122s, 1017s, 897s, 815s, 729s, 694vs, 590s,
520s. UV–vis (λmax, log ε): 222 (4.82), 240 (4.52), 323 (4.62).
2.5.2. Culture media
Two different media were used: (i) the Luria–Brettani broth (LB)
containing 1% (w/v) tryptone, 0.5% (w/v) NaCl and 0.5% (w/v) yeast
extract and (ii) the minimal medium salts broth (MMS) containing
1.5% (w/v) glucose, 0.5% (w/v) NH4Cl, 0.5% (w/v) K2HPO4, 0.1% (w/v)
NaCl, 0.01% (w/v) MgSO4·7H2O and 0.1% (w/v) yeast extract. The pH
of the media was adjusted to 7.0.
2.3.3. [CuI(mbtt)2]2 (3)
Yellow crystals (144 mg, 52%), m.p. 146 °C; Anal. Calc. for C32H28
N4Cu2I2S8: C, 34.75; H, 2.55; N, 5.07. Found: C, 35.06; H, 2.72; N,
5.22%. IR (cm−1): 3072m, 3017m, 2919m, 1584s, 1459vs, 1423vs,
1339vs, 1312vs, 1258vs, 1139vs, 1094vs, 961s, 934s, 743vs, 716s,
636s, 533s. UV–vis (λmax, log ε): 224 (4.77), 241 (4.68), 322 (4.45).
2.5.3. Screening for antibacterial activity
2.4. General procedure for the synthesis of complexes 4–6
The antibacterial efficiency of the compounds has been estimated by
their ability to inhibit the growth of microorganisms in the cultivation
medium Mueller–Hinton broth (Imuna). The tests were performed
according to minimum inhibitory concentration (MIC) in μg·mL−1
with five bacteria species: Escherichia coli (XL1), Streptococcus aureus
ATCC 29213, Bacillus subtilis (ATCC 6633), Bacillus cereus (ATCC 11778),
and Xanthomonas campestris (ATCC 33013). Bacterial growth was
performed in LB, while the screening for antibacterial activity was
performed by the minimal inhibitory concentration (MIC) method [58],
using the method of progressive double dilution in MMS contained the
concentrations of 100, 50, 25, 12.5, and 6.25 μg·mL−1 of the complexes
in DMSO were tested and the minimum inhibitory concentrations
(MIC) were determined. The concentration of microorganisms in the
cultivation medium was 105–106 cfu/mL. Thus, aliquots of 2 ml of
MMS were inoculated with 20 μL of a pre-culture of each bacterial strain,
which was grown in LB overnight at their optimal growth temperature to
assure the sufficient bacterial growth (cultures of reference). A second
group of the same cultures in addition was supplemented with the suit-
able concentration of the compounds tested. A third group of cultures
was supplemented with the same concentration of the compounds
tested and was used as cultures of reference to check the effect of each
compound on MMS. All samples were in duplicate. The stock solutions
of the compounds (10 mg·mL−1) were prepared by formerly dissolving
in a small quantity of DMSO. Then serial suitable dilutions were carried
out in MMS to introduce the compounds in the cultures at a final concen-
tration ranging from 100 to 25 μg·mL−1.We monitored the growth of
bacteria by measuring the turbidity of the culture in the tubes after
24 h, in order to check if bacteria grow at the concentration of compound
tested. All cultures were incubated at 37 °C, except X. campestris that was
cultivated at 28 °C, for 24 h.
A suspension of (0.5 mmol) copper(I) halide (49.5 mg for CuCl,
72 mg for CuBr, 95 mg for CuI) and triphenylphosphane (262 mg,
1 mmol) in 50 mL acetonitrile was stirred until a white precipitation
was formed. A solution of 90.5 mg (0.5 mmol) N-methylbenzothiazole-
2-thione in a small amount (~20 mL) of ethanol or methanol was then
added and the mixture was stirred to clearness. The resulting solution
was filtered of and kept at room temperature, whereupon crystals of
the respective product were obtained after few days, which were filtered
of and dried in vacuo.
2.4.1. [CuCl(mbtt)(PPh3)2] (4)
Pale yellow crystals (233 mg, 58%), m.p. 148 °C; Anal. Calc. for
C
44H37NCuClP2S2: C, 65.66; H, 4.63; N, 1.74. Found: C, 65.54; H, 4.51;
N, 1.72%. IR (cm−1): 3044 m, 2923w, 1619 m, 1586 m, 1484 s, 1464 s,
1431vs, 1352vs, 1319 s, 1272 s, 1108 s, 1094vs, 1028 s, 976vs, 748vs,
699vs, 514vs, 489vs. UV–vis (λmax, log ε): 226 (5.02), 239 (4.89), 275
(4.56), 322 (4.82).
2.4.2. [CuBr(mbtt)(PPh3)2] (5)
Pale yellow crystals (229 mg, 54%), m.p. 136 °C; Anal. Calc. for
C
44H37NCuBrP2S2: C, 62.22; H, 4.39; N, 1.65. Found: C, 61.71; H,
4.30; N, 1.71%. IR (cm−1): 3047m, 2925m, 1619m, 1582m, 1491s,
1460s, 1430vs, 1348vs, 1315s, 1269s, 1140s, 1098vs, 982s, 748vs,
696vs, 517vs, 484s. UV–vis (λmax, log ε): 221 (4.72), 238 (4.49),
287 (4.08), 321 (4.56).
2.4.3. [CuI(mbtt)(PPh3)2] (6)
Pale yellow crystals (278 mg, 62%), m.p. 150 °C; Anal. Calc. for
C
44H37NCuIP2S2: C, 58.96; H, 4.16; N, 1.56. Found: C, 58.74; H,
2.5.4. DNA binding/cleavage experiments in agarose gel electrophoresis
The cleavage/binding reaction of DNA with metal complexes was
monitored using agarose gel electrophoresis. The DNA cleavage/binding
efficiency of the complexes was estimated by determining the degree of
retardation/or acceleration (precedence of the electrophoretic mobility
4.04; N, 1.56%. IR (cm−1): 3172w, 3040w, 2995w, 1663w, 1581m,
1479s, 1432vs, 1344vs, 1315vs, 1268s, 1135s, 1087vs, 983vs, 742vs,
694vs, 517vs, 495vs. UV–vis (λmax, log ε): 226 (5.10), 240 (4.53), 280
(4.45), 321 (4.84).

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M.A. Tsiaggali et al. / Journal of Inorganic Biochemistry 121 (2013) 121–128
reflected in an up-shift or down-shift of the DNA to higher/or lower
molecular weight DNA products respectively). Reactions, which con-
tained aliquots of 5 μg of the nucleic acid (DNA), were incubated at
a constant temperature of 37 °C for 60 min (or as indicated in the
legends) in the presence of each compound in a buffer A to a final vol-
ume of 20 μl. It was terminated by the addition of 5 μl loading buffer
consisting of 0.25% bromophenol blue, 0.25% xylene cyanol FF (acid
blue 147) and 30% glycerol in water. The products resulting from inter-
actions of the metal complexes with DNA were separated by electro-
phoresis on agarose gels (1% w/v), which contained 1 μg/ml ethidium
bromide in 40×10−3 M Tris–acetate, pH 7.5, 2×10−2 M sodium ace-
tate, 2×10−3 M Na2EDTA, at 5 V/cm. Agarose gel electrophoresis
was performed in a horizontal gel apparatus (Mini-SubTM DNA Cell,
BioRad) for about 4 h. The gels were visualized after staining with the
fluorescence intercalated dye ethidium bromide under a UV illuminator
which forms a fluorescent complex when it binds to DNA.
attributed to intraligand π→π* transitions on the thione and phosphane
aromatic rings, whereas the lower energy band can be considered as a
thione originating CT transition at the C_S bond [62,63]. None of the
thione bands is found to express any significant shift upon coordination
to copper. Further, exact assignment of the bands due to the presence of
triphenylphosphane in the spectra of compounds 4–6 is difficult since
both the N-methylbenzothiazole-2-thione and triphenylphosphane
strongly absorb in the same regions.
The infrared spectra of compounds 1–6, recorded in the range
4000–250 cm−1 contain all the characteristic bands required by the
presence of the N-methylbenzothiazole-2-thione ligand. In particular,
the intense bands at 1411 cm−1 and 1259 cm−1 in the spectrum of
free 3mbztzth, attributed to the C\N stretching vibration, appear in
the spectra of all complexes slightly shifted to higher energies, indicat-
ing an exclusive S-coordination of the ligand. On the contrary, the
expected red shift due to S-coordination for the band at 1095 cm−1
assigned to the C_S stretching [64], is not always observed. The same
applies to the bands at the 964 and 532 cm−1, which also contain
contributions from the C_N and C\N stretching vibrations, as well as
to the band at 717 cm−1 due to the ν(C\S) vibration on the five-
member ring [65], for which the shifts are relatively small and not
always in the same direction, thus less informative with regard to the
ligand's coordination mode.
3. Results and discussion
3.1. Preparative considerations
Heterocyclic thiones are versatile S- and/or N-donor ligands and
their interaction with a soft Lewis acid like monovalent copper
turns out to be very flexible, resulting in the formation of a rich vari-
ety of coordination compounds ranging from mono- and dinuclear
complexes to polynuclear networks. Of particular interest are the
reactions with copper(I) halides, the result of which depends on the
stoichiometry and the conditions chosen. Thus, treatment of copper(I)
iodide with three equivalents of pyridine-2-thione (py2SH) in hot
CH3Cl/C2H5ΟΗ mixture leads to the formation of [CuI(py2SH)2]2, in
which the two copper ions are doubly bridged by the S-atoms of two
thione units [59]. On the other hand, the result of the reaction between
equimolar amounts of pyrimidine-2-thione (pymtH) and CuCl or CuBr
in a CH3CN/CH2Cl2 mixture, is a polymer in which the thione act as an
ambidentate S/N-ligand [60].
Usually, steric demands of the ligated molecules are considered as
an additional factor that may influence both the local and the overall
structure of a coordination compound. However, during our long
standing studies of thione ligated copper complexes we never noticed
any correlation between the ligand's bulkiness and the structural
characteristics of the complexes being formed. Quite to the contrary,
we recently reported the formation of three-coordinated mononucle-
ar species [CuX(th)2] (th=2-thiohydantoin) possessing a sterically
less demanding ligand [61]. In this context, the outcome of the reac-
tions within the present study turned out to be independent from
the choice of the more bulky N-methylbenzothiazole-2-thione, lead-
ing to four-coordination which is the most favored one for copper(I).
Moreover, regardless of the reactants ratio chosen (CuX: mbtt=1:2 or
1:3) the composition of compounds 1–3 remained the same, namely
CuX(mbtt)2, which corresponds either to three-coordinated mononu-
clear species or to doubly bridged dimers, bearing a Cu2S2 or a Cu2X2
core. Consequently, though dimerization within complexes of monova-
lent copper halides with heterocyclic thioamides is quite common as
it allows the copper ion to obtain a pseudotetrahedral environment,
formation of halide bridged dimmers in the case of compounds 1–3,
even for an 1:3 reactants ratio, suggests that electronic factors rather
than the stoichiometry of the reaction or the bulkiness of the thione
ligand could determine the structure being preferably formed.
3.3. Description of the structures
The X-ray crystal structures of [CuCl(mbtt)2]2 (1) and
[CuI(mbtt)(PPh3)2] (6) (details of crystal and structure refinement
are shown in Table 1) have been determined. Yellow crystals of 1
have been obtained on slow evaporation of a saturated acetonitrile
solution. The compound crystallizes in the monoclinic system P21/c,
with two discrete molecules in the unit cell. Main bond lengths and
angles are given in Table 2 and a perspective drawing showing the
atom numbering is shown in Fig. 1.
Each of the two inequivalent Cu\S bonds of 2.3160(7) and
2.3213(7)Å is comparable to those found in analogous copper(I) com-
plexes with terminally bonded thione-S atoms [7,66,67]. Likewise, each
of the two inequivalent Cu\Cl bonds of 2.3598(7) and 2.5228(6)Å com-
pares well with the values found in analogous copper(I) complexes with
double bridging chloride ions, but the marked feature of the present
structure is the large asymmetry in the two bridging distances.
Pale yellow crystals of [CuI(mbtt)(PPh3)2] (6) have been obtained
on slow evaporation of an acetonitrile/methanol solution. The com-
pound crystallizes in the monoclinic system P1 21/c 1, with four discrete
molecules in the unit cell. Main bond lengths and angles are given in
Table 3 and a perspective drawing showing the atom numbering is
shown in Fig. 2.
The geometrical characteristics of this four-coordinate monomer
generally refer to those of other copper(I) halide complexes tetrahe-
drally coordinated by thione and phosphine ligands. Each of the
interbond angles around the central copper atom shows moderate
deviations from the idealized tetrahedral geometry except for the
P1\Cu1\P2 angle which a value of 121.76(5)° represents the most
significant distortion as a result of steric imposition of the bulky phos-
phane ligands. It is worth noting that the Cu\S distance of 2.4188(17)Å
Table 2
Selected bond distances [Å] and angles [°] in [CuCl(mbtt)2]2 (1).
3.2. Spectroscopy
Cu(1)\Cl(1)
Cu(1)\Cl(1)′
Cu(1)\S(1)
Cu(1)\S(3)
S(1)\C(1)
2.3598(7)
2.5228(6)
2.3160(7)
2.3213(7)
1.680(2)
1.676(2)
Cl(1)\Cu(1)\Cl(1)′
Cl(1)\Cu(1)\S(1)
Cl(1)\Cu(1)\S(3)
Cl(1)′\Cu(1)\S(1)
S(1)\Cu(1)\S(3)
102.50(2)
111.79(3)
117.70(3)
100.08(2)
1240.22(3)
The electronic absorption spectra of complexes 1–6, recorded in
acetonitrile at room temperature, show three intense broad bands
with maxima in the range of ~220–230, 240 and ~320 nm. With
reference to the absorption spectrum of the uncoordinated N-
methylbenzothiazole-2-thione, the two high energy bands can be
S(3)\C(9)
Symmetry code: (′)−x+2, −y+2, −z+1.

M.A. Tsiaggali et al. / Journal of Inorganic Biochemistry 121 (2013) 121–128
125
C24
C23
C6
C42
C41
C25
C11
C7
C22
C21
C10
C5
C4
C43
C40
C32
C2
N1
C8
C1
S1
C31
C28
C12
C26
C9
C44
C30
C29
C39
P2
C3
C13
C14
C27
P1
C20
Cu1
S2
C15
C16
C34
C35
Cl1
C19
C33
C17
Cu1`
S1`
Cu1
C18
C4
I1
C38
C36
S4
S2
S1
C1
N8
Cl1`
C37
C9
C12
S3
C3
C11
C8
C13
C14
N2
C10
C2
C7
C5
C15
C16
C6
Fig. 2. A view of compound 6 with atom labels. Displacement ellipsoids are shown in
the 50% probability level. Hydrogen atoms have been omitted for clarity.
Fig. 1. A view of compound 1 with atom labels. Displacement ellipsoids are shown in
the 50% probability level.
origin because of a possible participation of the halogen in the emissive
excited states, in the form of a ligand-to-metal charge-transfer (XMCT)
or an interligand charge-transfer (ΧLCT, X→thione) [71,72,18,19]. In
this respect, there is a small dependence of the emission maxima on
the kind of the halide present, with a small red shift in the order
Cl→Br→I.
Finally, the fluorescence observed in many multinuclear copper(I)
halide complexes with metal–metal distances lower than the sum of
the van der Waals radii (2.8 Å) has been often assigned to metal–
metal bonding interactions [73–75]. However, in the case of com-
pounds 1–3, such intermetallic interactions are unlikely to participate
in any excited states responsible for the observed emissions, as the
Cu⋯Cu separations clearly exceed this limit.
In conclusion, the determination of the emissive excited states in
the compounds under investigation is a difficult task, with research
in this area being yet in the beginnings. The emissive states are
most likely of mixed MLCT/XLCT/IL character, and this applies all
the more for the mixed-ligand complexes 4–6 in which the presence
of triphenylphosphane also affects in some degree the energy of the
emission.
is one of the largest values observed in tetrahedrally coordinated
copper(I) halide complexes with thione-S donors [67]. Both the Cu\I
bond length of 2.6301(7)Å as well as the two individual Cu\P distances
of 2.3005(15)Å and 2.3248(15)Å, are comparable to the corresponding
values previously found in related four coordinate complexes with ter-
minal iodine and thione-S donors [68–70].
3.4. Luminescence
Room temperature photoexcitation at 287–331 nm of solid samples
of the complexes produces broad emission bands with peak maxima
in the 499–535 nm region. The emission spectra of complexes 4–6 are
depicted in Fig. 3.
After maximum excitation at 300 nm, the room temperature emis-
sion spectrum of solid mbtt consists of a broad band with maximum
at 390 nm, whereas in the spectra of complexes 1–6, as can be seen
from Fig. 3 and the data listed in Table 4, the emission maxima appear
significantly shifted towards lower energies (by 109–145 nm), which
indicates the excited states to be of different origin than the intra-
ligand (IL) single transitions in the free ligand. In fact, the lowest energy
emissive excited state in such thione-S ligated CuI complexes is believed
to originate from metal-to-ligand charge-transfer (MLCT) transitions of
type CuI→thione, since it is very likely for the d10 ion to express strong
tendency for charge transfer of this type. On the other hand, these emis-
sions cannot be considered as one of pure thione centered intraligand
Table 3
Selected bond distances [Å] and angles [°] in [CuI(mbtt)(PPh3)2] (6).
Cu(1)\S(1)
Cu(1)\P(1)
Cu(1)\P(2)
Cu(1)\I(1)
S(1)\C(1)
2.4188(17)
2.3005(15)
2.3248(15)
2.6301(7)
1.671(6)
I(1)\Cu(1)\P(1)
I(1)\Cu(1)\P(2)
I(1)\Cu(1)\S(1)
P(1)\Cu(1)\P(2)
S(1)\Cu(1)\P(1)
S(1)\Cu(1)\P(2)
C(1)\S(1)\Cu(1)
107.68(4)
104.93(4)
108.14(5)
121.76(5)
114.57(6)
98.73(6)
116.1(2)
Fig. 3. Solid state room temperature emission spectra of complexes 4–6.

126
M.A. Tsiaggali et al. / Journal of Inorganic Biochemistry 121 (2013) 121–128
Table 4
tested in all cases, in comparison to that of each of the free ligands.
Specifically, mbtt exhibited only feeble activity against any of the bac-
teria investigated, whereas no significant antimicrobial activity was
found for PPh3. This higher antimicrobial activity of the metal com-
plexes, may be ascribed to electronic and/or structural changes of
the ligated molecules due to coordination, making the metal com-
plexes act as more powerful and potent bacteriostatic agents, thus
inhibiting the growth of the micro-organisms [75,76].
Room temperature solid state excitation and emission maxima for compounds 1–6.
Compound
λexc [nm]
λem [nm]
1 [CuCl(mbtt)2]2
2 [CuBr(mbtt)2]2
3 [CuI(mbtt)2]2
4 [CuCl(mbtt)(PPh3)2]
5 [CuBr(mbtt)(PPh3)2]
6 [CuI(mbtt)(PPh3)2]
312
308
287
310
315
330
518
521
535
499
502
517
In general, the antibacterial activity of metal complexes is attributed
to a direct interaction of the metal ion with biological ligands such as
DNA, proteins, enzymes and membranes [74–76] and may be associated
with their ability to easily undergo ligand displacement reactions with
these biological ligands [77–79]. In this respect, the somewhat poorer
activities of the homoleptic complexes 1–3 investigated in this study
may be due to a higher stability which inhibits interaction with the bio-
logical target.
3.5. Evaluation of biological activity
3.5.1. Antibacterial activity of copper(I) halide complexes 1–6
The antimicrobial activities of the copper (I) halide complexes of
N-methylbenzo-thiazole-2-thione (average of three measurements)
were estimated by monitoring the growth of certain Gram-positive
(B. subtilis, B. cereus, S. aureus) and Gram-negative (X. campestris,
E. coli) bacterial strains in the presence of various concentrations of
these complexes ranging from 0 to 100 μg·mL−1. In a parallel exper-
iment, the antimicrobial activity of a standard drug (ampicillin) was
determined for comparison against all the same strains. The commer-
cially available antibiotic ampicilin is highly effective against the
studied bacteria and its antibacterial MIC values obtained is consis-
tent with the values previously reported [60]. The minimum inhibitory
concentration (MIC) values obtained for each stain and each compound
are presented in Table 5.
Among the three homoleptic copper (I) halide complexes (1–3),
the effectiveness of the antibacterial activity follows the order
[CuI(mbtt)2]2>[CuBr(mbtt)2]2>[CuCl(mbtt)2]2, with half-minimum
inhibitory concentrations (IC50) values ranging from 22 to 29 μg·mL−1
against E. coli and from 23 to 27 μg·mL−1 against B. subtilis. The IC50
values against S. aureus ranged between 32 and 53 μg·mL−1 but the
order is a little different as follows the complexes with CuBr>CuCl>CuI,
against X. campestris between 31 and 39 μg·mL−1 in the order CuCl>
CuI>CuBr, and against B. cereus between 57 and 62 μg·mL−1 CuCl>
3.5.2. In vitro dsDNA interactions with complexes 1–6
It is already known that copper complexes and especially trihalide
complexes are able to promote hydrolytic cleavage of phosphodiester–
DNA bonds under physiological pH conditions (7.5) [80]. Therefore,
the effect of all the copper compounds on the integrity of the CT-DNA
was tested and assessed by gel electrophoresis stained with ethidium
bromide. The experiments for studying the dsDNA interactions with
complexes were carried out in the presence of 50 mM Tris–HCl buffer
pH 7.5. When CT-DNA was incubated with 0.5 mM of each of the com-
pounds for 60 min at 37 °C (Fig. 4, lanes 1–8), a partial migration of
the main bulk of the CT-DNA band to higher molecular weight DNA
molecules was observed (Fig. 4, lanes 1, 3, 4, 5, and 6). Specifically, two
new DNA bands corresponding to high molecular weight complexes
appeared, as result of binding of some DNA molecules to several mole-
cules of the tested compounds able to increase the molecular weight of
the main DNA band. The argument for this explanation is the decrease
of the main initial DNA band and its up-shifting migration. In some
cases DNA molecules appeared as a band on the top of the gel differing
in intensity, which barely came across the gel due to the very high molec-
ular weight of the adducts formed between DNA and the tested com-
pounds (Fig. 4, lanes 3–7′).
A comparative experiment was performed in a second higher con-
centration. When CT-DNA was incubated with 1 mM of each of the
compounds for 60 min at 37 °C, the same results become more obvi-
ous (Fig. 4, lanes 4′, 5′, and 6′). Moreover it is also notable that the
CT-DNA was obviously degraded in some cases as it was deduced
from the diminution of the initial amount of DNA after incubation
with compounds. The effectiveness of these compounds for interac-
tion with DNA is completely different. It seems that compounds 1
and 2 assault DNA in a degradative manner under these conditions
deduced from the decrease of the initial DNA (Fig. 4, lanes 1, 1′, 2
and 2′). Examination of the ligands effect on DNA showed that mbtt
did not affected DNA integrity significantly (Fig. 4A, lanes 7, and 7′)
CuBr>CuI. Concerning the minimum inhibitory concentrations (IC100
)
values ranged from 50 to 100 μg·mL−1 against all strains tested and all
the three complexes (1–3).
Among the three heteroleptic complexes 4–6, the values of
half-minimum inhibitory concentrations (IC50) are significantly low
and very comparable for all the complexes 4–6 ranged from 3 to
9 μg·mL−1, while the minimum inhibitory concentrations (IC100
)
ranged from 6 to 24 μg·mL−1, against all the strains tested except
E. coli. The IC100 value for E. coli reached 100 μg·mL−1 or higher.
Evaluation of these results shows that the presence of triphenyl-
phosphane in complexes 4–6 results in a significant increase of
the antimicrobial activity when compared to the activity of the
phosphane-free compounds 1–3. On the other hand, the antibacterial
activity of all the compounds under study is higher against all strains
Table 5
Antimicrobial activities of luminescent copper (I) halide complexes of N-methlbenzothiazole-2-thione evaluated by the half-minimal inhibitory concentration (IC50) and the inhib-
itory concentration (IC100) (μg·mL−1).
Complexes
E. coli
X. campestris
S. aureus
B. cereus
B. subtilis
IC50 (μg/mL) IC100 (μg/mL) IC50 (μg/mL) IC100 (μg/mL) IC50 (μg/mL) IC100 (μg/mL) IC50 (μg/mL) IC100 (μg/mL) IC50 (μg/mL) IC100 (μg/mL)
[CuCl(mbtt)2]2
[CuBr(mbtt)2]2
[CuI(mbtt)2]2
29 (31.4)
28 (27.7)
22 (19.9)
100 (108.3)
100 (98.8)
100 (90.4)
>100
31 (33.6)
50 (49.4)
39 (35.3)
3 (3.7)
50 (54.2)
100 (98.8)
100 (90.4)
6 (7.5)
32 (34.7)
27 (26.7)
53 (47.9)
4 (5)
100 (108.3)
100 (98.8)
100 (90.4)
12 (14.9)
57 (61.7)
60 (59.3)
62 (56.1)
6 (7.5)
100 (108.3)
100 (98.8)
100 (90.4)
12 (14.9)
27 (29.2)
26 (25.7)
23 (20.8)
7 (8.7)
50 (54.2)
50 (49.4)
50 (45.2)
24 (29.8)
[CuCl(mbtt)](PPh3)2 20 (24.8)
>(124.2)
>100
>(117.7)
>100
[CuBr(mbtt)](PPh3)2 22 (25.9)
3 (3.5)
6 (6.7)
6 (7.1)
6 (7.1)
3 (3.3)
25 (29.4)
6 (6.7)
7 (8.2)
8 (8.9)
12.5 (14.7)
12 (13.4)
3 (3.5)
9 (10)
6 (7.1)
[CuI(mbtt)](PPh3)2
20 (22.3)
24 (26.8)
24 (26.8)
>(111.6)
Values in parentheses are expressed in μΜ.

M.A. Tsiaggali et al. / Journal of Inorganic Biochemistry 121 (2013) 121–128
127
Fig. 4. Agarose (1%) gel electrophoresis of double-stranded DNA. Each sample containing 3 μg of dsDNA was treated with the indicated concentrations of compounds 1–7 at 37 °C
for 60 min. Lane C1: control, dsDNA incubated without treatment in water; Lanes 1–6: dsDNA treated with 0.5 mM of each compound, respectively. Lanes 1′–6′: dsDNA treated
with 1 mM of each compound, respectively. Lanes 7 and 7′: dsDNA treated with 0.5 and 1 mM of the ligand mbtt. Lanes 8 and 8′: dsDNA treated with 0.5 and 1 mM of the ligand
PPh3. Lane C2: control, dsDNA incubated without treatment in the presence of DMSO.
at concentrations 0.5 and 1 mM respectively while the ligand PPh3
seems to affect DNA integrity with a degradative manner in both con-
centrations tested 0.5 and 1 mM respectively (Fig. 4, lanes 8 and 8′).
All changes of the electrophoretic mobility (measured in Rf) taking
place in the main DNA band as a result of interaction with the com-
plexes under investigation are illustrated in the curves obtained by
the Gelpro Analyzer V.3 computer program (Fig. 5). Arrows show
formation of new bands attributed to the DNA-complexes interaction.
In conclusion, for the complexes under investigation, coordinative
binding between the metal and DND should be considered as less
likely because of the favorable soft-soft interaction between the soft
acid CuI and the soft P- and S-donor ligands, since such a kind of
binding would correspond to a replacement of a soft P- or S-donor
by a hard N-donor. However an intercalative (or other kind of bind-
ing) manner such as interstrand cross-linking might not be excluded
as it appears from the migration of the band located on the top of
the gel. In this later case DNA molecules might be cross-linked with
metal complexes to create high molecular weight complexes unable
to enter onto the gel exhibiting delayed electrophoretic mobility
[in relative mobility (Rf) values] compared with the major DNA band
of the control. The results showed that the interactive effect is concen-
tration dependent since lower concentrations seem to be less effective
on DNA integrity causing simply binding with DNA, while higher con-
centration started to provoke degradation. In addition, this effect is
Fig. 5. Panels for compounds 1–8: curves represent quantitative and qualitative determination of the changes taking place in the total DNA amount obtained after evaluation of each
lane of the gel by the Gelpro Analyzer V.3 computer program.

128
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The coordination behavior of mbtt towards copper(I) halides in
the presence and absence of triphenylphosphane has been explored.
It could be found that the N-methylbenzothiazole-2-thione acts as a
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