Ag(I) and Zn(II) isonicotinate complexes: Design, characterization, antimicrobial effect, and CT-DNA binding studies

Article abstract of DOI:10.1080/00958972.2015.1101074

Trinuclear Ag(I) (1) and dinuclear and mononuclear Zn(II) isonicotinate (2 and 3) complexes were prepared and characterized by X-ray crystallography, elemental analysis, IR spectroscopy, and thermal analysis. Single-crystal analysis of the Ag(I) complex reveals two different monodentate carboxylate coordination modes, protonated and deprotonated, respectively. IR spectra showed correlations between isonicotinate coordination modes and Δ(ν_as-ν_s)_IR values. In addition, the hydrogen bonds significantly influence a position of carboxylate absorption bands. Moreover, IC₅₀ and MIC data for bacteria, yeasts, and filamentous fungi were determined and the binding of Ag(I) and Zn(II) complexes to calf thymus DNA was investigated using electronic absorption, fluorescence, and CD measurements. Biological tests showed that the Ag(I) complex is more active than commercially used Ag(I) sulfadiazine against Escherichia coli. The fluorescence spectral results indicate that the complexes can bind to DNA through an intercalative mode. The Stern-Volmer quenching constants for investigated complexes obtained from the linear quenching plot are in the range of 1.67 × 10⁴-3.42 × 10⁴ M^-1.

Full text of DOI:10.1080/00958972.2015.1101074

Journal of Coordination Chemistry
ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: http://www.tandfonline.com/loi/gcoo20
Ag(I) and Zn(II) isonicotinate complexes: Design,
characterization, antimicrobial effect and CT–DNA
binding studies
M. Almáši, Z. Vargová, D. Sabolová, J. Kudláčová, D. Hudecová, J. Kuchár, L.
Očenášová & K. Györyová
To cite this article: M. Almáši, Z. Vargová, D. Sabolová, J. Kudláčová, D. Hudecová, J. Kuchár,
L. Očenášová & K. Györyová (2015): Ag(I) and Zn(II) isonicotinate complexes: Design,
characterization, antimicrobial effect and CT–DNA binding studies, Journal of Coordination
Chemistry, DOI: 10.1080/00958972.2015.1101074
To link to this article: http://dx.doi.org/10.1080/00958972.2015.1101074
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Date: 05 October 2015, At: 21:10

Publisher: Taylor & Francis
Journal: Journal of Coordination Chemistry
DOI: http://dx.doi.org/10.1080/00958972.2015.1101074
Ag(I) and Zn(II) isonicotinate complexes: Design, characterization,
antimicrobial effect and CT–DNA binding studies
M. ALMÁŠI1, Z. VARGOVÁ*1, D. SABOLOVÁ2, J. KUDLÁČOVÁ2, D. HUDECOVÁ3, J. KUCHÁR1,
L. OČENÁŠOVÁ4 and K. GYÖRYOVÁ1
1Department of Inorganic Chemistry, Faculty of Science, P. J. Šafárik University, Moyzesova 11,
SK-041 54 Košice, Slovak Republic
2Deparment of Biochemistry, Faculty of Science, P. J. Šafárik University, Moyzesova 11,
SK-041 54 Košice, Slovak Republic
3Department of Biochemistry and Microbiology, Slovak University of Technology, Radlinského 9,
SK-812 37 Bratislava, Slovak Republic
4Department of Organic Chemistry, Faculty of Science, P. J. Šafárik University, Moyzesova 11,
SK-041 54 Košice, Slovak Republic
Trinuclear Ag(I) (1) and dinuclear and mononuclear Zn(II) isonicotinate (2 and 3) complexes
were prepared and characterized by X–ray crystallography, elemental analysis, IR spectroscopy
and thermal analysis. Single crystal analysis of the Ag(I) complex reveals two different
monodentate carboxylate coordination modes, protonated and deprotonated, respectively. IR
spectra showed correlations between isonicotinate coordination modes and Δ(νas–νs)IR values. In
addition, the hydrogen bonds significantly influence a position of carboxylate absorption bands.
Moreover, IC50 and MIC data for bacteria, yeasts and filamentous fungi were determined and the
binding of Ag(I) and Zn(II) complexes to calf thymus DNA was investigated using electronic
absorption, fluorescence and CD measurements. Biological tests showed that the Ag(I) complex
is more active than commercially used Ag(I) sulfadiazine against E. Coli. The fluorescence
spectral results indicate that the complexes can bind to DNA through an intercalative mode. The
Stern–Volmer quenching constants for investigated complexes obtained from the linear
quenching plot are in the range of 1.67 × 104 to 3.42 × 104 M–1.
Keywords: Ag(I) and Zn(II) Complexes; Isonicotinate; Mid–IR spectra; Antimicrobial activity;
Intercalative DNA binding; Fluorescence
*Corresponding author. Email: zuzana.vargova@upjs.sk

1. Introduction
Bacterial resistance to antibiotics and antibacterial agents continues to occur. This is not a new
phenomenon, e.g. resistance to penicillin was documented in the 1940s by Fleming [1].
Resistance usually begins in hospital environments, where patients suffering from severe
illnesses are treated with the most recent and sophisticated antibiotics.
The research presented herein provides alternatives to some of the products on the
market, to widen the spectrum of microbial pathogens susceptible to silver and also to target
organisms which are resistant to current silver complexes [2-6] and for other biological
properties [7].
The state of knowledge about the interactions of silver metal, salts and nanoparticles with
biological systems (from single–celled organisms over cell culture to whole organisms) are
reviewed in Epple's and Mijnendonckx's articles [8, 9].
Development of new active metal complexes that have antibacterial [10, 11] or
antimicrobial properties [12-15], enzyme inhibition activity [16] and interact with biomolecules
(proteins, DNA) has been a subject of intensive investigation [17, 18].
Bioinorganic chemists focus their interest on broad-range and multifunction antibiotics.
They use the combination of biologically appropriate ligand and antimicrobial metal (Zn(II),
Cu(II), Ag(I)). Three ligand approaches are suggested [19-22]: transporters, which provide metal
transport to infection, carriers which provide metal transport and its gradual delivery,
multifunctional ligands, that can act as transporters, carriers and antibiotics or analgetics
simultaneously.
Silver carboxylates [23, 24], amines [25], carbenes [26] and sulfoamides [27, 28] were
prepared and tested to produce effective antibiotics. Results confirm that a few significant
aspects influence the final antimicrobial effect: silver coordination mode, silver abundance in the
molecular unit, complex stability in solution and solid state. Ag(I) pyridinecarboxylates are
extensively studied as prospective antibody agents. Their structural [29-32], spectral [22, 33, 34],
thermal [34], antibacterial [22, 34] and antifungal [34] properties have been described.
Zinc(II) as an essential, low toxic and bioavailable metal is also used in clinical medicine.
Zinc carboxylates [35, 36, 16], amines [37, 38] and zinc complexes with Schiff–base ligands

[17, 39] with similar stable configuration of bioactive metal (like silver) are produced and
studied from different points of view (structural, spectral, antimicrobial, cytotoxic, etc.).
Isonicotinic acid, as a part of antidepressants (nialamide, iproniazid) [40, 41], provides
two donor functions (pyridine and carboxylate) for coordination. The structure of isonicotinate
determines its coordination mode and application. As a spacer ligand, isonicotinate is frequently
used in supramolecular architectures with unique magnetic properties [42-49]. Similar to copper
isonicotinate complexes [50], silver and zinc complexes most commonly adopt coordination
mode A [51-53] (scheme 1) in the solid state; modes B [54], C [55], D [56], E [57], F [58] and G
[59] (scheme 1) are rare in Ag(I) and Zn(II) isonicotinates.
The flexibility of Ag(I) and Zn(II) coordination spheres allows various 2D or 3D
polymeric solid-state structures with bridging isonicotinate ligands. Their low solubility provides
stable composition of the complex in aqueous solution. Therefore the isonicotinate ligand with
its coordination ability becomes an important driving force for broad-range and multifunction
silver-based antibiotics.
To compare antimicrobial effects we prepared the polymeric Ag(I) (1) and Zn(II)
isonicotinate complexes (2 and 3). Moreover, the composition and influence of their metal
coordination modes and noncovalent interactions on spectral and thermal properties are
discussed. Hereby we have compared the antibacterial effect of Ag(I) and Zn(II) isonicotinates
(1, 2, 3) with the commercially used Ag(I) sulfadiazine. DNA–binding studies were also
performed.
2. Experimental
2.1. Material and methods
Isonicotinic acid was obtained from Sigma–Aldrich and AgNO3 from Lachema companies. The
chemicals were analytically pure and used without purification. Infrared spectra of the
compounds were recorded on an Avatar FT–IR 6700 spectrometer from 4000 to 400 cm−1 using
ATR (attenuated total reflectance) technique.
Elemental analyses were performed with a CHNOS Elemental Analyzer Vario MICRO
from Elementar Analysensysteme GmbH. TG/DTG and DTA measurements were carried out
using TA instruments Netsch 409 PC. The masses of prepared samples and isonicotinic acid
were 15-20 mg. Samples were heated in air (flow rate 50 cm3.min−1) with heating rate 9 °C·min−1

from 25 to 700 °C and measured thermoanalytical curves were analyzed using the Proteus
Analysis program [60].
The crystal structure of 1 was measured with Xcalibur four–circle CCD diffractometer
(Oxford Diffraction) equipped with a graphite monochromator and using Mo Kα radiation (λ =
0.71073 Å). The structure was solved by direct methods using SIR92 [61] and refined on F2
using the SHELXL97 program [62]. All non–hydrogen atoms were refined anisotropically and
hydrogens were included in the calculated positions. The isotropic thermal parameters were fixed
to 1.2 Ueq. of the parent atom for all hydrogens. Crystal data for 1 are listed in table 1. Figure 1
was drawn using DIAMOND software [63].
PXRD measurements of 2 and 3 were carried out at BW2 wiggler beamline of DORIS
positron storage ring in DESY (Deutches Elektronen Synchrotron, Hamburg, Germany). The
patterns were collected with beam energy of 18 keV, corresponding to a wavelength of 0.68986
Å. In our experiments, we have used the gradient Si/Si (111) double crystal to monochromatize
the polychromatic beam. Samples catena–{[Zn2(INA)4]}n (2) and [Zn(INA)2(H2O)4] (3) were
sealed into 0.1 mm diameter quartz capillary and measured. The diffracted photons were
collected using an on-site readable image plate detector OBI [64] and [65] over the 2θ range
2-20° with a step size of 0.004°. Analysis of the synchrotron powder diffraction patterns was
carried out using the FullProf program package and CMPR.
1H NMR spectra were recorded in DMSO–d6 with a Varian Mercury Plus 400
spectrometer at 400 MHz using TMS as the internal reference. Before NMR experiments, freshly
prepared samples of 1, 2 and 3 were dissolved for 3 min by ultrasonic homogenizer. After this
procedure the 1H NMR experiments were performed and the samples were kept in the dark for
48 and 96 h, respectively, and the measurements were repeated.
UV–VIS measurements were also performed in DMSO with spectroscopic purity and
carried out on the Analytik Jenna Specord 250 UV–VIS spectrophotometer. The concentration of
solutions used in the measurements were 5 μmol·dm–3.
2.1.1. Preparation of catena–{[Ag3(INA)3(HINA)]}n (1). Silver nitrate (139 mg AgNO3,
0.818 mmol) with isonicotinic acid (200 mg C5H4N(COOH) (HINA), 1.620 mmol) was stirred in
deionized water (15 ml). The reaction mixture was placed in a 40 ml Parr Teflon–lined stainless–
steel vessel, which was heated to 90 °C with heating rate of 3 °C min−1 for 72 h. Then the

reaction mixture was cooled to room temperature with cooling rate of 0.1 °C·min–1. Dry product
was used for further characterization. Anal. calcd for Ag3C24H16N4O8 (Mr = 812.02, yield:
62.7 mg, 9.4%): C, 35.45%; H, 2.09%; N, 6.89%. Found: C, 35.22%; H, 2.08%; N, 6.92%,
1H NMR (400 MHz, [D6]DMSO): δ 7.81 (d, J = 4.63 Hz, 1H, Hb), 8.12 (s, 0.1H, Ha), 8.75
(s, 0.9H, Ha) ppm.
2.1.2. Preparation of catena-{[Zn2(INA)4]}n (2). Isonicotinic acid (50 mg, 0.406 mmol), zinc
nitrate hexahydrate (120 mg, 0.404 mmol) and pyrazine (100 mg, 1.249 mmol) were dissolved in
15 cm3 of ethanol and placed in a Parr Teflon–lined stainless–steel autoclave. The reaction
mixture was heated to 125 °C for 60 h with heating rate 3 °C·min–1 and finally slowly cooled at
0.15 °C·min–1 to ambient temperature. Long needle-like crystals of catena–{[Zn2(INA)4]}n were
filtered off, washed with ethanol and dried in a stream of air. Anal. calcd for C24H16N4O8Zn2
(Mr = 619.19, yield: 68 mg, 27%): C, 46.55%; H, 2.60%; N, 9.05%. Found: C, 45.46%; H,
2.54%; N, 9.13%. 1H NMR (400 MHz, [D6]DMSO): δ 7.89 (s, 1H, Hb), 8.20 (s, 0.16H, Ha), 8.65
(s, 0.84H, Ha) ppm.
2.1.3. Preparation of [Zn(INA)2(H2O)4] (3). A mixture of isonicotinic acid (77 mg,
0.625 mmol), zinc nitrate hexahydrate (186 mg, 0.625 mmol) and pyrazine (150 mg,
1.873 mmol) was dissolved in 15 cm3 of ethanol/water (1:1/v:v) and stored in a Parr Teflon line–
steel autoclave. The reaction mixture was heated to 110 °C with heating rate 3 °C·min–1 and kept
at this temperature for 100 h. The mixture was cooled to room temperature at 0.1 °C·min–1.
Colorless needle–like crystals of [Zn(INA)2(H2O)4] were collected by filtration, washed with
water and dried. Anal. calcd. for C12H16N2O8Zn1 (Mr = 381.65, yield: 89 mg, 37%): C, 37.76%;
H, 4.23%; N, 7.34%. Found: C, 38.16%; H, 4.52%; N, 7.78%. 1H NMR (400 MHz, [D6]DMSO):
δ 7.80 (d, J = 4.11 Hz, 1H, Hb), 8.13 (s, 0.2H, Ha), 8.72 (s, 0.8H, Ha) ppm.
2.1.4. Biological tests
2.1.4.1. Antimicrobial activity. The antibacterial activities of Ag(I) and Zn(II) isonicotinates and
free (isonicotinic acid) were evaluated by micro–dilution method using G+ bacteria
Staphylococcus aureus CCM 3953 and G− bacteria E. coli CCM 3988 [66]. The effects of these
compounds on the growth of yeasts Candida parapsilosis were determined by macro–dilution

method in L–shaped tubes adapted for direct measurement of absorbance [67]. Cultures of
bacteria (in Mueller–Hinton growth medium) and yeasts (Sabouraud’s growth medium) were
incubated under vigorous shaking. The effects of compounds on growth of filamentous fungi
Rhizopus oryzae CCM F–8284, Alternaria alternata CCM F–128 and Microsporum gypseum
CCM F–8342 were observed by macro–dilution on solidified Sabouraud’s medium during static
culturing and the diameters of growing fungal colonies were measured at intervals [68, 69].
Chromatographically pure compounds were dissolved in DMSO. Its final concentration never
exceeded 1.0 vol. % in either control or treated samples. Concentration of the tested compounds
was 0.1 × 10−3−2.0 mM in all experiments. The antimicrobial activity of the tested compounds
was characterized by IC50 values (concentration of a compound which in comparison to the
control inhibits the growth of model microorganisms to 50%) and also by the minimal inhibitory
concentration (MIC) values (MIC of a compound which inhibits microbial growth by 100%).
The IC50 and MIC values were read from toxicity curves. MIC experiments on subculture dishes
were used to assess the minimal microbicidal concentration (MMC). Subcultures of model
microorganisms were prepared separately in Petri dishes containing appropriate agar growth
medium, and incubated at 30 °C for 48 h (bacteria, yeasts) and at 25 °C for 96 h (filamentous
fungi). The MMC value was taken as the lowest concentration which showed no visible growth
of microbial colonies on the subculture dishes.
2.1.4.2. Electronic spectral measurements. To study the binding of complexes to DNA a Varian
Cary 100 UV–VIS spectrophotometer was used for absorption spectral studies. A solution of
CT DNA in buffer (10 mM Tris–HCl) gave a ratio of UV absorbance at 260 and 280 nm of
1.8–1.9, indicating that the CT DNA was sufficiently free from protein. The concentration of
DNA was determined using its extinction coefficient at 260 nm (6600 mol.dm−3.cm−1) [70].
Concentrated stock solutions (2.5 mM) of the Ag(I) and Zn(II) complexes were prepared in
DMSO. The absorption titrations in 0.01 M Tris–HCl buffer (pH = 7.4) were performed using a
fixed complex concentration (25 μM) to which equivalent increments of the DNA stock
solution were added to both measuring and reference cuvette, to eliminate any interference due
to absorbance of nucleic acid itself.

2.1.4.3. DNA–Ethidium bromide fluorescence quenching. Fluorescence measurements were
made by using a Varian Cary Eclipse spectrofluorometer. The fluorescence studies of
investigated compounds with ethidium bromide (EB) have been measured to examine whether
drugs are able to displace EB from its DNA–EB complex. Concentration of stock solutions was
5 mM for the Ag(I) complex and 2.5 mM for the Zn(II) complexes (because of weak solubility)
in DMSO. The DNA–EB complex was prepared by adding 4 μM EB and 20 μM of CT DNA for
measurements with 1; 2 μM of EB and 10 μM of CT DNA for measurements with 2 and 3,
respectively. The fluorescence spectra of DNA–EB were measured using excitation wavelength
of 510 nm, with a slit width of 10 nm for excitation and emission beams. All measurements were
performed in 0.01 M Tris–HCl buffer (pH = 7.4) at 23 °C. The spectra were recorded from 560–
660 nm and analyzed according to the classical Stern–Volmer equation (1) [71, 72]:
I0/I=1+KSV [Q]
(1)
where I0 and I are the fluorescence intensities at 602 nm in the absence and presence of the
quencher, respectively, KSV is the Stern–Volmer quenching constant and [Q] is the concentration
of quencher.
2.1.4.4. CD spectroscopy. CD spectra of CT–DNA were carried out on a Jasco J–810
spectropolarimeter at room temperature with a quartz cell of 1 mm path length by concentration
of CT–DNA (2.5 mM) and complex (4.5 mM). Each CD spectrum was collected after averaging
over three accumulations from 230–330 nm and a scan speed of 200 nm·min–1.
3. Results and discussion
3.1. Solid state studies
3.1.1. Complex 1, 2, 3 crystal structure description. Complex 1 (figure 1) crystallizes in the
monoclinic space group P21/c with two formula units in the cell. Detailed crystallographic data
and processing parameters are given in table 1 and selected bond lengths and angles are noted in
table 2. The two Ag(I) ions provide different coordination modes in the structure. Ag2 is
coordinated by two nitrogens (N(2) and N(2)#2, where #2 = –x+1, –y+1, –z+2) of isonicotinate
ligand providing linear arrangement of ligands. Ag1 has three donors in the coordination sphere,
O(1), O(3) and N(1)#1 (where #1 = x–1, –y+3, z+1/2), which form a distorted trigonal planar

Ag(I). Isonicotinate bridges Ag(1) and Ag(1)#3 atoms (#3 = x+1, –y+3/2, z–1/2) by monodentate
carboxylate group (O(1)) and pyridine nitrogen (N(1)) and also is bonded to Ag(1) and Ag(2) by
O(3) and N(2). One oxygen (O(4)) of carboxylic group is protonated. The Ag–O and Ag–N
distances are typical, 2.133–2.662 and 2.135–2.278 Å, for similar Ag(I) isonicotinates [73]. In
addition, [Ag(1)INA] forms 1D chains propagating along the a axis and [Ag(2)HINA] units
connect Ag(1) ions forming 2D network. Non–covalent, π–π stacking and hydrogen bonds (see
table 3) link the coordination chains into a 3D supramolecular structure. Similar building blocks
were determined in isostructural complexes [74, 57], however, different links between the
building units lead to different 3D networks in these structures.
Complexes 2 and 3 crystallize in the orthorhombic, chiral space group P212121 with four
ꢁ
formula units in the cell and in the triclinic space group ꢀ1 with one formula unit in the cell,
respectively [75, 76]. Since their single crystal analysis was already solved, we now report the
powder XRD data for these two compounds. The experimental PXRD patterns correspond well
with the results simulated from the single crystal data, indicating pure phases of prepared
compounds (see figure S1 in the Supplementary Information). The differences in the intensities
of diffraction lines can be attributed to the variation in preferred orientation of the crystallites in
the powdered samples.
3.1.2. Vibrational spectroscopy. The mid–IR spectra of free HINA and its Ag(I) and Zn(II)
complexes 1, 2 and 3 were measured. The characteristic absorption bands for the complexes are
given in table 4. For comparison, the table is completed by characteristic absorption bands of
sodium isonicotinate and isonicotinic acid. While free HINA provides significant absorption
bands at 3380 and 1697 cm–1 assigned to ν(O–H) and ν(C=O), sodium isonicotinate affords an
IR spectrum with characteristic absorption bands (νas(COO–) and νs(COO–) at 1534 and
1410 cm-1) typical for ionic carboxylate. Similar assignment was reported by Lewandowski [77]
and Yuan [78].
The presence of isonicotinic acid in 1 is demonstrated by the broad absorption of ν(O–H)
at 3411 cm–1 and strong absorption of ν(C=O) at 1715 cm–1. Isonicotinate ligand provides two
very strong absorption bands, νas(COO–) and νs(COO–) stretches (1543 and 1347 cm–1) in 1.
Values indicate a monodentate carboxylate that was also determined from the crystal structure.
The value of Δν can help to assign the carboxylate coordination mode towards metal ions [79].

Expected Δν values for monodentate coordination should be significantly higher than those
observed for ionic compounds of the ligand and separations significantly less than ionic values
are indicative of chelating and/or bridging carboxylate groups [79]. The value of Δ(νas–νs)IR is
196 cm–1 for 1 that indicates monodentate coordination. The value of Δν for sodium isonicotinate
of 124 cm−1 (table 4, 134 cm–1 was observed by Lewandowski [77]) is lower than the
corresponding Δν value observed in 1. Moreover, the calculated Δν values from structural data
(by Nara et al. equation [80]) are 224, 268 cm–1 for 1. Two calculated values correspond to two
different monodentate binding modes of carboxylate, protonated and deprotonated, respectively
(see figure 1). The lower experimental Δν value is probably caused by weak silver–oxygen
bonding (Ag(2)–O(2), 2.866 Å) connecting the building units in the structure. Käll et al.
described similar connection in H[Ag(NICOT)2] (NICOT = nicotinate) [81].
The isonicotinate absorption bands of 2 and 3 provide similar changes toward free ligand
as seen in 1. The values of Δ(νas–νs)IR (230 cm–1 2, 262 cm–1 3) indicate monodentate carboxylate
coordination in Zn(II) complexes. The calculated Δν values from structural data [80] are 268 and
167 cm–1. Significantly lower Δνcalc value indicates the ionic carboxylate (in agreement with
Deacon and Phillips) that also confirms the structure of 3 [76]. To explain this considerable
difference, the influence of hydrogen bonds was considered. It is evident (from crystal structure)
that carboxylate oxygen is connected to intermolecular hydrogen interaction that significantly
influences the carboxylate vibration mode (wavenumber position of νas(COO–) is higher,
νs(COO–) is lower than in free ligand, table 4) simulating monodentate behavior of carboxylate.
The hydrogen bond effect on carboxylate vibration mode was also observed in our previous
experiments with Cu(II), Zn(II) and Ag(I) pyridinecarboxylates [34, 50, 82].
3.1.3. Thermal stability. Complex 1 thermoanalytical curves (TG/DTG–DTA) are shown in
figure 2. Complex 1 is thermostable to 270 °C. Thermal decomposition occurs in two steps. The
first mass loss from 270 to 300 °C with endothermic enthalpic effect (minimum at 287 °C)
corresponds to isonicotinic acid release (15.1/17.2%, clcd./exp.). This endothermic effect is
typical for thermal behavior of isonicotinic acid and this observation was confirmed by
thermogravimetric analysis of HINA (see inset of figure 2). The remaining organic part is
decomposed from 300–600 °C with a significant exothermic effect (maximum at 352 °C)
accompanying the thermal pyrolysis. Observed mass loss (43.7%) indicates three isonicotinate

molecules released, in agreement with the calculated value 45.1%. The solid residue after
thermal decomposition is silver (39.8/39.4%, clcd./exp.).
The 3D polymeric Zn(II) complex 2 and anhydrous Zn(II) complex 3 (dehydration takes
place in one step from 60 to 115 °C, 4 H2O, 18.0/18.1%, clcd./exp.) are more stable (figure 2)
than the 2D polymeric Ag(I) complex 1. They are thermostable to 410 °C and thermal
decomposition processes are similar for both Zn(II) complexes above this temperature.
Isonicotinate is released in a strong exothermic effect with maximum at 443 °C (2) and 446 °C
(3). The experimental mass losses (73.0% 2, 60.8% 3) correspond with calculated ones (73.7% 2,
60.4% 3). The solid residue after thermal decomposition is ZnO in both cases (residual mass
26.0%/28.1% 2, 21.6%, 22.4% clcd./exp. 3). Similar thermal decomposition for Zn(II)
isonicotinate tetrahydrate has been described [83].
Comparing thermal stability of 1 with previously studied Ag(I) complexes [34] provides
evidence that covalent bond character among building blocks plays a significant role in thermal
behavior. Similarly, the anhydrous Zn(II) isonicotinate higher thermal stability than anhydrous
Ag(I) complexes is caused by the presence of predominantly covalent interactions in 2D or 3D
directions, respectively.
3.2. Solution studies
To confirm complex composition and stability in DMSO solution UV–VIS (figure 3) and 1H
NMR (figure 4) spectra were measured.
Isonicotinic acid shows two absorptions at λmax = 213 and 260 nm on UV spectrum
(figure 3). The more intense absorption belongs to π*←π electron transfer of pyridine
conjugative system and the weak signal to π*←n electron transfer from lone pair presence on
nitrogen.
Isonicotinic acid expresses itself by two signals Ha and Hb in the aromatic region of the
1H NMR spectrum [84]. Assignment of the protons is shown in figure 4. Metal coordination
causes the Ha signal to split and these aromatic protons change their chemical shift to lower
values (ΔHa = 0.64 (1), 0.56 (2), 0.63 (3), compared with free acid Ha protons). Corresponding
values of the chemical shifts for prepared complexes are listed in sections 2.1.1 (for 1), 2.1.2 (2)
and 2.1.3 (3), see above.

The initial UV–VIS and 1H NMR spectra (directly after synthesis) and corresponding
spectra after 48 and 96 h confirm the stability of 1, 2 and 3 during incubation for biological
testing.
3.3. Biological tests
3.3.1. Antimicrobial activity. Antimicrobial activities of free ligand and its Ag(I) and Zn(II)
complexes (figure 5) by IC50 and MIC values are summarized in table 5.
Free HINA was antimicrobially inactive against all model bacteria G+ Staphylococcus
aureus, G– Escherichia coli, yeasts Candida parapsilosis and filamentous fungi Rhizopus oryzae,
Alternaria alternata, Microsporum gypseum. Its IC50 and MIC values were higher than 2
mmol.dm–3.
Growth of model microorganisms was significantly suppressed by 1, but very weak
inhibition effects were observed by 2 and 3 added in growth medium (see table 5). From the
antimicrobial activities, the presence of metal ions in the prepared compounds has significant
effect on biological activity in comparison to free ligand. Complex 1 inhibited the growth of G–
E. coli (IC50 = 0.03 mM) more compared to growth of G+ S. aureus (IC50 = 0.068 mM). Total
growth inhibition of S. aureus was observed at 0.5 mmol.dm–3 for 1 with microbicidal effect on
bacterial cells; 100% growth inhibition of E. coli was observed even at one-fifth the
concentration of 0.1 mM with microbistatical effect on individual cells. 2 was antibacterially
inactive. Growth inhibition of S. aureus by 3 (IC50 = 0.84 mM) was higher than the growth
inhibition of G– E. coli (IC50 = 1.3 mM) but its antibacterial activity was lower with comparison
to 1. Ag(I) and Zn(II) complexes significantly influenced the growth of yeasts C. parapsilosis
(see table 5). Similar to bacteria cases, anti–yeast activity of 1 (IC50 = 0.007 mM, MIC =
0.005 mM) was higher than inhibition activity of 2 (IC50 = 0.7 mM, MIC = 1 mM) and 3 (IC50 =
1.2 mM, MIC = 2 mM), respectively. IC50 value of 0.007 mM for 1 indicates considerable
inhibition effect.
Comparing 1 and Ag(I) isonicotinamide inhibition effect (MIC = 0.5 and 0.078 mM
[85]), 1 has lower antimicrobial effect against S. aureus. On the other hand, 100% growth
inhibition of S. aureus was observed at the same concentration (MIC = 0.5 mM) in the case of
Zn(II) 4–hydroxybenzoate [86]. In contrary, antibacterial effect of 2 and 3 was lower (IC50 >
2 mM, IC50 = 1.3 mM).

While 1 showed antifungal activity, 2 and 3 were inactive against filamentous fungi
(IC50, MIC > 2 mM). Based on a comparison of IC50 values (table 5) it can be concluded that
inhibition fungal growth in the presence of 1 decreases in the following order: R. oryzae >
A. alternata > M. gypseum.
Total growth inhibition of A. alternata and M. gypseus by Ag(I) complex was the same
(MIC = 1 mmol·dm–3), however with different effect on fungal spores, microbicidal effect for
A. alternata and microbistatical effect for M. gypseus, respectively.
Complex 1 offers higher antibacterial effect than [Ag(INA)2]·4H2O [22] against G–
bacteria E. coli. Moreover, its antibacterial effect (against E. coli) was more than two times
higher (IC50 = 0.03 mM) than commercially used polymeric Ag(I) sulfadiazine (IC50 =
0.073 mM) [87].
Ag(I) and Zn(II) nitrates were tested toward the microorganisms (table 5). It is evident
that nitrates show higher antimicrobial activity than 1, 2 and 3. Moreover, the antimicrobial
effect of the Ag(I) isonicotinate (1) is considerably lower than in the case of pyridinecarboxylate
analogues ([AgPIC], [AgNIC], [Ag(HDIPIC)]·0.75 H2O [29]). The results correspond with
Abarca's idea that increasing antimicrobial activity of Ag(I) complexes is influenced by ligand–
biological fragment exchange reactions, silver composition (63 wt. % Ag in AgNO3, 40 wt. % in
1, 30 wt. % Ag(I) sulfadiazine) and silver coordination mode (AgNO3 – predominantly ionic
interactions, 1 – predominantly covalent interactions) [22].
3.3.2. Electronic absorption spectra. Electronic absorption spectra are initially employed to
determine the binding of complexes to DNA. Intercalation of the chromophore into the double
helix usually results in hypochromism. The former phenomenon can be ascribed to decrease of
the π→π* transition energy as π* orbital of the intercalated compound couples with the π orbital
of the base pairs [88, 89].
The absorption spectrum of the Ag(I) complex consists of two well–resolved bands with
maxima at 213 and 267 nm. Upon addition of CT–DNA the absorption at 267 nm showed
significant hypochromic effect (about 50%) and slight red shift of this maximum about 2 nm
(figure 6). These phenomena indicate that the complex interacts with CT–DNA by intercalation
[72]. Similar spectroscopic behavior was observed for 2 and 3. The binding parameters from
spectrophotometric analysis are summarized in table 6.

3.3.3. Fluorescence spectral studies. Intercalative binding is also demonstrated through
quenching experiments using ethidium bromide (EB). The fluorescence intensity of EB in the
presence of DNA can be greatly enhanced due to intercalation with DNA [90]. On addition of
1-3 to a DNA–EB mixture, the metal complex competes with EB to bind with DNA [91]. This
leads to decrease in the binding sites of DNA available for EB, and hence quenching of
fluorescence intensity of the DNA–EB mixture occurs (figure 7A, B, C). The quenching plot
illustrates that the quenching of EB bound to DNA by metal complexes is in agreement with the
linear Stern–Volmer equation [92].
The determined Stern–Volmer constants decreased in the order (3.42 × 104 M–1) for 1 <
(2.19 × 104 M–1) for 2 < (1.67 × 104 M–1) for 3. It was established that the KSV value of Ag(I)
complex is approximately two–times higher than the KSV value of 3. The determined KSV values
are close to the constants obtained for other zinc complex by Anjomshoa et al. [93]. These
measurements show that the interactions of 1-3 with DNA are strong, probably due to
intercalative binding [72, 92].
3.3.4. Circular dichroic spectral studies. Circular dichroism (CD) spectroscopy is an optical
technique measuring a difference in the absorption of left and right circularly polarized light. CD
experiment was performed to define the orientation of the compounds with respect to the DNA
helix. The compounds have no circular dichroism spectra when free in solution but have an
induced CD spectrum when in the complex with DNA. The B–form conformation of DNA
shows two CD bands in the UV region, a positive band at 278 nm due to the base stacking and a
negative band at 246 nm due to the polynucleotide helicity [94, 95]. When Ag(I) complex was
incubated with CT–DNA, the positive band showed an increase in molar elipticity and the
negative band showed a decrease in intensity at 246 nm with a slight red shift of the band
maximum (figure 8). Similar spectra are found for the Zn(II) complexes. The helical band at
246 nm corresponds to DNA unwound extent exhibiting decrease for all the compounds in
similar order as that of previously studied Cu complexes [89]. However, the observed CD
spectral changes are typical for intercalative binding [96].

4. Conclusion
The synthesis of Ag(I) and Zn(II) isonicotinate complexes has been accomplished and their
structural, spectral, thermal and antimicrobial properties were described, correlated and
compared. Ag(I) structural polymorph shows a new 3D structure in solid state and highest
antimicrobial effect in comparison to its Zn(II) analogues.
The interaction of the synthesized complexes with CT–DNA has been performed with
UV spectroscopy revealing their ability to bind to DNA. Competitive binding experiments show
that the enhanced emission intensity of ethidium bromide in the presence of DNA was quenched
by addition of Ag(I) and Zn(II) complexes, indicating that they displace EB from its binding site
in DNA. From UV–VIS and fluorescence studies the complexes can bind to CT–DNA by
intercalation. CD measurements confirm the mentioned mode of binding, which correlates well
with aromatic ring system in the ligand. In vitro antimicrobial screening showed that Ag(I)
complex was most active against tested yeasts C. parapsilosis with an IC50 value of 0.007 mM
and two times more active against bacteria E. Coli than similar polymeric complex Ag(I)
sulfadiazine, commercially used.
Acknowledgements
This work was supported by the Slovak Research and Development Agency under contract No.
APVV–0280–11, by VEGA 1/0001/13, VEGA 1/0535/16 and VVGS PF–2015–488. The authors
are very grateful to Mária Vojtasová and Prof. Ján Imrich from NMR Laboratories, Department
of Organic Chemistry, P. J. Šafárik University in Košice for the NMR spectra measurements.
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Table 1. Crystal data and structure refinement for 1.
Empirical formula
Formula weight
Temperature
C24H17Ag3N4O8
813.03
173(2) K
Wavelength
0.71073 Å
Monoclinic
P 21/c
Crystal system
Space group
Unit cell dimensions
a = 8.1779(4) Å
b = 19.5901(14) Å
c = 7.4107(5) Å
1 185.96(12) Å3
2
α = 90°
β = 92.807(5)°
γ = 90°
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
2.280 g.cm–3
2.514 mm–1
788
Crystal size
0.2011 × 0.2000 × 0.1397 mm3
Theta range for data collection
Index ranges
3.247 to 26.494°
-10 ≤ h ≤ 10; -24 ≤ k ≤ 23; -9 ≤ l ≤ 9
12 653
Reflections collected
Independent reflections
Completeness to theta (26.50°)
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I > 2 (I)]
R indices (all data)
Largest diff. peak and hole
2 459 [R(int) = 0.0285]
99.8 %
Numerical
0.58 and 0.43
Full-matrix least-squares on F2
2 459 / 0 / 179
1.235
R1 = 0.0278, wR2 = 0.0804
R1 = 0.0359, wR2 = 0.0944
0.732 and -1.356 e.Å–3

Table 2. Selected bond distances (Å) and angles (°) for 1.
Bond distances
Ag(2)–N(2)#2
Ag(2)–N(2)
Ag(1)–O(1)
Ag(1)–O(3)
Ag(1)–N(1)#1
2.148(3)
2.147(3)
2.132(3)
2.660(2)
2.170(3)
O(3)–C(7)
O(4)–C(7)
O(1)–C(1)
O(2)–C(1)
O(4)–H(1O4)
1.218(4)
1.279(4)
1.268(4)
1.231(4)
0.8400
Bond angles
O(3)–Ag(1)–O(1)
O(3)–Ag(1)–N(1)#1
O(1)–Ag(1)–N(1)#1
N(2)–Ag(2)–N(2)#2
C(7)–O(3)–Ag(1)
C(1)–O(1)–Ag(1)
C(5)–N(1)–Ag(1)#3
113.96(9)
87.81(9)
155.8(1)
180.0(1)
132.3(2)
115.8(2)
122.5(2)
C(4)–N(1)–Ag(1)#3
C(10)–N(2)–Ag(2)
C(11)–N(2)–Ag(2)
O(2)–C(1)–O(1)
120.1(2)
123.1(2)
119.4(2)
125.8(3)
125.5(3)
109.5(3)
O(3)–C(7)–O(4)
C(7)–O(4)–H(1O4)
Symmetry transformations used to generate equivalent atoms: #1 x–1, –y+3/2,
−z+1/2; #2 –x+1, –y+1, –z+2; #3 x+1, –y+3/2, z–1/2

Table 3. Possible hydrogen bonds (Å, °) for 1.
D–H···A
d(D-H)
0.95
0.95
0.95
0.95
0.95
0.95
d(H···A)
2.37
d(D···A)
3.126(4)
3.386(4)
3.268(4)
3.126(4)
3.386(4)
3.268(4)
<(DHA)
136.3
138.1
142.9
136.3
138.1
142.9
C(4)–H(4)···O(3)#3
C(10)–H(10)···O(2)#4
C(11)–H(11)···O(2)#5
C(4)–H(4)···O(3)#3
C(10)–H(10)···O(2)#4
C(11)–H(11)···O(2)#5
2.62
2.46
2.37
2.62
2.46
Symmetry transformations used to generate equivalent atoms: #1 x-1,-y+3/2,z+1/2; #2 -x+1,-
y+1,-z+2; #3 x+1,-y+3/2,z-1/2; #4 x,y,z+1; #5 -x+1,-y+1,-z+1