Mononuclear coordination compounds containing a pyrazole-based ligand: Syntheses, magnetism and acetylcholinesterase inhibition assays

Journal Pre-proof Mononuclear coordination compounds containing a pyrazole-based ligand: Syntheses, magnetism and acetylcholinesterase inhibition assays Isac M. Dias, Henrique C.S. Junior, Sabrina C. Costa, Cristiane M. Cardoso, Antonio G.B. Cruz, Claudio E.R. Santos, Dalber R.S. Candela, Stéphane Soriano, Marcelo M. Marques, Glaucio B. Ferreira, Guilherme P. Guedes PII:

S0022-2860(19)31673-4

DOI:

https://doi.org/10.1016/j.molstruc.2019.127564

Reference:

MOLSTR 127564

To appear in:

Journal of Molecular Structure

Received Date: 2 August 2019 Revised Date:

1 December 2019

Accepted Date: 9 December 2019

Please cite this article as: I.M. Dias, H.C.S. Junior, S.C. Costa, C.M. Cardoso, A.G.B. Cruz, C.E.R. Santos, D.R.S. Candela, Sté. Soriano, M.M. Marques, G.B. Ferreira, G.P. Guedes, Mononuclear coordination compounds containing a pyrazole-based ligand: Syntheses, magnetism and acetylcholinesterase inhibition assays, Journal of Molecular Structure (2020), doi: https:// doi.org/10.1016/j.molstruc.2019.127564. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Mononuclear coordination compounds containing a pyrazole-based ligand: syntheses, magnetism and acetylcholinesterase inhibition assays

Isac M. Dias, Henrique C. S. Junior, Sabrina C. Costa, Cristiane M. Cardoso, Antonio G. B. Cruz, Claudio E. R. Santos, Dalber R. S. Candela, Stéphane Soriano, Marcelo M. Marques, Glaucio B. Ferreira and Guilherme P. Guedes

Graphical Abstract Three coordination compounds with formula cis-[M(L)2(OH2)4] (M=FeII, CoII or NiII and L is 5-amino-1(benzo[d]thiazol-2-yl)-1H-pyrazole-4-carboxylate

ligand

were

synthesized

and

characterized

by

spectroscopic techniques and X-ray diffraction. Magnetic measurements for iron and cobalt complexes revealed the key role played by the zero-field splitting and the experimental fit data were correlated and supported by CASSCF calculations. All compounds were investigated towards the acetylcholinesterase activity, affording inhibition rates ranging from 20% to 56% at nanomolar concentration.

Mononuclear coordination compounds containing a pyrazole-based ligand: syntheses, magnetism and acetylcholinesterase inhibition assays Isac M. Dias1,φ, Henrique C. S. Junior2, φ, Sabrina C. Costa1, Cristiane M. Cardoso1, Antonio G. B. Cruz1, Claudio E. R. Santos1, Dalber R. S. Candela3, Stéphane Soriano3, Marcelo M. Marques4, Glaucio B. Ferreira2 and Guilherme P. Guedes2,*

1

Universidade Federal Rural do Rio de Janeiro, Instituto de Química, Seropédica, Rio de Janeiro,

Brazil. 2

Universidade Federal Fluminense, Instituto de Química, Niterói, Rio de Janeiro, Brazil.

3

Universidade Federal Fluminense, Instituto de Física, Niterói, Rio de Janeiro, Brazil.

4

Colégio Universitário Geraldo Reis, Universidade Federal Fluminense, Niterói, Rio de Janeiro,

Brazil φ

The authors contributed equally for this work.

*Corresponding author Prof. Dr. Guilherme P. Guedes Universidade Federal Fluminense, Instituto de Química, Departamento de Química Inorgânica Outeiro de São João Batista, s/n – Niterói – Rio de Janeiro – Brazil. CEP: 24.020-141 +55 21 2629-2170 [email protected]

Dedicated to the memory of Cassiano P. Silva.

1

Abstract: A series of three pseudo-octahedral coordination compounds with general formula cis[M(L)2(OH2)4], where M stands for FeII (1), CoII (2) or NiII (3), and HL is 5-amino-1(benzo[d]thiazol-2-yl)-1H-pyrazole-4-carboxylic acid proligand was synthesized by slow diffusion methodology and thoroughly characterized by spectroscopic techniques, magnetic measurements and ab initio calculations. Single crystal X-ray diffraction data obtained for 1 and 2 revealed that the crystal packing is stabilized by a hydrogen bond network while X-ray powder pattern, Raman and IR spectra indicated that compounds 1 and 3 are isomorphic. Mössbauer spectra recorded at 3 and 300 K for 1 showed that the FeII ion is in its high spin state. Magnetic studies carried out for complexes 1-2 showed the key role played by the zero-field splitting and the experimental fit data were correlated and supported by CASSCF calculations. The activity of acetylcholinesterase enzyme was investigated towards L and 1-3 by using Elman’s methodology, affording inhibition rates of 20%, 56%, 35% and 36%, respectively at nanomolar concentrations.

Keywords: pyrazole-based ligand, mononuclear compound, anticholinesterase activity assay, CASSCF calculations, magnetic properties.

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1) Introduction Aromatic heterocycles have been largely studied in the field of medicinal chemistry, building blocks for coordination compounds or in polymer sciences[1]. Among these heterocycles, the pyrazole and its derivatives represent a key class recognized due to several pharmacological activities, such as anti-inflammatory[2], analgesic[3], anticancer[4] and antimicrobial[5] occupying a unique place in the medicinal chemistry field. From the synthetic point of view, a large number of derivatives could be obtained by several routes affording a large number of molecules screened towards target biological activities, as reported elsewhere[6]. For instance, the tacrine drug functionalized with a pyrazolyl motif showed an acetylcholinesterase enzyme (AchE) inhibition rate at the nanomolar concentration[7]. The AchE inhibition is the main strategy, although only in a palliative way, to delay the symptoms of Alzheimer's disease, which is a neurodegenerative illness that irreversibly compromises the central nervous system[8]. In this sense, the use of a pyrazolebased system is very appealing as new drugs for AchE inhibition[9]. Although a large attention has been devoted to the biological activities of the pyrazole-based molecules, they are also very interesting as building blocks in coordination chemistry, affording systems with different topologies and nuclearities[10,11]. The versatility of these molecules as ligand is related to both nitrogen atoms – namely pyridinic and pyrazolic ones, in such a way that up to 23 coordination modes of the pyrazole are known[11] depending on the synthetic conditions, such as pH and stoichiometric ratio. Besides, the flexibility as ligand increases when this heterocycle is functionalized with other coordinating groups, such as amine[12], carboxylate[13] or hydroxyl[14]. The chemistry of pyrazole-based complexes of the first-row transition metals is well documented, highlighting its application in coordination compounds showing spin-crossover phenomena in the molecular magnetism field[15,16] or also in medicinal chemistry[17] as potential antimicrobial systems[18]. From the best of our knowledge, despite of several studies on pyrazole derivatives towards the AchE inhibition, reports on substituted pyrazole-containing complexes with this property are very rare[19]. In this way, our work is focused on the synthesis, crystal structures, 3

spectroscopy, magnetic properties and anticholinesterase activity of three coordination compounds with general formula cis-[M(L)2(OH2)4], where M stands for FeII (1), CoII (2) or NiII (3), while HL is 5-amino-1-(benzo[d]thiazol-2-yl)-1H-pyrazole-4-carboxylic acid proligand.

2) Experimental section 2.1) General All the solvents and reagents were purchased from commercial sources and used without further purification. 1H and

13

C nuclear magnetic resonance (NMR) spectra were recorded on a

BRUKER-AC 400 MHz or BRUKER-AC 500 MHz, with deuterated dimethylsulfoxide (dmso-d6) as the solvent. Tetramethylsilane was used as internal reference for 1H-NMR spectra (tms, δ = 0.00 ppm). The spectra were plotted and analyzed with the software Mestre Nova[20]. Gas Chromatography/Mass Spectrometry (GC-MS) measurements were performed on a SHIMADZU model QP-2010 Plus by injection in a gas chromatograph coupled with a mass spectrometer (CG / MS) using a silica column of HP-5 (30 x 0.25 x 0.25). Spectroscopic grade methanol, ethanol, acetone and chloroform were used as eluents with the injection flow rate of 1 mL/min at 250 ºC in the split mode. 2.2) Syntheses 2.2.1) Ethyl 5-amino-1-(benzo[d]thiazol-2-yl)-1H-pyrazole-4-carboxylate (C) In a round bottom flask, 0.500 g (3 mmol) of 2-hydrazinobenzothiazole (A) was dissolved in 20.0 mL of absolute ethanol. Then, 0.460 g (3 mmol) of ethyl(ethoxymethylene)cyanoacetate (B) was added under constant stirring (Scheme 1, i). The solution was heated in reflux for two hours. After the end of the reaction, which was confirmed by CCD chromatography, the solution was allowed to cool down to 10°C for 24 hours. A beige crystalline solid was isolated by filtration and washed with cold ethanol. Yield: 85%; melting point: 167°C; molecular ion: 288 m/z. IR spectra (ATR; ν in cm1) 3449 (νN-H); 3334 (νN-H); 3080 (νH-Csp2); 2976 (νH-Csp3); 2910 (νH-Csp3); 4

1678 (νC=O); 1600-1450 (νC=C); 1550 (νC-N) (Figure S 1). 1H-NMR (400 MHz, dmso-d6): δ 8.10 (d, J = 8.0 Hz, CH); 7.94 (d, J = 7.0 Hz, 1H, CH); 7.90 (s, 1H, NH2); 7.66 (s, 2H); 7.54 (dt, J1= 7.40 Hz, J2=1.17 Hz, 1H, CH); 7.43 (dt, J1= 6.96 Hz, J2=1.17 Hz, 1H, CH ); 4.26 (q, J = 7.10 Hz, 2H, CH2); 1.31 (t, J = 7.10 Hz, 3H, CH3) (Figure S 2).

13

C-NMR (100 MHz, dmso-d6): δ 163

(C=O); 62 (C=N); 151 (C-N); 150.7 (C=C); 144 (C-H); 132, (C-S); 127 (C-H); 125 (C-H); 123 (CH); 122 (C-H); 95 (C=C); 60 (C-H2); 15 (C-H3) (Figure S 3).

2.2.2) 5-amino-1-(benzo[d]thiazol-2-yl)-1H-pyrazole-4-carboxylic acid (D) The procedure was carried out according to the methodology adapted from reported[21]. In a round bottom flask, 0.864 g (3 mmol) of ethyl 5-amino-1-(benzo[d]thiazol-2-yl)-1H-pyrazole-4carboxylate was suspended in 25 mL of ethanol (Scheme 1, ii). Then, 1.20 mL of a solution KOH (4.20 mmol, 20% m/v) was added dropwise to the mixture. The final solution was heated to reflux for 48 hours. A white-gray solid was collected by filtration and washed with cold ethanol. Then, the solid was solubilized in 50 mL of distilled water at room temperature and an aqueous HCl 3.00 mol L-1 solution was added dropwise until pH = 3. The acid addition leads to the formation of a pale pink solid, which was collected by filtration and washed with a small amount of water (~30 mL). Yield: 67%; melting point: 250°C; molecular ion: 216 m/z. IR spectra (ATR; ν in cm1) : 3453 (νNH); 3309 (νN-H); 3059 (νH-Csp2); 1651 (νC=O); 1595-1433 (νC=C/C=N); 1543 (νC-N); broad band 3088-2555 (νO-H) ) (Figure S 4). 1H-NMR (400 MHz, dmso-d6): δ 12.31 (s, 1H, OH); 8.08 (d, J = 7.0 Hz, 1H, CH); 7.94 (d, J = 6.9 Hz, 1H, CH); 7.87 (s, 1H, CH); 7.56 (m, 3H, NH2 and CH); 7.43 (m, 1H, CH) (Figure S 5). 13C-NMR13C (100 MHz, dmso-d6): δ 164.77 (C=O); 161.63 (C=N); 151.16 (C-N); 150.75 (C=C); 144.46 (C-H); 131.63 (C-C); 127.30 (C-H); 125.42 (C-H); 122.70 (C-H); 122.23 (C-H); 95.81 (C=C) (Figure S 6).

5

2.2.3) Potassium 5-amino-1-(benzo[d]thiazol-2-yl)-1H-pyrazole-4-carboxylate (L) 0.168 g (3 mmol) of KOH was added to a suspension of 1.15 g (3 mmol) of 5-amino-1(benzo[d]thiazol-2-yl)-1H-pyrazole-4-carboxylic acid in 50 mL of distilled water (Scheme 1, iii). The disappearance of the suspended solid upon addition of the base, indicates the formation of its soluble potassium salt. The solution was concentrated to ~10 mL and 50 mL of acetonitrile was added to the solution in order to precipitate the product. The white-yellowish solid was collected by filtration and washed with cold acetonitrile. For L: Yield (85%), melting point (280°C). IR spectra (ATR; ν in cm-1: 3453 (νN-H); 3309 (νN-H); 3059 (νH-Csp2); 1651(νC=O); 1595-1433 (νC=C/C=N); 1543 (νC-N); (Figure S 7). 2.2.4) General procedure for cis-[M(L)2(OH2)4] (M= FeII (1), CoII (2) and NiII (3)) MCl2.nH2O (0.075 mmol) [15 mg of FeCl2.4H2O (1), 9 mg of CoCl2 (2) or 18 mg of NiCl2.4H2O (3)] was dissolved in 5 mL of distilled water and the solution was added to a 20 mL test tube. A mixture of ethanol/water (1:1, 5.0 mL) was slowly added to the metal ion solution, leading a second layer. Then, 44 mg (0.15 mmol) of L previously dissolved in 5.0 mL in mixture ethanol:water (2:1) was slowly added, affording a third layer (Scheme 1, iv) . After about six days, yellow (1), pink (2) or light green (3) single crystals were obtained. They were isolated by filtration and washed with cold ethanol. For 1: yield: 30%; decomposition above 300°C. Anal. Calc. C22H22FeN8O8S2.H2O: C, 39.77; H, 3.64; N, 16.86%. Found: C, 40.25; H, 3.38; N, 16.90%. For 2: yield: 56%; decomposition above 300°C. Anal. Calc. C22H22CoN8O8S2 C, 40.68; H, 3.41; N, 17.25%. Found: C, 40.34; H, 3.38; N, 16.98%. For 3: yield: 70%; decomposition above 300°C. Anal. Calc. C22H22NiN8O8S2 .2H2O C, 38.55; H, 3.82; N, 16.35%. Found: C, 38.64; H, 3.57; N,16.13%. Although the crystal structures obtained by single crystal X-ray diffraction pointed out for two lattice water molecules, our microanalysis results of the bulky material indicated just one water molecule for the iron(II)-based complex, while the cobalt one are solvent free.

6

2.3) Spectroscopic techniques Attenuated total reflectance FT-IR spectra were recorded at room temperature in a Varian 660 (Varian, Inc; USA) and Nicolet iS50 (Thermo Scientific, USA) spectrometers in the range 4000-200 cm-1 (mid and far-infrared regions) with 64 scans and spectral resolution of 4 cm-1. FT-Raman spectra were collected with a Bruker Multi Ram spectrometer at room temperature with a germanium detector and Nd-YAG laser line (1064 nm) as the excitation source in the region of 4000-100 cm−1. Samples were measured in the hemispheric bore of an aluminum sample holder. Raman spectra were acquired with a laser power of 50 mW from 400 scans and spectral resolution of 4 cm−1. The 57Fe Mössbauer spectroscopy experiments were performed at room temperature and 3 K in transmission geometry with the Co-57 in Rh-matrix source moving in a sinusoidal mode. In order to perform the low temperature measurements, the sample was installed in a Janis variable temperature close cycle cryostat and the source was kept at room temperature. All the isomer shift (δ) values are given in relation to metallic iron.

2.4) Single crystal and powder X-ray diffraction Single crystal X-ray diffraction data were collected on a Bruker D8-Venture diffractometer using MoKα radiation (λ = 0.7107 Å) at room temperature for 1 and at 150 K for 2. Data collection and cell refinement were performed using the Bruker Instrument Service v4.2.2 and APEX2, respectively[22]. Data reduction was performed using the SAINT software[22]. The absorption corrections were made using equivalent reflections with SADABS program[23]. The structure solutions and full-matrix least-squares refinements based on F2 were carried out with SHELXS-97 and SHELXL-2014[24]. All atoms, except hydrogen, were refined anisotropically. Hydrogen atoms were treated by a mixture of independent and constrained refinement. The structures drawings were made by MERCURY[25]. A summary of crystal, data collection and refinement for compounds 1

7

and 2 are gathered in Table 1. Geometric parameters associated with hydrogen bonds are summarized in Table S 1. Powder X-ray patterns were obtained with a Bruker D8 Advance diffractometer using CuKα radiation (λ = 1.545 Å) for 1 and 3, and using CoKα radiation (λ = 1.789 Å) for 2. Samples of 1-3 were scanned from 2θ = 3° to 40°, with a step size of 0.02° and counting time of 0.5 s/step. The indexing of the maximum of intensity for compound 3 was carried out with DICVOL91, implemented in the EXPO software package[26], using 22 reflections observed in the 2θ = 3 - 30º range. The powder X-ray patterns (Figure S 12) and discussion can be seen in the ESI. Table 1 - Summary of crystal, data collection and refinement for compounds 1 and 2. 1 2 Chemical formula C22H26FeN8O10S2 C22H26CoN8O10S2 Crystal system Monoclinic Monoclinic Molar mass (g.mol-1) 682.48 685.56 space group P21/n P21/n Temperature (K) 293 150 ρ(mg.m-3) 1.64 1.69 a (Å) 6.4866 (2) 6.4310 (5) b (Å) 54.451 (2) 54.238 (5) c (Å) 7.9255 (3) 7.7941 (7) β(°) 99.454 (1) 98.548 (4) V (Å3) 2761.28 (17) 2688.4 (4) Z 4 4 Radiation type MoKα MoKα µ (mm−1) 0.77 0.87 Crystal size (mm) 0.38 × 0.15 × 0.09 0.56 × 0.42 × 0.14 F(000) 1408 1412 Measured reflections 20236 70296 Reflections with [I > 2σ(I)] 5115 4743 R[F2 > 2σ(F2)] 0.043 0.039 2 wR(F ) 0.093 0.085 Independent reflections 5651 5112 Rint 0.025 0.054 ∆ρmax; ∆ρmin (Å-3) 0.39; -0.30 55; -0.36 Index ranges h= -8→8 h= -7→7 k= -59→68 k= -66→66 I= -9→9 I= -9→9 CCDC number 1910281 1910282

2.5) Magnetic measurements Magnetic measurements were performed on a Quantum Design MPMS3 SQUID magnetometer (for 1) or using the VSM option of a Quantum Design PPMS (for 2), in the 8

temperature range 3-300 K and under a 0.1 T DC field. The compounds were wrapped in polytetrafluoroethylene tape and pressed into a pellet. Data were corrected from the diamagnetic contribution of the sample and holder. The magnetic fit data were performed using Magprop, available under DAVE platform[27]. 2.6) Computational details Theoretical studies of 1 and 2 were performed using the ORCA Package[28] and the molecular structures obtained by single crystal X-Ray diffraction with all hydrogen atoms optimized by Density Functional Theory on the PBE0/Def2-TZVP level[29,30]. Electronic and magnetic features were evaluated using the State-Averaged Complete Active Self-Consistent Field (SA-CASSCF)[31] with Def2-TZVP basis set and the N-Electron Valence State Perturbation Theory (NEVPT2)[32] as perturbational treatment. The SA-CASSCF calculation for 1 was performed on 5 quintets, 45 triplets and 50 singlet states with an active space containing the two bonding orbitals from the ligand, the five 3d orbitals from the metal ion and a second d shell (Figure S 8), counting 10 electrons and 12 orbitals, (CAS(10, 12)). The SA-CASSCF calculation for compound 2 was performed on 10 quartets and 40 doublet states with an active space containing the two ligand’s bonding orbitals, five 3d orbitals from the metal center and a second d shell (Figure S 9), totalizing 11 electrons and 12 orbitals, (CAS(11, 12)). Since the crystal structure for 3 was not obtained, ab initio calculations for this compound are discussed in the ESI. Spin-orbit coupling (SOC) contributions to the Zero-Field Splitting (ZFS) were calculated using the CASSCF+NEVPT2 wavefunctions applying the quasi-degenerate perturbation theory (QDPT)[33]. Axial and rhombic ZFS parameters D and E were obtained by means of two methods: (i) the second-order perturbation theory (2PT), which is accurate for weak spin-orbit coupling or energetically well-separated non-degenerate ground state, and (ii) the more general Effective Hamiltonian Theory[34]. The reference axis that diagonalizes the ZFS parameters was chosen to fulfill the condition that 0 ≤  ⁄ ≤ 1⁄3[35]. Crystal field (CF) parameters were obtained with

9

the application of the Ab Initio Ligand-Field Theory (AILFT) implemented by Neese et al. [36] in the ORCA package. 2.7) Acetylcholinesterase inhibitory activity assay Acetylcholinesterase enriched fraction was prepared from euthanized mouse brain homogenized in five volumes of distilled water (10 strokes in a Potter-Elvehjem type instrument). The homogenate was centrifuged at 20000 G for 60 min at 4ºC. The supernatant was discarded and the decanted was suspended in 2 volumes of 1% Triton X-100. The suspension was stirred for 30 minutes at room temperature and centrifuged at 10000 G for 90 min at 4°C. Then the decanted was discarded and the supernatant was used as the acetylcholinesterase fraction. After addition of 0.02% of sodium azide to the preparation containing the enzyme, it was then kept stable under refrigeration[37]. The acetylcholinesterase activity of the compounds was determined using a modified Ellman's method in ELISA microplate reader. The coordination compounds 1-3 were solubilized in a water/dimethylsulfoxide solution (9:1 in 1 mL) and then diluted using phosphate buffer to achieve assay concentrations. The assay mixture comprised of 63 µL phosphate buffer (0.10 mol L-1, pH 7.5), 100 µL of 5,5’-dithio-bis-2-nitrobenzoate (dtnb) 0.70 mol L-1, 25 µL of enzyme (0.2 U/mL) and 22 µL of inhibitor (final concentration: 10 µmol L-1) was incubated for 10 minutes at room temperature. Ultimately, 10 µL of the substrate (acetylthiocholine iodide, 0.33 mM) was added and the change of absorbance at 412 nm was measured for 1 min. All experiments were performed on a Thermo Scientific Multiskan Go in triplicate[38].

3) Results and Discussions 3.1) Syntheses The substituted pyrazole C was obtained by condensation of ethyl 2-cyano-3-ethoxyacrylate B and 2-hydrazinobenzothiazole A in good yield (85%). The hydrolysis of the ester group C afforded the corresponding carboxylic acid D in moderate yield (67%). The addition of a 20 % m/m 10

KOH solution to a suspension of compound D at 25 ◦C, afforded the compound L (85% yield). The aimed coordination compounds were obtained as single-crystals from the mother liquor (1 and 2) or as polycrystalline powder (3) by slow diffusion methodology. For compound 1, the single-crystals were transferred to a becker, washed several times with plentiful amount of ethanol in order to remove a brown colloidal-like precipitate. The characterization of the brown precipitate is out of the scope of this work; however the Mössbauer spectroscopy indicated beta-FeOOH (Akaganeite) nanoparticles (see below).

Scheme 1 - i. Ethanol, reflux, 2 h; ii. a) 20% aq. KOH solution, ethanol, reflux, 48 h, b) H2O, 3 mol L-1 HCl aq.; iii. a) 20 % aq. KOH, 2h; b) CH3CN.; iv. MCl2.nH2O M = FeII (1), CoII (2) and NiII (3) ethanol:water, 6 days.

3.2) Spectroscopic characterization The ligand and related coordination compounds were characterized by FT-IR spectroscopy in the mid-infrared region, as shown in Figure 1. The FT-IR spectra for the coordination compounds show a broad band between 3445-2500 cm-1 which may be assigned to the O-H bonds vibrations. These vibrations arise from coordinated or crystal lattice water molecules involved in intra- or intermolecular hydrogen bonds[39]. The amine symmetric and asymmetric N-H stretching appear in the range 3400-3200 cm-1 for L, while for 1-3 these absorptions are seen in the range 3346-3327 11

cm-1, indicating a change in the chemical environment of this group after the coordination of L to the metal ions (see Figure 1 and Table 2).

Figure 1 – Mid-FTIR spectra for the L and compounds 1-3.

The bands in the range 3050-3060 cm-1 and 1600-1420 cm-1 were assigned to the aromatic C-H stretching and to the vibration of the aromatic moieties, respectively. The carboxylate asymmetric axial deformation is seen at 1610 cm-1 for 1 and at 1609 cm-1 for 2 and 3, while the symmetric one appeared as a shoulder at approximately 1409 cm-1 for all complexes. The coordination mode can be inferred from the energy difference (∆) between the carboxylate asymmetric and symmetric vibrational modes[40]. The calculated ∆ values are 202 cm-1 for 1, and 200 cm-1 for 2 and 3, suggesting the carboxylate is monocoordinated to the metal ions[41]. Furthermore, the similarity among the mid-infrared spectra of 1-3 indicates that all the metal ions share the same coordination environment.

12

Table 2 - Selected absorptions (cm-1) and tentative assignments in the infrared region for L and 1-3 Assignments L 1 2 3 νO-H 3445-2500 3445-2500 3445-2500 νN-H 3400-3200 3346-3327 3346-3327 3346-3327 νC-H 3045 3056 3060 3056 νC=C/C=N 1620-1400 1600-1420 1587-1420 1598-1420 νCOO as 1614 1610 1609 1609 νCOO-s 1427 1408 1409 1409

FT-IR spectra in the far-infrared region for all complexes and ligand are shown in the ESI (Figure S 11). For the 1-3, the bands nearly to 430 cm-1 were assigned to the M-O bonds vibrations[42–45]. The Raman spectra of L and compounds 1-3 are depicted in Figure 2. The spectral patterns for 1-3 are analogous, suggesting the same coordination environment, as also verified by FT-IR spectroscopy. The similarity of the spectrum recorded for L with those for 1-3 confirms the presence of the pyrazole-based ligand in the coordination sphere of the metal ions. The vibrational mode related to the aromatic hydrogen atoms (C-Hsp2) is observed at 3055 cm-1 in 1 and at 3058 cm1

for 2 and 3, while the carboxylate asymmetric and symmetrical vibrational modes were verified in

νas/νs (1610/1420

cm-1) for 1, νas/νs (1606/1422 cm-1) for 2, and νas/νs (1613/1418 cm-1) for 3. The

pyrazole ring has a wide range of vibrational modes depending on the substitution. The aromatic ring vibrations νC=C and νC=N were observed in the region of 1570-1400 cm-1 for all spectra[46,47].

13

Figure 2 – Raman spectra for L and compounds 1-3

In order to correctly assign the oxidation and spin states for the iron-containing complex 1, Mössbauer spectroscopy experiments were performed at room temperature and at 3K. The respective Mössbauer spectra are shown in Figure 3. The spectrum at room temperature is properly fitted with 3 paramagnetic doublets whose hyperfine parameters are shown in Table 3. Two of them, with absorption areas of 80.4% and 15.1%, are attributed to FeII ions in a high spin state. The hyperfine parameters of the weak doublet (absorption area of 4.5%) indicate the formation of a very small amount of akaganeite (β-FeOOH) nanoparticles during the sample preparation process [48]. Therefore, disregarding the small impurity, all the FeII of the compound (~96%) are in a high spin state. The spectrum at 3 K is fitted with only two doublets. The doublet with an absorption area of ~96% corresponds to the FeII in a high spin state and the small doublet to the impurity phase, already observed at room temperature. As can be observed in Table 3 the quadrupole splitting ∆

of the FeII at 3K is higher than the one observed at room temperature. The increase of this hyperfine 14

parameter is expected and related to the effect of vibronic coupling. So, the low temperature Mössbauer experiments show no evidence of a spin transition for the FeII in agreement with the magnetization results (see below).

Figure 3 - Mössbauer spectra for 1 at 300 K and 3 K

Table 3 - Mössbauer hyperfine parameter of iron-containing complex 1 at room temperature and 3 K. The parameters are the temperature T, isomer shift δ, quadrupole splitting ∆E , linewidth Γ and the absorption area A (proportional to the Fe concentration) Temperature Sites IS(mm/s) A(%) ∆ (mm/s) Γ(mm/s) 300 K

3K

Fe(II) Fe(III)

1.24 1.45 0.41

2.59 2.13 0.76

0.32 0.30 0.40

80.4 15.1 4.5

Fe(II) Fe(III)

1.36 0.47

2.98 0.75

0.35 0.35

95.8 4.2

3.3) Crystal structures of 1 and 2 Suitable single crystals of 1 and 2 were obtained by slow diffusion from water/ethanol solutions. Both compounds crystallized in the monoclinic P21/n space group and their asymmetric units contain one neutral mononuclear cis-[Fe(L)2(OH2)4] (1) or cis-[Co(L)2(OH2)4] (2) complex 15

and two lattice water molecules. It was not possible to obtain single crystals for the cis[Ni(L)2(OH2)4] and an analysis concerning the powder X-ray pattern will be discussed in ESI (Figure S 12). Figure 4 shows the molecular unit for 1 and 2. Selected bond lengths and angles are gathered in Table 4.

Figure 4 - Molecular structure of the cis-[M(L)2(OH2)4] (M= FeII (1) or CoII (2)). Crystallization solvent molecules were omitted for sake of clarity. Color codes: red (oxygen), gray (carbon), purple (nitrogen), yellow (sulfur) and orange (iron or cobalt).

The metal ion is cis-coordinated to two carboxylic oxygen atoms from different L moieties and to four water molecules, displaying an elongated tetragonal distortion. This observation also supports our infrared spectra conclusions, which also pointed a monodentate coordination mode of L. Concerning compound 1, the charge balance in the mononuclear complex suggests that iron is in the 2+ oxidation state, as confirmed by Mössbauer spectroscopy. The M-Ocarboxylate (M-O1 and MO3) bond distances range from 2.100(3) to 2.084(2) Å in 1, while they are slightly shorter [2.094(2) to 2.071(2) Å] in 2 due to the decrease of the ionic radius of CoII ion compared to the FeII one. The same trend was also seen in the average M-OH2O bond distances, being 2.159(2) Å and 2.115(2) Å,

16

respectively for 1 and 2, and are in the typical range found for other high-spin iron(II) or cobalt(II)containing compounds[49–51].

Table 4 - Selected bond lengths (Å) and torsion angles (º) for 1 and 2. (i=-x, -y, -z) Atom Label

1

2

M-O1

2.100(3)

2.094(2)

M-O3

2.084(2)

2.071(2)

M-O5

2.196(2)

2.158(2)

M-O6

2.139(2)

2.098(2)

M-O7

2.148(3)

2.097(2)

M-O8

2.154 (2)

2.093(2)

N2-N3

1.394(3)

1.393(3)

N6-N7

1.393(3)

1.392(3)

C1-O1

1.275(3)

1.275(3)

C1-O2

1.260(3)

1.266(3)

C12-O3

1.266(3)

1.264(3)

C12-O4

1.270(3)

1.274(3)

M …M

6.487(5)

6.4310(7)

M …M i

6.741(2)

6.623(1)

C15-N6-C16-N8

2.60 (4)

3.50(4)

C4-N2-C5-N4

-0.25(3)

-0.20(4)

N3-N2-C5-S1

1.87(3)

2.55(3)

N7-N6-C16-S2

-0.12(5)

-0.01(3)

In the L moiety, the average C-O bond distances in the carboxylate group are 1.268(3) and 1.270(3) Å, indicating the electronic resonance in this group[52]. Within the pyrazole ring, the N-N bond distances show a single character, with values nearly 1.39 Å, while the carbon-carbon ones have average distances typical for a double bond (1.397(4) and 1.401(4) Å, respectively for 1 and 2, as reported elsewhere [53]. The C-N bond lengths are comprised between 1.311(4) and 1.383(3) Å, shorter than a typical C-N single bond (1.44 Å), but larger than a double one (1.27 Å), showing an electronic delocalization within the pyrazole nucleus[54]. The monodentate coordination mode of L in 1 and 2 instead of the bidentate one can be justified due to the establishment of intramolecular hydrogen bonds between the free carboxylate oxygen atoms and water molecules coordinated in the equatorial position of the metal ion. The pyrazolyl and the benzothiazole rings are almost coplanar. This geometrical feature can be 17

addressed by intramolecular hydrogen bonds between the amine and the benzothiazole nitrogen atoms (N1-H...N4 and N5-H...N8), as well as between amine group and coordinated water molecules (N5-H…O3). Furthermore, an intramolecular hydrogen bond between the amino groups from two L units coordinated is observed only for the cobalt-containing derivative. Geometry parameters associated to these interactions are listed in Table S1. The shortest M…M distances between two adjacent molecules are 6.487(5) Å and 6.4310(7) Å for 1 and 2, respectively. Finally, the crystal packing of both compounds was also stabilized by a series of intermolecular hydrogen bonds involving the [M(L)2(H2O)4] units and crystallization water molecules, as shown in Figure 5. However, a slightly difference was found between 1 and 2 due to the crystallization water molecules positions.

Figure 5 - Details of the crystal packing of compounds 1 (A) and 2 (B). Symmetry operation to generate equivalent atoms: i = -x, -y, -z.

18

3.4) Magnetic properties of (1) and (2) The thermal dependence of the χMT product under a static magnetic field of 1000 Oe for 1 is shown in Figure 6a. The room temperature value is 3.1 cm3 K mol-1, which is close to the calculated one for a non-interacting FeII ion in high-spin state (3.0 cm3 K mol-1, g=2.00) as pointed out by Mössbauer spectroscopy. Upon cooling, χMT value remains constant until 50 K, and then decreases continuously to 1.5 cm3 K mol-1 at 5 K. The decrease of χMT at low temperatures may come from antiferromagnetic interactions between the spin carriers and/or from zero-field splitting effects. Since the shortest distances between the iron(II) ions in the crystal packing are large (~8.5 Å), it is expected very weak exchange interactions. Therefore, only ZFS axial and rhombic terms were considered in the following Hamiltonian (eq.1) to fit the magnetic data[55,56].

=  '$   −   +  −  + !"# $. &

(eq. 1)

Figure 6 – Thermal dependences of χMT for compounds 1 (A) and 2 (B). Solid lines represent the best fits (vide text).

Furthermore, even if the results at high temperatures from Mössbauer show two different coordinations sites of FeII ion in a high spin state, in order to avoid any overparametrization the 19

Hamiltonian considers only one type of FeII ion (S=2). The best fit leads to values of g = 2.06 ± 0.02, D = 18.3 ± 1.2 cm-1 and E = 4.2 ± 0.7 cm-1 ( Figure 6a). The axial and rhombic ZFS parameters are in good agreement with the ones obtained by CASSCF calculations (see below), albeit a little higher. In particular, the rhombic character is quite important from the fitting of the susceptibility data. This difference may come from the simplicity of the Hamiltonian used with isotropic g values and only one kind of FeII site considered. EPR measurements should be interesting to get closer insight into the ZFS terms. For compound 2, the thermal dependence of the χMT product is depicted in Figure 6b. At 300 K, the χMT value is 2.86 cm3 K mol-1, within the usual range found for octahedral cobalt(II) ion[57]. Upon cooling χMT value remains constant in temperature range down to 150 K, and then decreases continuously to a minimum value of 1.87 cm3 K mol-1 at 2 K. The cobalt-containing compound displays a similar crystal structure compared with (1); therefore, it is also expected that the decrease of χMT is due to the zero-field splitting effects. The magnetic data of 2 was fitted using the Figgis Hamiltonian (eq. 2), in which ∆ax is the crystal-field splitting, gL is the orbital reduction factor and J12 takes into account both the orbital reduction factor and the spin-orbit coupling constant[58,59]. ( = Δ* [,- − ,, + 1/3] − 0 , '$. $ + "1 & '$. !2 , '$ + !$

(eq. 2)

The best fit leads to !2 = -1.44 ± 0.5 and 0 = - 168 ± 2 cm-1, considering fixed values for Δ* = + 463 cm-1 (obtained by ab initio calculations and discussed in detail below) and ! = 2.00 ( Figure 6b). The orbital reduction factor and the crystal-field splitting ∆ax values lie within the usual range observed for hexacoordinated cobalt(II) ion and J12 is consistent with the spin-orbit coupling constant observed in other complexes[57]. 3.5) Electronic structure

20

The SA-CASSCF calculation for 1 shows that the ground state of the molecule is a high spin quintet state whose wavefunction is dominated by two electronic configurations: 60.9% (dxz)2 (dyz)1(dxy)1(dz2)1(dx2-y2)1 and 31.6% (dxz)1(dyz)2(dxy)1(dz2)1(dx2-y2)1. NEVPT2 corrected transition energies show that the ground state and the first singlet (diamagnetic) state are separated by an energy gap of 16,476.8 cm-1 (2.04 eV). A comparison between pure CASSCF transition energies and the NEVPT2 corrected transition energies shows that the average correction is |0.47| eV, indicating that static electronic correlation is prominent in the molecule since the inclusion of dynamic correlation does not provide large improvements. For compound 2, SA-CASSCF calculation shows that the ground state of the molecule is a high spin quartet dominated by the combination of two electronic configurations: 62.8% (dyz)2(dxz)2(dxy)1(dz2)1(dx2-y2)1, 12.2% (dyz)2(dxz)1(dxy)2(dz2)1(dx2-y2)1. A comparison between pure CASSCF transition energies and the NEVPT2 corrected energies shows that the average correction is |0.2| eV, indicating that static electronic correlation is, also, prominent in the molecule since the inclusion of dynamic correlation does not provide large improvements. 3.6) Zero-Field Splitting ab initio calculations With the use of Ab Initio Ligand-Field Theory (AILFT) we could estimate the Spin-Orbit Coupling constant (ζ) for compound 1 as 412.4 cm-1 (0.051 eV), allowing the use of both SecondOrder Perturbation Theory (2PT) and Effective Hamiltonian Theory (EHT) to calculate the ZeroField Splitting parameters. This assumption shows to be correct due to the excellent agreement in the values obtained for the axial anisotropic component (D) by both theories: D(2PT) = 13.21 cm-1 with E/D = 0.09 and D(EHT) = 12.82 cm-1 with E/D = 0.06 indicative of a system dominated by axial anisotropy whose eigenvectors are depicted in the molecular frame in Figure 7a. The calculated gtensor components are gx = 2.00, gy = 2.21, gz = 2.24 and giso = 2.15, depicted in the molecular frame in Figure 7b.

21

AILFT calculation shows that Spin-Orbit Coupling Constant (ζ) is stronger in compound 2 (526.6 cm-1 or 0.065 eV) than in compound 1 and that the two lowest d-orbitals are in a quasidegenerate energy level (ESI Figure S10) breaking the theory used by the 2PT formalism to calculate Zero-Field Splitting properties[34]. The strong disagreement between D values obtained by 2PT and EHT confirms that the theories are unreliable for a correct description of the anisotropic components: D(2PT) = -245.45 cm-1 with E/D = 0.24 and D(EHT) = 123.74 cm-1 with E/D = 0.12. Therefore, due to the distortions experienced by the CoII ion in the ligand field, the magnetic properties in 2 are better described using the Figgis Hamiltonian (Eq. 2). For completeness, we depict the D tensor components obtained from the Effective Hamiltonian alongside the g-tensor components gx = 1.72, gy = 2.41, gz = 2.90 and giso = 2.34 in Figure 7c and Figure 7d, noting that these results should be considered with care.

(a)

(b)

(c)

(d)

Figure 7 - Depiction of D and g-tensor components obtained by Effective Hamiltonian in the molecular frames of compound 1 (a and b, respectively) and compound 2 (c and d respectively).

As shown elsewhere[60–62], the axial crystal-field splitting parameter |∆ax| used in the Figgis Hamiltonian can be obtained from a correlation of the d-orbitals and Kramer’s doublets 22

during an AILFT calculation. The obtained relative energies (in cm-1) of the d-orbitals in compound 2 are: 0.0, 383.8, 655.1, 7354.5 and 8371.7, consistent with an arrangement in the D4h symmetry. As shown in Figure 8, the splitting of the 4T1g cubic term due to symmetry lowering by the tetragonal distortion gives rise to the

4

 3 53 63 73 63

and

4

83 534 63 73 63

terms. Per

analysis of the electronic configuration we found that the ground state in compound 2 is represented by the orbital singlet 4A2g with ML = 0. |∆ax| can be obtained as the energy difference between the b2g orbital and the center of gravity generated by the rhombic crystal-field splitting (∆rh) of the eg orbitals. Following this procedure, we obtained |∆ax| = 463 cm-1 and, since the ground state of compound 2 is the orbital singlet 4A2g, the expected sign of |∆ax| is positive, characteristic of a positive anisotropy[62]. The lowest Kramer’s doublet is dominated by |±1/2> (see ESI, Table S 6), also indicative of a positive anisotropy and giving rise to g-factors gx(eff) = 2.71, gy(eff) = 3.86, gz(eff) = 6.37 and giso(eff) = 4.31 showing that, despite the z-axis being dominant, the system cannot be classified as having an easy magnetization axis due to the, also large, value of gy(eff).

23

Figure 8 - Splitting of the cubic term 4T1g (top left) into the symmetry reduced 4A2g (identified as the ground state) and 4Eg (top right) for compound 2. (bottom) Diagram representing the splitting of the 4T1g term under influence of Crystal Field Splitting parameters.

3.7) Acetylcholinesterase activity The in vitro biological assay for the acetylcholinesterase inhibition was performed using Ellman’s methodology. All the synthesized compounds were evaluated against their effects on the activity of acetylcholinesterase (AChE) at concentration of 10 µmol/L as well as positive control AChe inhibtors. Figure 9 showed the AChE residual activity for L, complexes 1-3 and some reference drugs (positive control) as tacrine (T), bis-tacrine(BT) and propoxur (P). The complexes 1-3 presented more attention-grabbing results than L, obtaining 56%, 35%, 36% and 20% of inhibition respectively. These results demonstrated that complex 1 stood out among the others assayed compounds. In addition, as can be observed in Figure 9, there is no significant difference between 2 and 3. However, the complexes 1-3 inhibited less enzymatic activity when compared to T, BT and P reference drugs (Figure 9). Although our results are not expressed in IC50, a moderate inhibition has been achieved at low concentrations for L. CuII and CoII complexes containing the 24

pyrazole condensed to 4,5,6,7-tetrahydro-1H-indazole as ligand showed inhibition of the AChE in the range of 55 to 82%; however, the assay concentrations were much higher than that used in the present work (between 1404 - 1618 µmol L-1)[19].

Figure 9 - Acetylcholinesterase residual activity assay for L, tacrine (T), bis-tacrine (BT), propoxur (P) and complexes 1-3 in 10 µmol L-1. **p ≤ 0.01 and ns = not statistically significant.

The FeII, CoII and NiII precursors (FeCl2, CoCl2 and NiCl2) were also evaluated by acetylcholinesterase activity assay, showing low inhibition rates (FeII (10%), CoII (5%) and NiII (17%). A comparison among inhibition rates of the precursor metal salts and 1-3 is displayed in Figure 10.

25

Figure 10 - Acetylcholinesterase residual activity for 1-3 as well as their respective precursor metal salts in 10 µmol L-1. **p ≤ 0.01; ***p ≤ 0.001 and ns = not statistically significant.

4) Conclusions A new series of mononuclear coordination compounds containing a pyrazole-based ligand was synthesized and characterized. The crystal structures of compounds (1) and (2) were elucidated by single crystal and the unit cell parameters of 3 were determined using powder X-ray diffraction. Although the crystal structure of the nickel-containing compound could not be obtained yet, from the powder X-ray pattern it could be deduced that 3 is isomorphic to 1. The characterization by FTIR and Raman spectroscopies revealed the net effect of the hydrogen bond network interactions to the vibrations of the functional groups, while the ultraviolet spectroscopy showed π-π* or n-π* transitions as well as electronic transitions in visible spectra centered in the metal ions. The magnetic behavior of compounds 1 and 2 were attributed to ZFS effects of the metal centers, since the exchange interactions between the metal ions are negligible due to the large metal…metal distances in the crystal packing, with compound 2 presenting a considerably large positive anisotropy. Ab initio calculations corroborate the experimental results, as summarized in Table S 2. From the Mössbauer spectroscopy, the FeII ion in compound 1 is in high spin state at 3 K and 300 K, without spin transition. 26

Concerning the anticholinesterase activity studies, our results show a good inhibition rate at nanomolar concentration for all compounds (10 µM). It is important to stress that the inhibition rates increased after coordination of L to the metal ions. Even if similar reported coordination compounds present higher inhibition rates, the compounds described here may inhibit the enzyme at concentrations a hundred times smaller.

27

Acknowledgements The authors are grateful to the financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq (project numbers 446186/2014-7 and 423086/2018-9) and Fundação Carlos Chagas de Amparo à Pesquisa do Estado do Rio de Janeiro - FAPERJ (project number E-26/202.720/2018). This work was also supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES), within the Capes-PrInt program, financial code 001, project number 88887.310269/2018-00. I.M.D. acknowledges CAPES for the master fellowship. We also thank to LDRX, LAME, LMQC for use of laboratory facilities. Supporting information NMR-1H and NMR-13C and infrared spectra for all the steps of the syntheses of the proligand (HL) (Figure S1-S6). Hydrogen bonds geometric parameters of 1 and 2 (Table S1). Additional details of CASSCF calculations (Figure S 8-S 10, Table S 3-S5). FAR-IR spectra for complexes 1-3 are in Figure S 11. Powder X-ray diffraction (Figure S 12). CCDC ID: 1910281 and 1910281 contain the supplementary crystallographic data for 1 and 2. These data can be obtained free of charge from the Cambridge

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Mononuclear coordination compounds containing a pyrazole-based ligand: syntheses, crystal structures, spectroscopy, magnetic properties and acetylcholinesterase inhibition activity assays

Isac M. Dias, Henrique C. S. Junior, Sabrina C. Costa, Cristiane M. Cardoso, Antonio G. B. Cruz, Claudio E. R. Santos, Dalber R. S. Candela, Stéphane Soriano, Marcelo M. Marques, Glaucio B. Ferreira and Guilherme P. Guedes

Research Highlights

• Crystal structures of mononuclear complexes containing a pyrazole-based ligand. • Magnetic behavior is dependent of the zero-field splitting (ZFS). • ZFS parameters were simulated by CASSCF calculations. • Compound were evaluated towards acetylcholinesterase inhibition activity.

Mononuclear coordination compounds containing a pyrazole-based ligand: syntheses, magnetism and acetylcholinesterase inhibition assays

Isac M. Dias, Henrique C. S. Junior, Sabrina C. Costa, Cristiane M. Cardoso, Antonio G. B. Cruz, Claudio E. R. Santos, Dalber R. S. Candela, Stéphane Soriano, Marcelo M. Marques, Glaucio B. Ferreira and Guilherme P. Guedes

Authors Contributions 1) Isac M. Dias – Syntheses of the ligand and complexes. 2) Henrique C. S. Junior – CASSCF calculations. 3) Sabrina C. Costa – Biological assays. 4) Cristiane M. Cardoso – Biological assays. 5) Antonio G. B. Cruz – Spectroscopy (Raman and IR spectroscopy). 6) Claudio E. R. Santos – Organic synthesis and biological assay. 7) Dalber R. S. Candela – Mössbauer spectroscopy. 8) Stéphane Soriano – Magnetic measurements and their interpretation. 9) Marcelo M. Marques – Powder X-ray diffraction. 10) Glaucio B. Ferreira – CASSCF calculations and spectroscopy. 11) Guilherme P. Guedes – Syntheses, single crystal X-ray diffraction, magnetic measurements.

1

Mononuclear coordination compounds containing a pyrazole-based ligand: syntheses, magnetism and acetylcholinesterase inhibition assays Isac M. Dias1,φ, Henrique C. S. Junior2, φ, Sabrina C. Costa1, Cristiane M. Cardoso1, Antonio G. B. Cruz1, Claudio E. R. Santos1, Dalber R. S. Candela3, Stéphane Soriano3, Marcelo M. Marques4, Glaucio B. Ferreira2 and Guilherme P. Guedes2,*

The authors declared no conflict of interest

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