Mn(II), Co(II), Ni(II) and Zn salicylates: Synthesis, structure and biological properties studies

Article abstract of DOI:10.1016/j.ica.2021.120606

Reaction of acetylsalicylic acid (aspirin) (H₂L) with Mn(II), Co(II), Ni(II) and Zn acetates allow to obtain salicylates of related metals. The solid-state structures of prepared complexes were determined by single crystal X-ray crystallography and spectroscopic techniques. Zinc, nickel and cobalt(II) complexes are mononuclear and their crystal structures composed of neutral discrete molecules [Zn(sal)₂(H₂O)₂], [Ni(sal)₂(H₂O)₄] and [Co(sal)₂(H₂O)₄] while manganese derivative has 2D polymeric structure. The cardiorespiratory and skin microcirculation activity of these metal complexes was evaluated. Particularly, the promising therapeutic activities displayed by 1–4 complexes make them potential candidates for the development of a promising drugs.

Full text of DOI:10.1016/j.ica.2021.120606

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Research paper
Mn(II), Co(II), Ni(II) and Zn salicylates: synthesis, structure and biological
properties studies
Alexey Gusev, Yuriy Baluda, Elena Braga, Mariya Kryukova, Mikhail
Kiskin, Elena Chuyan, Marina Ravaeva, Igor Cheretaev, Wolfgang Linert
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https://doi.org/10.1016/j.ica.2021.120606
ICA 120606
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21 July 2021
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5 September 2021
Please cite this article as: A. Gusev, Y. Baluda, E. Braga, M. Kryukova, M. Kiskin, E. Chuyan, M. Ravaeva, I.
Cheretaev, W. Linert, Mn(II), Co(II), Ni(II) and Zn salicylates: synthesis, structure and biological properties
studies, Inorganica Chimica Acta (2021), doi: https://doi.org/10.1016/j.ica.2021.120606
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Mn(II), Co(II), Ni(II) and Zn salicylates: synthesis, structure and biological properties
studies
Alexey Gusev a*, Yuriy Baluda a, Elena Braga a, Mariya Kryukova b, Mikhail Kiskin c,
Elena Chuyan a, Marina Ravaeva a, Igor Cheretaev a, Wolfgang Linert d*
a Сrimean Federal University, Simferopol, 295007, Crimea
b Institute of Chemistry, Saint Petersburg State University, Universitetskaya Nab. 7/9,
Saint Petersburg, Russia
c N.S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
Moscow, Russia
d Institute of Applied Synthetic Chemistry, Vienna University of Technology,
Getreidemarkt 9/163-AC, A-1060 Vienna, Austria
Reaction of acetylsalicylic acid (aspirin) (H2L) with Mn(II), Co(II), Ni(II) and Zn acetates allow to
obtain salicylates of related metals. The solid-state structures of prepared complexes were determined
by single crystal X-ray crystallography and spectroscopic techniques. Zinc, nickel and cobalt(II)
complexes are mononuclear and their crystal structures composed of neutral discrete molecules
[Zn(sal)2(H2O)2], [Ni(sal)2(H2O)4] and [Co(sal)2(H2O)4] while manganese derivative has 2D polymeric
structure. The cardiorespiratory and skin microcirculation activity of these metal complexes was
evaluated. Particularly, the promising therapeutic activities displayed by 1-4 complexes make them
potential candidates for the development of a promising drugs.
Keywords: Metal complexes, aspirin, salicylate, X-ray crystallography microcirculation activity,
cardiorespiratory system.
________________________________________________________________
1. Introduction
Since being first synthesized and purified by Felix Hoffmann in 1897, Aspirin is today the most
widely used drug all over the world. It belongs to the class of non-steroidal anti-inflammatory drugs
(NSAIDs) and has a number of therapeutic uses: analgesic, anti-inflammatory, anti-platelet and anti-
pyretic [1-2]. Aspirin use in preventing cardiovascular and cerebrovascular diseases has been one of the
biggest pharmaceutical achievements of the twentieth century. Low-dose everyday use of aspirin is
known to be beneficial in reducing risk of secondary heart-attacks and for the prevention of preterm
* Corresponding authors.
Email adresses: galex0330@gmail.com (A. Gusev), email: wolfgang.linert@tuwien.ac.at (W. Linert)

delivery in nulliparous women with a singleton pregnancy [3-6]. Besides possible role of low-dose
aspirin in reducing the long-term risk of several cancers has opened a new era of aspirin use [7-10],
making a solution to this issue very desirable. In recent years, many clinical epidemiological studies
have found that with an increase in aspirin intake, tumor mortality decreases exponentially in the colon,
breast, lung, prostate and other organs of cancer patients.
It is well known that in the course of metabolism, aspirin is hydrolyzed to salicylic acid, which is
the active biological component [1]. Getting into a complex system of the internal environment, salicylic
acid can interact not only with organic components, but also complexation with inorganic cations, which
can lead to the formation of new biologically active forms of coordinated salicylic acid [11-15]. Actually,
complexing properties of salicylic acid offers one of the routes for its modification. For example, some
3d-metal complexes of salicylic acid and its derivatives are known to be more potent anti-inflammatory
agents than the acids themselves, and they have been shown to have low toxicity and less side effects
[16, 17]. Moreover, such complexes exhibit antiradical activity and have superoxide dismutase mimetic
properties [18–20]. Zinc(II) salicylate complexes possess anticonvulsant action [21]. However, a number
of biological activities of metal coordination compounds are still poorly studied, in particular, neuro-
and psychotropic properties and the response of the cardiorespiratory system to the introduction of such
coordination compounds.
It should be noted, also, that most of the biologically active metal complexes on ssalicylate-anion
basis are obtained directly from salicylic acid. This does not correctly reproduce the possible chemistry
of the complexation process in the cell when using aspirin as a precursor. Taking into account the
fundamental possibility of interaction of acetylsalicylic acid with 3d-metal cations present in the body,
it seems interesting to analyze the composition and properties of such complexes. The study of
biologically active metal complexes obtained by interaction with aspirin can lead not only to new
biologically active compounds of this class, but also explain the mechanism of aspirin action in
previously unexplored processes. In this article, we describe structure, physicochemical and some
biological properties of Mn(II), Co(II), Ni(II) and Zn coordination compounds with salicylate anions
obtained by complexation of corresponding metal acetates with acetylsalicylic acid
2. Experimental
2.1. Materials and physical methods
All reagents and solvents employed were commercially available and used as received without
further purification. The purity and composition of the prepared complexes were confirmed by means
of elemental analysis, electrospray-ionization mass-spectrometry (ESI–MS), and FT-IR spectroscopy,
XRPD and single crystal X-ray structure analysis.

Elemental analyses of C, H, and N were performed with a Perkin–Elmer 240 C analyser. IR spectra
were measured with a Spectrum Two PerkinElmer Inc spectrometer in the range 4000-400 cm–1.
Electrospray mass spectra of complex were measured with the Finnagan TSQ 700 mass spectrometer in
positive ion mode. Samples were prepared at a concentration of ∼2 mg/ml MeOH. The mass spectra
were acquired over the m/z range of 50-2000; several scans were averaged to provide the final spectrum.
2.2. Synthesis
General procedures for complexes.
Water solution (40 ml) of acetylsalicylic acid (1.8 g, 0.01 mol) was added to an aqueous solution
of respected metal(II) acetate (0.005 mol). Vigorous stirring at room temperature followed for two hour
and the fltrate left for slow evaporation at room temperature. After a few days crystalline product of tar
was deposited and collected by filtration. Target complexes were purified by recrystallization from a
minimal volume of water.
White crystals [Zn(Sal)2∙2H2O] - 1. Elemental analysis found: C: 44.80; H: 4.01%; calculated for
C14H14O8Zn C: 44.76; H: 3.76%. IR (cm-1): 3410 (br), 3229 (br), 1625 m, 1600 s, 1563 s, 1445 s, 1386
vs, 1244 s, 755 s, 658 m 428 m; UV-vis (water): λmax = 314 nm (log ε = 3.0). HRMS m/z: 339.3784;
calculated for [Zn(Sal)2H]+ m/z: 339.3275
Pink crystals. [Co(Sal)2∙4H2O] - 2. Elemental analysis found: C: 41.74; H: 4.63%; calculated for
C14H18O10Co C: 41.50; H: 4.47%. IR (cm-1): 3390 (br), 1620s, 1608s, 1580 s, 1456 s, 1371 vs, 1241 s,
751 s, 663 m 420 m; UV-vis (water): λmax = 315 nm (log ε = 3.1), λmax = 511 nm (log ε = 0.04),. HRMS
m/z: 334.1667; calculated for [Co(Sal)2H]+ m/z: 334.2418
Nude-colour crystals. [Mn3(Sal)4(OAc)2∙4H2O]∙3H2O - 3. Elemental analysis found: C: 40.32; H:
4.51%; calculated for C32H40O23Mn3 C: 40.14; H: 4.21%. IR (cm-1): 3345 (br), 1681m, 1625m, 1599s,
1555 s, 1456 s, 1386 vs, 1306 m, 1246 s, 754 s, 665 m 466 m;; UV-vis (water): λmax = 315 nm (log ε =
3.0).
Light green crystals. [Ni(Sal)2∙4H2O] - 4. Elemental analysis found: C: 41.21; H: 4.37%;
calculated for C14H18O10Ni C: 41.52; H: 4.48%. IR (cm-1): 3390 (br), 1621s, 1605s, 1582 s, 1453 s, 1373
vs, 1246 s, 751 s, 661 m 421 m; UV-vis (water): λmax = 315 nm (log ε = 3.1), λmax = 511 nm (log ε =
0.04),. HRMS m/z: 334.7164; calculated for [Ni(Sal)2H]+ m/z: 334.6804
2.3. X-ray Crystallography
The single crystal X–ray diffraction data for 1-3 were collected using the SuperNova
diffractometer equipped with a HyPix-3000 detector and a micro-focus CuKα radiation source (λ =
1.54184 Å) at the Centre for X-ray Diffraction Studies of Research park of St. Petersburg State
University. The structure of complex was solved by the direct methods and refined in the full-matrix

anisotropic approximation for all non–hydrogen atoms. The hydrogen atoms of water molecule were
found in differential Fourier maps and their parameters were refined using the riding model. The
hydrogen atoms of the carbon-containing ligand were positioned geometrically and also refined by a
riding model. All the calculations were performed by direct methods and using the SHELX–2014
program package [22, 23]. The crystallographic parameters and X-ray diffraction experimental-
parameters are given in Table 1.
< Table 1>
2.4. Biological activity studies
All studies on the animals were carried out according to the principles set out in Directive
2010/63/EU of the European Parliament and of the EU Council of 22.09.2010 on the protection of
animals used for scientific purposes.
Healthy sexually mature male laboratory Wistar rats, weighing 180-200 gr (“FSUE “Nursery of
laboratory animals “Rappolovo”) and quarantined for at least 14 days, were selected for the experiment.
The experiments were performed on 140 male rats, characterized by an average motor activity and low
emotionality in the “open field” test, and which make up the majority of the population; that is why they
develop the most typical reaction to the effect of different factors, including the tested chemical
compounds. The animals were kept under standard conditions of the vivarium at the temperature of 18–
22ºС on the bedding «Rechofix МК 2000» (on the basis of ear shanks) with the natural 12-hour day-
and-night cycle, with free access to water (State Standard 33215-2014 «The handbook of keeping and
nursing laboratory animals. The regulation rules on housing equipment and procedure organization»),
and to full-fledged granulated food of State Standard Р-50258-92. The research was carried out at the
Center for Collective Use of Scientific Equipment “Experimental physiology and Biophysics” of the
Department of Human and Animal Physiology and Biophysics of V.I. Vernadsky Crimean Federal
University. Detailed procedures regarding the study of the biological activity of the complexes are given
in the Supporting information file.
3. Results and discussion
Synthesis and characterization of the complexes.
Title complexes 1-4 were obtained by direct one-step reaction of corresponding metal acetate and
acetylsalicylic acid and isolated by the slow evaporation of aqueous solution at room temperature. Crude
sample of 1-4 obtained directly from reaction according of XRD are mixtures of acetylsalicylates and
salicylates of related metal in 1:2 molar ratio. Recrystallization from water lead to complete of
hydrolysis of acetic group and target complexes are pure salicylates. Composition of 1-4 were
determined according elemental and ESI-MS data complexes. Prepared compounds are air-stable and
soluble in water, alcohols and dimethylsulfoxide. According to the molar conductivity values (ΛM), the

complexes are non-electrolytes in water (ΛM = 7-9 S·cm2·mol−1, in 1 mM solution); thus, we may
consider that the compounds remain stable and do not dissociate in water solution
Structural determination of the complexes
Zinc salicylate were previously obtained by reaction of sodium salicylate with zinc chloride and
structurally characterized by spectral and XRD techniques [24,25]. P. Lemoine et all demonstrated that
the use of sodium acetylsalicylate as a precursor made it possible to isolate zinc acetylsalicylate that was
structurally characterized by XRD [21]. Our studies have shown that the reaction of acetylsalicylic acid
with zinc acetate is accompanied by crystallization of zinc salicylate. The molecular structure of 1 is the
close to the structure of [Zn(sal)2(H2O)2] reported by Klug [24] which was obtained by reaction of
sodium salicylate and zinc chloride, so here we didn’t describe it in detail.
Figure 1.
Cobalt(II) salicylates also described previously [26,27]. There are several polymorphs were
obtained earlier by reaction of sodium salicylate with Co(II) salts meanwhile at this work it was found
that the reaction of cobalt(II) acetate with acetylsalicylic acid leads to the crystallization of a new
polymorph of cobalt salicylate previously uncharacterized. Complex 2 crystallizes in the monoclinic
space group P 21/n. The molecular structure of 2 are centrosymmetric with the cobalt(II) ion sitting on a
center of symmetry coordinated to two salicylate ligands and four aqua ligands related by the inversion
center; therefore, the cobalt atom is six-coordinated having an octahedral geometry (Figure 2).
Figure 2
All the Co-O distances are of the same magnitude with the Co(1)-O carboxylate one being the
shortest (Co1-O3= 2.040(2) Å) and the Co1-O2 water (2.141(2) Å) being the longest ones. Taking into
account the small differences found in the Co–O distances in combination with the angles around cobalt
(O-Co-O) being in the range of 86.94(6)-93.06(6)°, the octahedron displays a slight distortion. The
carboxylate group in 2 coordinated in monodentate mode (C7-O6 = 1.245(3) Å and C7-O3 = 1.292(3)
Å). This distance compares favorably with the range usually observed for cobalt complexes revealing
monodentate coordination of the carboxylato group reported in the literature [30,31]. The two oxygens
from the salicylate ligands and two oxygens from two aqua ligands occupy the octahedron’s basal plane.
Also, two oxygen atoms from two aqua ligands O2, O2’ are lying at the axial position. The two salicylate
ligands and the four aqua ligands are all lying at trans position to one another.
The structure of 2 are further stabilized by intra and inter-molecular hydrogen bonds. Intra-cluster
hydrogen bonds are developed between the phenolic hydrogen atom and the coordinated carboxylato
oxygen atoms. Supramolecular structures are further stabilized due to intermolecular interactions
involving the aqua and salicylate ligands via O-H∙∙∙O, C-H∙∙∙O, and C-H∙∙∙π interactions between
neighboring molecules.

Unfortunately, we were unable to obtain high quality crystals to perform single-crystals XRD,
however, powder XRD data indicate that nickel complex is isostructural to 2.
Compound 3 crystallizes in the monoclinic space group P 21/c. Complex exhibits 2D coordination
networks in which trinuclear units [Mn3(Sal)4(OAc)2(H2O)4] are inter-linked by the acetate ligands. As
shown in Fig. 3 , there are two crystallographically independent Mn(II) atoms in 3 (Mn1 and Mn2).
The central Mn1 atom of the trimers is located on a crystallographic inversion center. The pseudo-
octahedral coordination geometry of Mn(1) is defined by four salicylate oxygen from carboxylate group
(O(1), O(1), O(4) and O(7)) and two oxygens from acetate-anions in trans positions. Mn(2) is
coordinated by two oxygen atoms from water, two oxygen atoms from two different salicylate ligands
and two oxygen atoms from two different acetate anions also forming six-coordinated environment
(Mn(2)-O distances, 2.263(2)–2.282(2) Å; Mn(2)–O distances, 2.149(4)–2.226(4) Å). The Mn–O bond
distances for both Mn1 and Mn2 fall in the range between 2.149(4) and 2.226(4) Å. Trinuclear core is
strictly linear with Mn⋯Mn separation is 3.670 Å.
Figure 3.
Salicylate anion adopts the (η1-η1)-μ2 bidentate bridging coordination mode linking neighboring
Mn1 and Mn2 atoms. Additionally, each pair of Mn(1) and Mn(2) ions are bridged by acetate-anion in
(η2-η1)-μ3 tridentate coordination mode. Аcetate-anion additionally connect individual trinuclear motifs
into a polymeric 2D-layer assembly. The shortest distances between manganese ions in trinuclear cores
is 4.797 Å. The intramolecular hydrogen bonds of hydroxyl groups of salicylate anions are present in
crystal structures of 3. Furthermore O–H⋯O hydrogen bonds between coordinated and uncoordinated
water molecules and carboxylic oxygen atoms of 3 extend the Mn3(Sal)4(OAc)2(H2O)4]n layer to 3D-
supramolecular assembly (Figure 4).
Figure 4.
IR, UV-vis spectroscopy and TG measurements
Spectral properties of all three complexes are in good agreement with structural data. Infrared
spectra of the complexes 1-4 comprise bands confirming the presence of all characteristic functional
groups. The presence of water molecules in title complexes is confirmed by one rather broad and
asymmetrical O–H absorption band showing one maximum at 3345-3410 cm−1 due to similarly strong
hydrogen bonds of both water molecule hydrogen atoms.
Typical carboxylate stretching frequencies for asymmetric stretching vibrations νas(COO-) in the
range 1555-1608 cm-1 and for symmetric stretching vibrations νsym(COO-) in the region 1371-1386 cm-
1. The difference between asymmetric and symmetric stretching vibrations (∆) that usually used to assign
the coordination mode of carboxylate anion for 1, 2 and 4 are in 237-214 cm-1 range and indicative of

asymmetrically binding mode of binding, while for 3 ∆ is 167 cm-1 and consistent with bidentate
chelating coordination of carboxylate group. Notably that intense band of ester group at 1750 cm-1
registered for starting aspirin and crude samples is absent which is a weighty argument in favor of
complete hydrolysis of the acetyl group during recrystallization. Stretching vibrations ν(C-O)OH are
found at 1241-1246 cm-1 and practically does not shift upon coordination. Characteristic absorption
bands of stretching vibrations ν(M-O) appear, below 460 cm-1.
The electronic spectra of aqueous solution of all studied complexes exhibit intraligand π-π*
transition bands at 314-315 nm that bathochromically shift with compare with free salicylate-anion.
Broad asymmetric ligand field bands attributed to d→d transitions with a maximum in the position at
511 nm were found for complex 2 assigned to 4T1g(F)–4T1g(P) transition in octahedral high-spin Co(II)
containing complexes with CoO6 chromophore. For nickel complex 3A2-3T1 transition typical for NiO6
chromophore was found at 673 nm.
The thermal behavior of 1-4 was studied by TGA techniques. Complexes demonstrate the multi-
stage decompositions upon heating and overall weight loss is in agreement with stoichiometry. Complex
1 is stable up to 95 ꢀ°C. The first weight loss of 9.8 % in the region of 95–175 °C (peak at 154 °C)
corresponds to the release of the lattice and coordinated water molecules (calculated 9.6 %). The
residual framework starts to decompose beyond 215 °C and does not stop until heating ends at 700 °C.
The final product of thermal decomposition was ZnO (the experimental mass 22.8%, the theoretical
mass 21.6%).
Thermal behaviors of cobalt and nickel complexes are close to each other. For 2 and 4 the weight
loss of the coordinated water occurs in the range of 60–240 °C with hardly to identify each steps.
However, the overall weight loss is about which corresponds to the release of four water molecules
(calculated 17.33%). The rapid decomposition process occur up to 260-270ꢀ°C with the drop of weight
loss around 46.0% corresponding the release of 1 mol of phenol together 1 mol of carbon monoxide
(calculated 47.9%) and then, a series of complicated weight losses were observed as the temperature
increased until heating ends at 700 °C.
For 3, the first weight loss of 5.75 % in the of 95−140 °C range corresponds to release of the lattice
water molecules (calculated 5.96%). The second step of weight loss of 49 % in the 190−340 °C range
corresponds to the release of the coordinated water, and products of decompositions of acetate and
salicylate anions and then, a series of complicated weight losses were observed as the temperature
increased until heating ends at 700 °C.
.
Indices of the cardiorespiratory system
It was found that in animals of control group at introduction of saline the examined parameters

of cardiorespiratory system (CRS) were within physiological norm (see Table 2, 3).
In the first series of the experimental study, the administration of ASA at a dose of 5 mg/kg
resulted in a significant decrease in the HR score per 22.5% (p≤0,05) relative to that in the control group
of animals. A similar trend was recorded when the dose of ASA increased to 10 mg/kg: HR decreased
by 21.8% (p≤0,05) relative to the values of these indicators in the control group of animals (see Table
2). The remaining animal CRS values did not change significantly when the test compounds were
administered at a dose of 5 and 10 mg/kg.
The results of the second series of experiments confirmed the data obtained in the 1st series.
Thus, in animals with intraperitoneal administration of ASA at doses of 5 and 10 mg/kg, a decrease in
the heart rate of bradycardia was observed. Moreover, this effect was almost identical in doses of 5 and
10 mg/kg. i.e. was not dose dependent.
By administering of 2 (see Table 2) at a dose of 5 mg/kg, HR decreased by 14.1% (p≤0.05) relative
to the values of this indicator in the control group of animals. Increasing the dose of 2 to 10 mg/kg also
resulted in a significant 6.9% reduction in HR (p≤0.05) relative to the values in the control group of
animals. At the same time, the blood pressure and respiratory rate in animals injected with 2 did not
significantly change. However, with an increase in the dose of 2 to 10 mg/kg, a significant increase in
HR by 19.2% (p≤0.05) and a significant decrease in DAP by 14% (p≤0.05) were recorded relative to
the values of these indicators in animals receiving ASA injections of the same dosage. Thus, 2 at doses
of 5 mg/kg and especially 10 mg/kg reduces the negative chronotropic effect characteristic of ASA.
The administration of 1 to animals (see Table 2), as with the administration of ASA and 2 was
accompanied by a decrease in HR relative to the test indicators values in the control group of animals.
Thus, when Zn2+ salicylate was administered to animals at a dose of 5 mg/kg, a significant decrease in
HR by 17% (p ≤ 0,05) was recorded in relation to the values of these indicators in the control group of
animals. Increasing the dose of this compound to 10 mg/kg also resulted in a 14.3% reduction in HR (p
≤ 0.05) relative to the values in the control group of animals. However, along with this, there was an
increase in RR by 56.3% (p ≤ 0.05), a decrease in SBP by 5.1% (p ≤ 0.05), an increase in DBP by
14.7%, which led to a significant decrease in PP by 38.3% (p ≤ 0.05) compared to similar indicators in
the control group of animals.
Thus, the reaction of animal CRS to the administration of 1 at a dose of 5 mg/kg was
unidirectional with ASA, which manifested itself in a negative chronotropic action. Increasing the dose
to 10 mg/kg led to a decrease in the severity of the negative chronotropic effect on the heart rhythm of
the test compound, as well as the appearance of new properties in 1 other than ASA, namely, an increase
in DBP and RR and a decrease in SBP and PP.
< Table 2>

When 3 was administered to animals at a dose of 5 mg/kg, the most pronounced changes in rat
CRS rates occurred, with both ASA and 1 and 2 which was expressed in a significant increase in HR
by 5%, DBP - by 5%, PP - by 15% (see Table 3). Increasing of the dose of 3 to 10 mg/kg, HR increased
by 7%, however, PI, on the contrary, decreased by 14% relative to the values in the control group of
animals, and the remaining indicators did not significantly change. At the same time, RR in animals
with 3 10 mg/kg was 25% lower compared to that in rats with the same compound at a dose of 5 mg/kg.
Thus, the administration of 3 to animals (see Table 3) resulted in effects other than the precursor
molecule (ASA), which manifested itself primarily in a positive chronotropic effect and an increase in
DBP. At the same time, the detected effects of 3 showed dose dependence: tachypnea was registered at
a dose of 5 mg/kg, and tachypnea was replaced by bradypnea at a dose of 10 mg/kg.
When 4 was administered at a dose of 5 mg/kg, there was a significant 15% reduction in RR
compared to control group of animals (see Table 3). With an increase in the dose of the test compound
to 10 mg/kg, the orientation of the animal CRS reaction to the administration of 4 remained, however,
the severity of the reduction in RR increased and amounted to 74% of that in the control group of
animals. Thus, 4, in contrast of ASA, does not affect HR, but leads to an increase in DBP at both doses
tested and a decrease in RR, especially expressed at a dose of 10 mg/kg, i.e., bradypnoea development.
< Table 3>
Indices of skin microcirculation of rats under action of acetylsalicylic acid and 1-4
The results of the study showed that the administration of ASA at doses of 5 mg/kg and 10 mg/kg
led to a significant increase in the amplitudes of endothelial oscillations (Ae), neurogenic (An),
respiratory (Ap) rhythms, an blood of pressure (BP) relative to those in the control group of animals (see
Table 4, 5).
In general, the dynamics of changes in MR values when ASA is administered to animals indicates
an increase in endothelium-dependent vasodilation, a decrease in peripheral resistance, an increase in
blood flow to the nutritive microvascular bed, an improvement in venular outflow. Changes in these
indicators reflects of the development to skin microvessels hyperemia. At the same time, dose
dependence in the response of skin microcircuit to the action of ASA in the analyzed concentrations was
not detected.
Using of complexes 1-4 instead of ASA lead to significant change in the parameters of skin
microhemodynamics of animals (see Table 4, 5). So, with the introduction of complex 2 at a dose of 5
mg/kg, the oscillation amplitudes of all rhythms increased. Thus, the vasotropic effect of 2 is similar to
that of ASA and is expressed in the development of vasodilation and hyperemia, however, unlike ASA,
compound 2 more increases the metabolic activity of endothelium and reduces the tone of precapillary
metarterioles due to the development of Ca2+ dependent muscle relaxation (Am increase), however, is

significantly inferior to ASA in the ability to modulate blood flow in all frequency bands (reduced MSD)
and activation of vasomotor control of microvascular bed tone (reduced Kv).
When complex 1 was administered to animals, as well as complex 2, it caused an increase in all
oscillatory and non-oscillatory parameters of microcirculation and, accordingly, the development of
vasodilation. It can be concluded that complex 1, like the initial substance of ASA, leads to the
development of vasodilation and hyperemia, however, unlike ASA, this effect is due to an increase in
the metabolic activity of the endothelium, a decrease in the Ca2+-dependent tone of precapillary
sphincters and precapillary metarterioles, an increase in the flow of arterial blood into the microarm and
activation.
When administering complex 4 at a dose of 5 mg/kg (see Table 5), there was only an increase in
Ae by 75.1% (р≤0,05) and a decrease in non-oscillatory basal blood flow: MSD - by 62.3% (р≤0,05)
and Kv - by 66.7% (р≤0,05), respectively, relative to values these indicators in the control group of
animals. Thus, the vasotropic effect of complex 4 is to increase the metabolic activity of the endothelium
and reduce the modulation of the microcircuit, this effect is manifested only at a dose of 5 mg/kg, and
at a dose of 10 mg/kg this compound is not effective.
When complex 3 was administered (see Table 5) to animals at a dose of 5 mg/kg, it increased the
metabolic activity of the endothelium. With an increase in the dose of compound 3 to 10 mg / kg, the
maximum increase in Ae was observed, which was reflected in an increase in tissue perfusion and an
improvement in venous outflow. Thus, complex 3, as well as complex 4 inhibiting almost all units of
microcirculation regulation, prevents the development of hyperemia observed with the action of ASA.
< Table 4>
< Table 5>
Antioxidant activity of the complexes
Nowadays, antioxidants that exhibit free radical scavenging activity are receiving increasing
attention. Free radicals are species which have unpaired electron(s) having an important role in the
inflammatory process. The transfer of the unpaired electron(s) of free radicals to a neighboring molecule
will induce the ignition of chain reactions which are responsible for a variety of undesired side-effects
in the organisms including swelling, inflammations, or even cancer. Antioxidants can scavenge free
radicals and/or inhibit the production of novel radicals and, subsequently, terminate the radical-initiated
side reactions. Consequently, compounds with antioxidant properties may be expected to offer
protection for a variety of undesired side-effects in the organisms including swelling, inflammations, or
even cancer. ASA and mainly its salicilate metabolite strongly scavenge HO radical [28,29]. The major
evidence for this activity is the ability of ASA and SA to undergo aromatic hydroxylation by
reacting with HO⸱. At the same time, there is no information in the literature on the antioxidant activity
of transition metal complexes based on salicylic acid. Within this context we used DPPH and ABTS-

radical method to evaluate antioxidant activity of 1-4. Results are summarizes in table 6.
< Table 6>
Our results demonstrate that the ability of ASA and complexes 1 and 4 to scavenge DPPH radical
(RA% = 21–28 %) is mainly time-independent, while the activity of complexes 2 and 3 against the
radical presents a noteworthy increase during time. The DPPH scavenging activity of 2 and 3 was found
in the range 54–60 % indicating about noticeable antioxidant activity. Despite of higher activity of 2
an3 obtained value is lower than that of the reference compounds NDGA
The scavenging of the cationic ABTS radicals is applicable for screening the total antioxidant
activity. The ABTS scavenging activity of the complexes 1-4 (ΑΒΤS % = 68–76%) was significant but
lower than that of the reference compound trolox (ΑΒΤS % = 92%) with complexes 2 (ΑΒΤS% = 84
%) and 3 (ΑΒΤS % = 88 %) being the most active ABTS scavengers. Similar scavenging selectivity
has been reported in the literature for many transition metal complexes showing selective scavenging
activity against either DPPH radicals or ABTS radicals [30-32]. Furthermore, we may conclude that
the present complexes 1-4 may exhibit selective scavenging ability towards ABTS radicals in contrast
to DPPH radicals
In general, the complexes exhibit higher radical scavenging than the corresponding free ASA; we
may, thus, conclude that the coordination of the ASA to metal centers enhances their antioxidant ability.
Obtained results is quite high to be considered as potential antioxidants.
Conclusion
Thus, our approach in creating new coordination compounds in which, in addition to a ligand with
bioactive properties, there is a transition metal-microelement, made it possible to obtain new compounds
that modulate the available biological properties of ASA and exhibit new ones.
In general, the results of the study showed that reaction of metals ions (Co2+, Zn2+, Mn2+, and
Ni2+) with ASA changes the ability of the precursor molecule to affect peripheral microcirculation. It is
this property that is essential for compounds used for the prevention and treatment of cardiovascular
diseases. At the same time, complexes 1 and 2 lead to the development of vasodilation and hyperemia,
which in some parameters exceeds that with the introduction of ASA. Complexes 3 and 4, on the
contrary, cause a decrease in almost all microcirculatory parameters and inhibition of hyperemia caused
by ASA. The complexes were more active than the corresponding free ASA in regard to the ability to
scavenge in vitro DPPH, and especially ABTS radicals.
Thus, the new coordination compounds obtained are promising for further studies of their
biological and pharmacological effects. The results of these experiments allow further deeper

investigation of the therapeutic potential of complexes, creating new compounds for analysis.
Acknowledgment
The authors would like to acknowledge the financial support from the Russian Foundation for basic
research (project № 20-33-70142) The study was carried out on the experimental equipment of the center
for collective use of scientific equipment "Experimental physiology and Biophysics" of the Department
of human and animal physiology and Biophysics of the Taurida Academy of the V. I. Vernadsky
Crimean Federal University. The authors acknowledge TU Wien Bibliothek for financial support
through its Open Access Funding Programme
6. Supplementary data
CCDC 2085284-2085286 contains supplementary crystallographic data for compounds 1, 2 and
3. These data can be obtained, free of charge, via http://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 e-mail: deposit@ccdc.cam.ac.uk.

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Figure 1.

Figure 2.

Figure 3.

Figure 4.
______________________________________________________________
Captions
Figure 1. Molecular structure of cobalt(II) salicylate – complex 1.
Figure 2. Molecular structure of cobalt(II) salicylate – complex 2.
Figure 3. Molecular structure of manganese(II) salicylate – complex 4.
Figure 3. Crystal structure of 4. View along b-axis

Table 1. Crystal data and structure refinements for the reported compounds.
Parameter/Complex
1
2
3
C14H12O8Zn
C14H16CoO10
C32H42Mn3O2
Formula
5
Crystal system
monoclinic
C2
monoclinic
P 21/n
monoclinic
Space group
I 2/a
9.35230(10)
16.0918(2)
27.9243(4)
96.2110(10)
4177.81(9)
_4
а, Å
15.4415(7)
5.3633(3)
8.9178(4)
93.145(4)
737.43(6)
2
6.82280(10)
5.11540(10)
22.7707(5)
91.080(2)
794.59(3)
2
b, Å
c, Å
βo
V, Å 3
Z
Mo. mm–1
8.988
2.709
8.072
Parameters
107
117
287
Number of symmetry-
independent reflections/
Number of reflections with I
> 2(I)
1487/1474
1652/1568
3951/3771
GOOF
1.061
0.0283
0.0742
1.069
0.0451
0.1222
1.058
0.0376
0.1027
R(I > 2(I))
wR2

Table 2. The characteristics of the cardiorespiratory system in rats after injecting the

acetylsalicylic acid (ASA) and complexes 1 and 2 at different doses
Group
SBP,
mm
DBP
PP
HR
RR,
,
mm
,
in
r.r./mi
m.c.
mm
m.c.
b./m
n
m.c.
74.3
2±1.49
76.5
3±1.05
C
(1)
5
118.4
1±1.66
114.2
0±1.86
44.1
1±1.56
37.7
1±2.33
468.19
363.25
98.14
±4.34
98.42
±3.27
ontrol
±9.22
A
mg/kg (2)
±10.72
SA
p1≤0
.05
10
117.7
1±1.89
79.2
1±1.03
38.5
5±1.85
366.15
±10.73
100.1
5±3.23
mg/kg (3)
p1≤0
389.40
p1≤0
.05
±6.14
.05
1
5
114.7
3±0.72
78.4
0±1.60
36.1
3±3.53
99.53
±2.43
mg/kg (4)
10
112.4
7±0.32
p1≤0.
05
p3≤0.
05
114.7
3±4.01
85.2
7±0.38
p1≤0
.05
27.1
2±1.05
p1≤0
.05
p3≤0
.05
42.6
6±1.14
402.27
p1≤0
153.8
7±0.46
p1≤0.
05
p3≤0.
05
97.53
±5.15
mg/kg (5)
±0.34
.05
5
72.0
7±1.02
403.00
p1≤0
2
mg/kg (6)
±7.92
.05
10
111.6
7±0.61
68.1
3±0.26
p3≤0
.05
43.5
4±1.31
436.87
p1≤0
95.73
±1.46
mg/kg (7)
±2.75
.05
p3≤0

.05
Note: М – mean, М±m –error of mean, р1-7 – the confidence level of indices difference according
to Mann-Whitney test concerning the corresponding animal groups; SBP – a systolic blood pressure;

DBP – a diastolic blood pressure; HR – heart rate; RR – a respiratory rate.

Table 3. The characteristics of the cardiorespiratory system in rats after injecting the

acetylsalicylic acid (ASA) and complexes 3 and 4 at different doses
Group
SBP.
mm
DBP.
mm
PP
HR.
RR.
mm
b./min
r.r./min
m.c.
m.c.
m.c.
C
A
(1)
5
113.14
72.20
70.17
70.07
75.73
41.12
43.09
41.93
38.87
378.24±
109.67
109.19
106.8±
126.07
ontrol
SA
±1.32 ±0.91
114.06
±0.98
±0.99
±0.90
±1.41
15.23
±4.38
±3.59
4.38
334.08±
16.72 p1≤0.05
347.63±
mg/kg (2)
10
±1.18 ±1.07
112.11
mg/kg (3)
5
±1.18 ±0.94
114.60
6.31 p1≤0.05
396.13±
3
mg/kg (4)
±1.94 ±1.25
11.85 p1≤0.05 ±8.26 p1≤0.05
р1≤0.05
p2≤0.05
p2≤0.05
p2≤0.05
p5≤0.05
p6≤0.05
10
112.40
75.07
37.33
406.73±
94.53±
mg/kg (5)
±2.08 ±0.79
±1.23
9.86 p1≤0.05
p3≤0.05
1.79 p1≤0.05
p3≤0.05
p3≤0.
05
p7≤0.05
p4≤0.05
p7≤0.05
5
113.73
73.53
40.12
35.53
412.87±
16.56
93.13±
4
mg/kg (6)
±1.95 ±1.07
±0.98
±1.11
2.71 p1≤0.05
p2≤0.05
p7≤0.05 p4≤0.05
p7≤0.05
81.01±
10
111.20
75.67
333.13±
12.89
mg/kg (7)
±2.09 ±1.08
2.16 p1≤0.05
p3≤0.
p5≤0.05 p3≤0.05
05
p6≤0.05
p5≤0.05
p6≤0.05
Notes: the same as in table 2.

Table 4. Indicators of the skin microcirculation in rats under the action of acetylsalicylic acid

(ASA) and complexes 1 and 2 in different doses
Oscillatory indices
Non-oscillatory indices
Group
Ae
ar
An
arb.
unit
A
A
ar
A
BP
M
K
m
p
r
per SD
v. %
b. unit
ar
ar f. unit
p
b. unit
b. unit b. unit
erf.
unit
C
(1)
3.
2±0.3
3.5
±0.4
3.
1±0.3
2.
4±0.2
3.
1±0.4
4.0
±0.7
3
54
ontrol
.6±0.2 .4±0.9
5
4.
8±0.5
p1
≤0.05
p4
≤0.05
p6
≤0.05
5.4
±0.6
p1≤
0.05
3.
9±0.6
4.
1±0.7
4.
4±0.9
7.2
±0.8
p1≤
0.05
p6≤
0.05
3
56
A mg/kg (2)
.1±0.5 .7±0.5
SA
p1≤0.05
10
5.
0±0.6
5.5
±0.5
p1≤
0.05
4.
2±0.6
4.
2±0.6
p1
≤0.05
4.
6±0.8
7.3
±0.5
p1≤
0.05
3
57
mg/kg (3)
.1±0.5 .1±0.7
p1
p1
≤0.05
≤0.05
p5
≤0.05
5
6.
5±0.5
p1
≤0.05
p2
≤0.05
6.5
±0.6
p1≤
0.05
5.
2±0.9
p1
≤0.05
4.
9±0.2
p1
≤0.05
6.
1±0.8
p1
≤0.05
7.1
±0.5
p1≤
0.05
4
61
1
mg/kg (4)
.5±0.5 .9±0.9
р
p1
4≤0.05 ≤0.05
p2
≤0.05
р4
≤0.05
10
5.
6.0
4.
4.
5.
7.5
3
64

mg/kg (5)
3±0.1
p1
≤0.05
р5
≤0.05
р6
≤0.05
±0.6
p1≤
0.05
7±0.5
p1
≤0.05
3±0.3
p1
≤0.05
2±0.8
p1
≤0.05
±0.4
p1≤
0.05
.8±0.1 .5±0.8
р
p1
5≤0.05 ≤0.05
p3
≤0.05
р5
≤0.05
5
5.
7±0.9
p1 p1≤0.05
≤0.05
p2
≤0.05
5.8
5.
5.3
p1
5.
7±0.7
p1
≤0.05
6.2
±0.6
p1≤
0.05
1
28
.9±0.3 .5±0.6
p1
≤0.05
p2
≤0.05
2
mg/kg (6)
±0.9
3±0.95 ±0.8
p1
p
≤0.05 ≤0.05
1≤0.05
10
6.
9±0.8
6.5
±0.5
p1≤
0.05
6.
5.
5.
2±0.8
p1
≤0.05
6.8
±0.5
p1≤
0.05
1
32
mg/kg (7)
0±0.4
p1
≤0.05
p3
≤0.05
0 ±0.5
.6±0.1 .8±0.9
p1
p1
p
p1
≤0.05
≤0.05
1≤0.05 ≤0.05
p3
p
p3
≤0.05
3≤0.05 ≤0.05
Note: M –mean, M ± m –error of the mean, p1-7 – the level of significance of differences according
to the Mann-Whitney criterion relative to those in the groups indicated 1 to 7, respectively; Ae – the
amplitudes of endothelial genesis, An – the amplitude of neurogenic oscillations, Am – the amplitude
of myogenic oscillations, Ar – the amplitude of respiratory oscillations, and Ap – the amplitudes of
pulse oscillations. BP – an blood of pressure, MSD – mean square deviation (flux, MSD, perf. Units),