Synthesis of 3-(pyridine-2-yl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamides and their copper(II) complexes

Elena K. Beloglazkina; Diana D. Korablina; Nikolai I. Vorozhtsov; Ludmila A. Sviridova; Anna A. Moiseeva; Dmitry A. Skvortsov; Victor B. Rybakov; Alexander G. Majouga; Nikolai V. Zyk

doi:10.1016/j.arabjc.2017.01.005

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Original article

12 (

); 1050-1060

doi:

10.1016/j.arabjc.2017.01.005

Synthesis of 3-(pyridine-2-yl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamides and their copper(II) complexes

Elena K. Beloglazkina^{^a,⁎}, Diana D. Korablina^{^b}, Nikolai I. Vorozhtsov^{^a}, Ludmila A. Sviridova^{^a}, Anna A. Moiseeva^{^a}, Dmitry A. Skvortsov^{^a}, Victor B. Rybakov^{^a}, Alexander G. Majouga^{^a}, Nikolai V. Zyk^{^a}

a Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, Moscow 119991, Russia

b Faculty of Fundamental Medicine, Lomonosov Moscow State University, Lomonosovsky Prospect 27/1, Moscow 119991, Russia

⁎Corresponding author. Fax: +7 495 939 0290. bel@org.chem.msu.ru (Elena K. Beloglazkina)

Received: 2016-6-17, Accepted: 2017-1-11, Published: 2017-11-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

New organic ligands 3-(pyridine-2-yl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamides (L) have been synthesized by a two or three step reaction sequence starting from substituted benzaldehydes and 2-acetyl pyridine. Copper(II) complexes with LCuCl₂ composition were obtained by the reactions of these ligands with CuCl₂·2H₂O. The crystal structure of two synthesized complexes has been determined by X-ray analysis. Copper atoms located in a strongly distorted square piramidal environment and coordinated by pyrazoline and pyridine nitrogen atoms, thiocarbamoyl sulfur atom and two chloride-anions. All complexes undergo reversible or quasi-reversible electrochemical reduction at 0.45–0.28 V with the formation of Cu(I) containing intermediates. The cytotoxicity of copper containing complexes, comparable to cisplatin and doxorubicin, was demonstrated using cancer cell lines MCF-7, A549 and HEK293.

Keywords

Copper(II) complexes

4,5-Dihydro-1H-pyrazole-1-thiocarboxamides

X-ray analysis

Voltammetry

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1 Introduction

2-Pyrazolines are an important class of heterocycles because of their high biological and pharmacological activities (Korablina et al., 2016). A recent approach in the treatment of many serious diseases such as cancer, AIDS, cardiovascular diseases and Alzheimer’s disease is the development of drugs with multiple targets(Abdolmalekia and Ghasemi, 2016; Gökhan-Kelekçi et al., 2007; Slikker et al., 1999 ). Substituted pyrazolines and their derivatives are of interest because of their anti-bacterial, anti-fungal, and anti-inflammatory activities (Abdellatif et al., 2015; Abid et al., 2009; Abid and Azam, 2005a, 2005b; Budakoti et al., 2007, 2006; Fathalla et al., 2003; Palaska et al., 2001; Turan-Zitouni et al., 2005 ). It has been reported that 3,5-diaryl-4,5-dihydro-1-thiocarbamoyl-1H-pyrazole derivatives possess considerable anti-inflammatory activity with no ulcerogenic effects (Barsoum and Girgis, 2009). Additionally, many analogues have been found to be highly inhibitory against monoamine oxidases A (MAO-A) and B (MAO-B) isoforms, which suggest efficiency in treating Alzheimer’s disease (Gökhan-Kelekçi et al., 2007) and use as anticonvulsants (Beyhan et al., 2017) and antidepressants (Özdemir et al., 2015).

N-Thiocarbamoyl-2-pyrazolines have been shown to exhibit antitubercular properties against Mycobacterium tuberculosis H37Rv (Ali et al., 2007), as well as antidepressant and anticonvulsant properties (Bilgin et al., 1993; Chinnaraja et al., 2016; Gökhan et al., 2003; Özdemir et al., 2007; Ruhoglu et al., 2005 ). Pyrazole derivatives containing 1-carbothioamide have exhibited EGFR inhibitory activity comparable to that of erlotinib. Furthermore, antiproliferative assay results have shown that some of these pyrazole derivatives have high antiproliferative activity against MCF-7 (Lv et al., 2010) and A549 (Yang et al., 2013) cell lines. Some N-Thiocarbamoyl-2-pyrazolines have also been shown to possess an antiepileptic activity (Vinayaditya et al., 2011).

In some cases, metal complexes of organic ligands have shown greater biological activity than the free ligands (Agwara et al., 2011; Aull et al., 1980; Ejidike and Ajibade, 2015; Lv et al., 2006; Villarreal et al., 2015 ). 1-Thiocarbamoylpyrazoline derivatives are well-known N,S-chelating ligands of metal ions and associate with the metal ion through the sulfur atom and the pyridine-like nitrogen (N₂) of the pyrazolyl moiety, yielding a stable five-membered ring (Budakoti et al., 2007; Evans et al., 2004; Husain et al., 2008 ). For this reason, this class of ligands may be particularly suitable for preparation of complexes with promising biological activities. In vivo antiamoebic activity against Entameoba histolytica A was tested with a variety of 1-thiocarbamoyl-2-pyrazoline derivatives and their palladium(II) complexes with the palladium complexes showing stronger antiamoebic properties than the non-complexed derivatives (Abid and Azam, 2005a, 2005b). 1-Thiocarbamoylpyrazolyl chelates of palladium(II) have been shown to display antitumor properties (Casas et al., 2008). Complexes of the type [PdX₂(tdmPz)] {X = Cl, Br, I or SCN; tdmPz = 1-thiocarbamoyl-3,5-dimethylpyrazole}) were tested for cytotoxicity against mammary adenocarcinoma (LM3 and LMM3) and lung adenocarcinoma (LP07). The cytotoxic effect against LM3 was comparable to that of cisplatin (Rocha et al., 2010). Furthermore, certain pyrazoline coordination compounds with various metal ions possess antimicrobial properties (Al-Jibori and Anaammajeedrasheed, 2013) greater than the activity of the free ligand (Elgazwy et al., 2012). Coordination compounds of thiocarbamoyl dihydropyrazoles with nickel and copper salts have shown good inhibitory activity against several strains of the genus Candida with decreasing activity such that CuL > NiL > L (Ali et al., 2012). 3,5-Diaryl substituted 2-thiocarbamoyl pyrazolines form stable coordination compounds with Cu(II), Ni(II) and Fe(III), which are able to bind to DNA (Saleem et al., 2013) and showed moderate antiproliferative activity against MCF-7 cell lines. Thiocarbamoyl pyrazoline derivatives containing a pyridine moiety in the 3-position are capable of forming complexes with gold, some of which are more cytotoxic than cisplatin against the HeLa cell line (Wang et al., 2011).

In the present work, we describe a series of 3-(pyridine-2-yl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamides and their copper(II) complexes with potent biological activity.

2 Experimental part

2.1

2.1 Materials and methods

All preparations were carried out in the reagent grade solvents. All chemicals used in the syntheses were obtained from Acros or Aldrich and were used without further purification. The progress of all reactions was monitored on Silufol precoated silica gel plates (with fluorescence indicator UV254) using ethyl acetate/n-hexane as solvent system. Melting points (mp) were taken in open capillaries on a Stuart melting point apparatus SMP11 and are uncorrected. Elemental analyses were made on a Vario MICRO cube CHNS/O Elementar. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker Avance 400 spectrometer using CDCl₃ as a solvent.

X-ray diffraction was measured with Bruker APEX II CCD diffractometer at 120(2) K (graphite monochromator, (MoKα) = 0.71073 Å, -scan type) and STOE STADIVARY Pilatus-100K diffractometer at 295 K (focusing mirrors, (CuKα) = 1.54186 K diffractometer at Å, /-scan type).

Electrochemical studies were carried out on a PI-50-1.1 potentiostat in DMF. 0.05 M Bu₄NClO₄ solution in DMF served as supporting electrolyte; Ag/AgCl/KCl (satur.) was used as a referenced electrode. All measurements were carried out under argon.

Chalcones 1a–e were synthesized according to the described methods: (Prasad et al., 2008) for 1a, (Marvel et al., 1955) for 1b, (Albaladejo and Alonso, 2013) for 1c, (Coates et al., 1996) for 1d, (Gilman and Cason, 1950) for 1e,f.

5-(3,4-Dimethoxiphenyl)-3-(pyridin-2-yl)-1-thiocarbamoyl-4,5-dihydro-1H-pyrazole (3a). A mixture of 1 eq. of chalcone 1a and 2 eq. of thiosemicarbazide in ethanol was heated until complete dissolution, then 10% aqueous solution of KOH (2 eq.) was added dropwise and the resulting solution was refluxed for 6–12 h until the reaction was completed (control by TLC). The reaction mixture was cooled, partly evaporated. The resulting precipitate was filtered and recrystallized from ethanol giving a beige powder, yield 40%, mp 182 °C. ¹H NMR (CDCl₃): 3.49 (1H, m, H⁴), 3.86 (3H, s, CH₃O), 3.88 (3H, s, CH₃O), 3.94 (1H, dd, J = 18.7, 11.5 Hz, H⁴), 6.04 (1H, dd, J = 11.6, 3.7 Hz, H⁵), 6.15 (1H, bs, NH₂), 6.80 (3H, m, H^Ar), 7.15 (1H, bs. NH₂), 7.36 (1H, m, H^Py), 7.79 (1H, t, J = 7.8 Hz, H^Py), 8.07 (1H, d, J = 8.00 Hz, H^Py), 8.65 (1H, d, J = 4.7 Hz, H^Py). Calculated for C₁₇H₁₈N₄O₂S: C 59.63%, H 5.30%, N 16.36%, S 9.36%; found: C 59.31%, H 5.53%, N 16.15%, S 9.36%.

2.1.1

2.1.1 Synthesis of 1-(N-phenylthiocarbamide) 2-pyrazolines

2.1.1.1

2.1.1.1 General procedure

3-Pyridyl-pyrazolines 2b–f. To a hot solution of 2 eq. of hydrazine hydrate in ethanol 1 eq. of chalcone 1b–f was added in several portions with stirring; then 2 eq. of acetic acid was added dropwise. The resulting mixture was refluxed for 2–5 h to complete the reaction (TLC control), cooled, partially evaporated and poured onto ice. The precipitate was washed with water and used immediately in subsequent reaction.
1-(N-phenylthiocarbamide) 2-pyrazolines 3b–f. Freshly prepared pyrazoline 2b–f (1 eq.) was dissolved in benzene and phenyl isothiocyanate (1.5 eq.) was added. The resulting mixture was stirred with a magnetic stirrer until the reaction was completed (TLC control). The reaction mixture was concentrated in vacuo, and the residue was dissolved in a minimum amount of ethanol, cooled, triturated with ether to form a precipitate. The precipitate was washed with ether and recrystallized from ethanol.

5-(3,4-Dimethoxiphenyl)-3-(pyridin-2-yl)-1-phenylthiocarbamoyl-4,5-dihydro-1H-pyrazole (3b). The yellowish-white powder, yield 41%, mp 134 °C. ¹H NMR (CDCl₃): 3.48 (1H, dd, J = 18.6, 3.6 Hz, H⁴), 3.83 (3H, s, CH₃O), 3.85 (3H, s, CH₃O), 3.96 (1H, dd, J = 18.6, 11.9 Hz, H⁴), 6.18 (1H, dd, J = 11.6, 3.7 Hz, H⁵), 6.80 (3H, m, H^Ar), 7.22 (1H, m, H^Ar), 7.39 (3H, t, H^Ar, J = 7.6 Hz, H^Py), 7.67 (2H, d, J = 8.1 Hz, H^Ar), 7.82 (1H, t, J = 7.6 Hz, H^Py), 8.1 (1H, d, J = 7.8 Hz, H^Py), 8.67 (1H, d, J = 4.6 Hz, H^Py), 9.31 (1H, s, NH). Calculated for C₂₃H₂₂N₄O₂S: C 66.01%, H 5.30%, N 13.39%, S 7.66%; found: C 66.52%, H 5.84%, N 13.03%, S 7.33%.

5-Phenyl-3-(pyridin-2-yl)-1-phenylthiocarbamoyl-4,5-dihydro-1H-pyrazole (3c). The yellowish-white powder, yield 12%, mp 165 °C. ¹H NMR (CDCl₃): 3.48 (1H, dd, J = 18.8, 3.7 Hz, H⁴), 3.99 (1H, dd, J = 18.6, 11.7 Hz, H⁴), 6.24 (1H, dd, J = 11.6, 3.8 Hz, H⁵), 7.22 (2H, m, H^Ar), 7.30 (2H, m, H^Ar), 7.37 (5H, m, H^Ar_, H^Py), 7.67 (2H, d, J = 8.0 Hz, H^Ar), 7.81 (1H, td, J = 7.8, 1.7 Hz, H^Py), 8.13 (1H, d, J = 7.8 Hz, H^Py), 8.66 (1H, d, J = 4.9 Hz, H^Py), 9.30 (1H, s, NH). Calculated for C₂₁H₁₈N₄S: C 70.36%, H 5.06%, N 15.63%, S 8.95%; found: C 69.90%, H 5.24%, N 15.16%, S 8.30%.

5-(4-Bromophenyl)-3-(pyridin-2-yl)-1-phenylthiocarbamoyl-4,5-dihydro-1H-pyrazole (3d). The white powder, yield 14%, mp 203 °C. ¹H NMR (CDCl₃): 3.41 (1H, dd, J = 18.7, 3.8 Hz, H⁴), 3.96 (1H, dd, J = 18.8, 11.9 Hz, H⁴), 6.14 (1H, dd, J = 11.9, 3.9 Hz, H⁴), 7.18 (3H, m, H^Ar), 7.36 (3H, br, H^Ar, H^Py), 7.44 (2H, d, J = 8.3 Hz, H^Ar), 7.62 (2H, d, J = 8.1 Hz, H^Ar), 7.78 (1H, t, J = 7.1 Hz, H^Py), 8.09 (1H, d, J = 7.9 Hz, H_Py), 8.63 (1H, d, J = 4.9 Hz, H^Py), 9.23 (1H, s, NH). Calculated for C₂₁H₁₇BrN₄S: C 57.67%, H 3.92%, N 12.81%, S 7.33%; found: C 57.74%, H 4.24%, N 12.54%, S 7.28%.

5-(4-Methylphenyl)-3-(pyridin-2-yl)-1-phenylthiocarbamoyl-4,5-dihydro-1H-pyrazole (3e). Yellow needle crystals, yield 46%, mp 152 °C. ¹H NMR (CDCl₃): 2.32(3H, s, CH₃), 3.49 (1H, m, H⁴), 3.96 (1H, dd, J = 18.7, 11.7 Hz, H⁴), 6.19 (1H, dd, J = 11.6, 3.8 Hz, H⁵), 7.18 (5H, m, H^Ar), 7.36 (3H, m, H^Ar, H^Py), 7.65 (2H, d J = 7.6 Hz, H^Ar), 7.79 (1H, td, J = 7.8, 1.7 Hz, H^Py), 8.1 (1H, d, J = 7.9 Hz, H^Py), 8.64 (1H, d, J = 4.8 Hz, H_Py), 9.28 (1H, s, NH). Calculated for C₂₂H₂₀N₄S: C 70.94%, H 5.41%, N 15.04%, S 8.61%; found: C 71.30%, H 5.50%, N 14.70%, S 8.45%.

5-(3-Nitrophenyl)-3-(pyridin-2-yl)-1-phenylthiocarbamoyl-4,5-dihydro-1H-pyrazole (3f). Lemon-yellow crystalline powder, yield 33%, mp 155 °C. ¹H NMR (CDCl₃): 3.45 (1H, dd, J = 18.9, 4.3 Hz, H⁴), 4.04 (1H, dd, J = 18.9, 12.0 Hz, H⁴), 6.26 (1H, dd, J = 12.0, 4.3 Hz, H5⁴), 7.21 (1H, m, H^Ar), 7.37 (3H, m, H^Ar, H^Py), 7.52 (1H, m, H^Ar), 7.61 (3H, m, H^Ar), 7.81 (1H, td, J = 7.8, 1.7 Hz, H^Py), 8.12 (3H, m, H^Ar, H^Py), 8.63 (1H, d, J = 4.3 Hz, H^Py), 9.26 (1H, s, NH). Calculated for C₂₁H₁₇N₅O₂S: C 62.52%, H 4.25%, N 17.36%, S 7.95%; found: C 62.51%, H 4.50%, N 17.05%, S 8.20%.

2.1.2

2.1.2 Synthesis of coordination compounds

2.1.2.1

2.1.2.1 General procedure

To a solution of ligand 3 (1 mmol) in 1–2 mL of methylene chloride 0.5–1 mL of methanol was added to form a two-phase system. Then the solution of CuCl₂^.2H₂O (1 mmol) in 1–2 mL of methanol was slowly poured. The reaction mixture was sealed and left to precipitation. The precipitate was filtered off, washed with cold methylene chloride, then with cold methanol/water mixture and dried under vacuum with heating. If no precipitate formed, the complex was reprecipitated by diethyl ether vapor diffusion in a closed vessel.

{[5-(3,4-Dimethoxiphenyl)-3-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-carbothioamide}copper(II) dichloride (4a). Dark green crystals yield 44%, mp 180 °C (dec.). Calculated for C₁₇H₁₈Cl₂CuN₄O₂S·H₂O: C 41.26%, H 4.07%, N 11.32%, S 6.48%; found: C 41.04%, H 3.86%, N 11.28%, S 6.89%.

[5-(3,4-Dimethoxyphenyl)-3-(pyridin-2-yl)-1-phenylthiocarbamoyl-4,5-dihydro-1H-pyrazole]copper(II) dichloride (4b). Brown powder, yield 76%, mp 200 °C (dec.). Calculated for C₂₃H₂₂Cl₂CuN₄O₂S: C 49.96%, H 4.01%, N 10.13%, S 5.80%; found: C 49.84%, H 4.19%, N 9.82%, S 6.02%.

[5-Phenyl-3-(pyridin-2-yl)-1-phenylthiocarbamoyl-4,5-dihydro-1H-pyrazole]copper(II) dichloride (4c). Dark green crystals yield 56%, mp 190–195 °C (dec). Calculated for C₂₁H₁₈Cl₂CuN₄S: C 51.17%, H 3.68%, N 11.37%, S 6.50%; found: C 50.94%, H 3.91%, N 11.06%, S 6.22%.

[5-(4-Bromophenyl)-3-(pyridin-2-yl)-1-phenylthiocarbamoyl-4,5-dihydro-1H-pyrazole]copper(II) dichloride (4d). Light green powder, yield 33%, mp 198–199 °C (dec). Calculated for C₂₁H₁₇BrCl₂CuN₄S: C 44.11%, H 3.00%, N 9.80%, S 5.61%; found: C 43.95%, H 3.28%, N 9.50%, S 5.35%.

[5-(4-Methylphenyl)-3-(pyridin-2-yl)-1-phenylthiocarbamoyl-4,5-dihydro-1H-pyrazole]copper(II) dichloride (4e). Light green powder, yield 39%, mp 180–182 °C (dec.). Calculated for C₂₂H₂₀Cl₂CuN₄S: C 52.12%, H 3.98%, N 11.05%, S 6.33%; found: C 51.95%, H 4.25%, N 10.81%, S 5.99%.

[5-(3-Nitrophenyl)-3-(pyridin-2-yl)-1-phenylthiocarbamoyl-4,5-dihydro-1H-pyrazole]copper(II) dichloride (4f). Dark green crystals, yield 85%, mp 195–200 °C (dec). Calculated for C₂₁H₁₇Cl₂CuN₅O₂S: C 46.89%, H 3.19%, N 13.02%, S 5.96%; found: C 46.75%, H 3.14%, N 12.90%, S 6.13%.

3 Results and discussion

3.1

3.1 Synthesis of ligands and complexes

The synthesis of 1-thiocarbamoyl pyrazoline derivatives 3a–f was performed with 2-acetyl pyridine chalcones 1a–f (Schemes 1, 2) as starting materials. The 1,3-diaryl-2-propen-1-ones chalcones 1a–f were synthesized according to previously described methods (Albaladejo and Alonso, 2013; Coates et al., 1996; Gilman and Cason, 1950; Marvel et al., 1955; Prasad et al., 2008 ). Condensation of 2-acetyl pyridine-based chalcone 1a with thiosemicarbazide in the presence of KOH yielded 5-(3,4-dimethoxyphenyl)-3-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-1-carbothioamide 2 (Scheme 1). The chalcones 1b-f reacted with hydrazine hydrate giving 3-pyridyl-pyrazoline derivatives 2b–f, which were reacted with phenyl isothiocyanate to yield the target phenylthiocarbamoyl-dihydropyrazoles 3b–f (Scheme 1). Using this method, products 1–10 were synthesized with moderate yields. Crude products were crystallized from ethanol. The structures of the compounds were characterized by ¹H NMR spectroscopy. The methylene protons and the methine proton in positions 4 and 5, respectively, of the dihydro-(1H)-pyrazole ring, give rise to a well-defined system of three double doublets at 3.5–6.0 ppm, indicating not only the formation of the pyrazoline, but also the exact position of the C = N double bond.

Synthesis of 5-(3,4-dimethoxyphenyl)-3-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-1-carbothioamide 3a.

Synthesis of 1-(N-phenylthiocarbamoyl)-pyrazolines 3b–f.

Apparently, chalcone 1a reacted with thiosemicarbazide in two stages. In the first step thiosemicarbazone 3a′ is obtained, which then cyclized forming the pyrazoline derivative 3a. In the ¹H NMR spectrum of the latter compound there are the signals of two non-equivalent H4 protons of pyrazoline cycle at 3.5 and 3.9 ppm; by virtue of the fact that the H5 proton of pyrazoline cycle has a strong impact of the neighboring thioamide group, its signal is observed in the ¹H NMR spectrum at 6.0 ppm, which is different from the average value of the type of signals (signal shifted downfield to a ∼1 ppm). Signals of NH₂ group appear as two low-intensity broadened peak at 6.15 and 7.10 ppm. In the IR spectrum of 3a NH₂-group provides characteristic absorption band at ∼3500 cm⁻¹.

A series of Cu(II) complexes with the obtained phenylthiocarbamoyl-pyrazolines 3a–f was synthesized by direct reaction of ligands, dissolved in CH₂Cl₂, with copper(II) chloride dissolved in CH₃OH (Scheme 3). All complexes were characterized by elemental analysis data. The crystal structures of complexes 4a and 4c were confirmed by X-ray diffraction. Coordination compounds with the composition LCuCl₂ (with L = 3-(pyridine-2-yl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamide) were isolated for all ligands. The copper atom formed two five-membered chelate rings because of coordination between the nitrogen atoms of the pyrazoline and pyridine moieties and the sulfur atom of the thiocarbamoyl substituent. This is similar to structures previously observed for other copper complexes with the ligands of this structure (Abid and Azam, 2005a, 2005b; Budakoti et al., 2007; Casas et al., 2008; Evans et al., 2004; Husain et al., 2008; Rocha et al., 2010; Wang et al., 2011 ).

Synthesis of copper(II) complexes of 1-thiocarbamoyl-pyrazolines 4a–f.

The structures of complexes 4a and 4c were confirmed by X-ray diffraction. The crystal structures are shown in Fig. 1; selected bond lengths and angles are given in Tables 1 and 2. Copper atoms in both complexes are coordinated by the two nitrogen atoms of two five-membered rings of the organic ligand, the thiocarbonyl sulfur atom and two chlorine ions. The metal atoms form a very distorted square piramidal shape; the Cu-N distances are 2.121–2.141 Ǻ (Cu-N_Pyrid) and 1.915–1.930 Ǻ (Cu-N_Pyraz). The pyrazoline rings of the ligands are almost flat. The phenyl substituent at the 3rd position of the ligand moieties in complexes 4a and 4c is almost perpendicular to the pyrazoline plane.

Molecular structures of coordination compounds 4a (left) and 4c (right).

Table 1 Selected bond lengths for coordination compounds 4a, 4b.

Compound	Cu-Cl1	Cu-Cl2	Cu-N(Pyrid)	Cu-N(Pyraz)	Cu-S
4a	2.4730(15)	2.2164(14)	2.141(3)	1.915(4)	2.3628(13)
4c	2.5071(8)	2.2032(8)	2.121(2)	1.930(2)	2.3508(8)

Table 2 Selected angles for coordination compounds 4a, 4b.

Compound	Cl1-Cu-Cl2	Cl1-Cu-N(Pyrid)	Cl1-Cu-N(Pyraz)	Cl2-Cu-N(Pyrid)	Cl2-Cu-N(Pyraz)	N-Cu-N	N(Pyrid)-Cu-S	N(Pyraz)-Cu-S	Cl-Cu-S
4a	106.20(6)	89.57(11)	95.62(11)	98.24(11)	157.50(12)	76.11(15)	154.11(12)	80.91(11)	98.46(5)
4a	106.20(6)	89.57(11)	95.62(11)	98.24(11)	157.50(12)	76.11(15)	154.11(12)	80.91(11)	104.53(6)
4c	111.25(3)	90.14(7)	98.97(7)	91.47(7)	156.92(8)	76.16(10)	155.61(7)	81.55(7)	97.67(3)
4c	111.25(3)	90.14(7)	98.97(7)	91.47(7)	156.92(8)	76.16(10)	155.61(7)	81.55(7)	97.61(10)

3.2

3.2 Electrochemistry

Electrochemical studies were carried out for the ligands 3a–f and their copper complexes 4a–f using cyclic voltammetry (CV) and rotating disk electrode (RDE) techniques, with glassy carbon and gold electrodes in DMF in the presence of 0.1 M Bu₄NClO₄ as supporting electrolyte. The potentials of the electrochemical oxidation and reduction, measured relative to Ag|AgCl|KCl (sat.) are presented in Table. 3. The cyclic voltammograms are shown in Figs. 2, 3 and in Supplementary Information.

Table 3 Electrochemical reduction (E_Red) and oxidation (E_Ox) potentials of ligands and complexes, measured relatively to Ag|AgCl|KCl (sat.) by cyclic voltammetry (E_p is the peak potential) at glassy carbon and Au electrodes. DMF, 0.1 M Bu₄NClO₄, 200 mV/s. The values after the slash marks represent the peak potentials for the reverse CV scans.

Compound	Electrode	E_pRed, V	E_pOx, V
3a	GC	−1.80	1.18
	GC	−2.34	1.57
	Au	−1.80	1.34
	Au	−1.80	1.62

4a	GC	0.44/0.55	1.18
		0.32/0.55	1.29
		−0.29
		−1.79
		−2.01
	Au	0.35/0.44	0.87
		0.02	1.56
		−0.70
		−1.99
		−2.02
		−2.22

3b	GC	−1.67	1.23
	GC	−2.20	1.54
	Au	−1.66	1.40
	Au	−1.66	1.57

4b	GC	0.28/0.52	0.97
		−0.82	1.33
		−1.99
		−2.21
		−2.38
	Au	0.39/0.68	1.07
		−1.01	1.31
		−1.96

3c	GC	−1.64	1.27
	GC	−2.14	1.37
	Au	−1.67	1.46

4c	GC	0.39/0.52	1.18
		−1.69	1.31
		−1.96	1.31
	Au	0.33/0.42	1.38
		−0.16
		−0.69
		−1.70

3d	GC	−1.55	1.40
	GC	−2.08/1.13	1.40
	Au	−1.65	1.57
		−1.88
		−2.19

4d	GC	0.42/0.55	1.08
		−0.70	1.21
		−1.63	1.39
		−1.93	1.60
		−2.20	1.60
	Au	0.31/0.42	0.77
		−0.63	1.14
		−1.64	1.43
		−1.93	1.55

3e	GC	−1.67	1.28
	GC	−2.21	1.38
	Au	−1.67	1.49
	Au	−2.21	1.49

4e	GC	0.41/0.53	1.05
		−1.67	1.32
		−1.98	1.52
		−2.25	1.52
	Au	0.30/038	1.02
		−0.61	1.36
		−1.69	1.46
		−1.97	1.46

3f	GC	−1.07/−1.00	1.45
		−2.03
		−2.26
	Au	−1.07/−1.01	1.60
		−1.62
		−2.25

4f	GC	0.44/0.54	1.08
		−0.75	1.16
		−1.11/−1.03	1.36
		−1.93
		−2.02
		−2.22
	Au	0.25/0.49	0.77
		−0.21	1.13
		−0.60	1.45
		−1.12/−1.03
		−2.06

CV for ligand 3e on GC (left) and Au (right) electrodes (10−3 M, DMF, Bu4NClO4).

CV for complexes 4e (left), 4f (center) and 4c (right) on Au electrodes (10−3 M, DMF, Bu4NClO4).

All ligands, except 3f, were reduced by the glass carbon electrode in two irreversible stages, during the first of which one electron was gained, and the second of which two electrons were gained. Ligands 3b and 3e, containing electron-donating substituents in the phenyl ring, as well as unsubstituted ligand 3c, are reduced at very similar potential values (see Table 3 and Fig. 2). Electron-withdrawing substituents have a greater influence on the potentials of cathodic peaks than other substituents. Compound 3d, with a p-bromophenyl substituent, was reduced with 90 mV less than 3c, which is due to the acceptor effect of the bromine atom in the phenyl ring. A reoxidation peak of Br⁻ at 1.13 V was observed for compound 3d after the second reduction step during the reverse scan (Fig. 2d), indicating reductive cleavage of the bromine anion. Compound 3f, with the nitro substituent on the phenyl ring, was reduced in three stages and at a lower cathodic potential value (570 mV) than the unsubstituted thiocarbamoyl-pyrazoline 3c. Unlike other ligands, the first stage of reduction of compound 3f was reversible, which, according to the reduction potential value, occurs on the non-conjugated nitro group (Butin et al., 1992).

Oxidation potentials of ligands 3a–f are more dependent on the nature of the substituents rather than the reduction potentials. For ligands 3b and 3e, with donor substituents at the phenyl ring, a cathode shift of oxidation potential was observed. For 3d and 3f, anode shifts were observed for compounds with electron accepting substituents (Table 3).

The CV curves of coordination compounds 4a–f from the GC electrode show the first reversible or quasi-reversible reduction peaks in the anode region at 0.45–0.28 V, corresponding to Cu(II) → Cu(I) transitions; subsequent irreversible low-intensity peaks correspond to Cu(I) → Cu(0) transitions. Cu(I) and Cu(0) containing intermediates are stable at these conditions.

In contrast, only the complexes 4a, 4b and 4e, with donor substituents at the aromatic ring, were stable in the anodic and cathodic regions during reduction with the Au electrode (Fig. 3, left). Complexes 4d and f, containing bromine or nitro groups, were decomposed by oxidation followed by release of copper metal, as evidenced by the desorption peaks of copper metal from the electrode surface on the CV curves during the reverse potential scan at 1.8 V (Fig. 3, center). Complexes were most likely decomposed after the oxidation, resulting in a ligand moiety oxidation product and CuCl₂. For the latter, the reverse scan CV curve increase is due to the reduction of free CuCl₂ to CuCl, which is unstable with metal electrodes and is disproportionate in terms of free metal release (CuCl → CuCl₂ + Cu) (Beloglazkina et al., 2006, 2008, 2009; Majouga et al., 2009 ).

For complex 4c, with an unsubstituted phenyl ring in the ligand fragment, a Cu(0) desorption peak was observed after the reduction in the complex during the CV reverse scan at the −1.8 V potential (Fig. 3, right). We found that Cu(0)-containing reduction products are unstable in this case and degrade by forming free ligand, metallic copper and chloride anions ([Cu⁰LCl₂]²⁻ → Cu⁰ + L + 2Cl⁻).

Thus, coordination compounds 4a–f are oxidized “to ligand” and reduced “to metal” in two stages, the first of which is reversible or quasi-reversible and the second of which is irreversible and leads to the formation of [Cu⁰LCl₂]²⁻. The further behavior of the reduction intermediate depends on the nature of the substituents in the ligand fragments and on the electrode material.

3.3

3.3 Cytotoxicity

Synthesized copper complexes were tested for their in vitro cytotoxicity against human lung cancer (A549), breast adenocarcinoma (MCF-7), human embryonic kidney (HEK293) and SV40-transformed human embryonic lung fibroblast (VA13) cells using a standard MTT assay (Mosmann, 1983). The comparison of the obtained result with the data for copper(II) chloride and clinically used drugs cisplatin and doxorubicin for copper complexes 4a–f is shown in Table 4.

Table 4 Cytotoxicity of ligands and complexes against A549, MCF7, HEK293T and VA13 cell lines measured by MTT-assay (μM).^a

Compound	A549, μM	MCF7, μM	HEK293T, μM	VA13, μM
4a	28.8 ± 5.5	48.4 ± 43	19.1 ± 3.3	39.6 ± 5.5
4c	11.6 ± 1.7	9.9 ± 0.3	8.0 ± 1.5	11.0 ± 2.1
4d	14.4 ± 1.5	24.1 ± 1.7	7.4 ± 2.5	9.4 ± 0.3
4e	9.5 ± 0.8	12.1 ± 1.5	8.1 ± 1.3	8.2 ± 0.5
4f	20.7 ± 0.8	23.2 ± 0.9	12.9 ± 2.2	19.2 ± 3.7
Doxorubicin^b	2.0 ± 0.8	2.1 ± 0.8	1.1 ± 0.1
Cisplatin^b	>30	64.13 ± 3.9	12.4 ± 3.9
CuCl₂·2H₂O^c		>100

a CuCl₂^·2H₂O and CoCl₂^·6H₂O have IC₅₀ more then 100 μM on the cell line Hek293T (the most sensitive cell line in our tests).

b Majouga et al. (2014).

c Zhong et al. (2015).

Coordination of metal ions was required for cytotoxicity of the tested compounds. The measured IC₅₀ values for free ligands were much higher (>200 μM) than the values for corresponding copper complexes. The cytotoxicity of the copper complexes with thiocarboxamide ligands was also substantially higher than the cytotoxicity of copper chloride. The nature of substituent at the thioamide nitrogen atom is important for cytotoxicity: complex 4a, with an unsubstituted amide, was 2–4 times less cytotoxic than complexes 4c–f, with an N-aryl-substituted ligand. Compound 4f, containing a 3-nitrophenyl substituent at the thioamide nitrogen atom, was also less active than other N-arylthioamides (4c–e). HEK293 was most affected by the tested compounds. The cytotoxicity of complexes 4c–e toward all tested cell lines was higher than that of cisplatin.

4 Conclusions

As a result of this research, a series of novel tridentate organic ligands 1-(N-phenylthiocarbamoyl)-pyrazolines and their coordination compounds with copper chloride were synthesized. The characterization of ligands and coordination compounds was based on NMR, elemental analysis, and cyclic voltammetry data. Two copper complexes were characterized by single-crystal X-ray analysis. The cytotoxicity of copper containing complexes, comparable to cisplatin, was demonstrated for cancer cell lines MCF-7, A549, HEK293 and VA13.

Acknowledgments

This study was fulfilled using a STOE STADI VARI PILATUS-100K diffractometer purchased by MSU Development Program.

The authors gratefully acknowledge Russian Foundation for Basic Research – Russia (Grant # 16-03-00921) for the financial support of this work.

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Appendix A

Supplementary material

CCDC-1470442 and CCDC-1485872 contain the supplementary crystallographic data for 4a and 4c. 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. Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2017.01.005.

Appendix A

Supplementary material

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[1] Abdellatif K.R., Abdelall E.K., Fadaly W.A., Kamel G.M., . Synthesis, cyclooxygenase inhibition, and anti-inflammatory evaluation of novel diarylheterocycles with a central pyrazole, pyrazoline, or pyridine ring. Med. Chem. Res.. 2015;24(6):2632-2644.
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[2] Abdolmalekia A., Ghasemi J.B., . Dual-action hybrid compounds – a new dawn in the discovery of multi-target drugs: lead generation approaches. Curr. Top. Med. Chem.. 2016;16(1):1-19.
[Google Scholar]

[3] Abid M., Azam A., . 1-N-substituted thiocarbamoyl-3-phenyl-2-pyrazolines: synthesis and in vitro antiamoebic activities. Eur. J. Med. Chem.. 2005;40(9):935-942.
[Google Scholar]

[4] Abid M., Azam A., . Synthesis and antiamoebic activities of 1-N-substituted cyclised pyrazoline analogues of thiosemicarbazones. Bioorg. Med. Chem.. 2005;13(6):2213-2220.
[Google Scholar]

[5] Abid M.D., Bhat A.R., Athar F., Azam A., . Synthesis, spectral studies and antiamoebic activity of new 1-N-substituted thiocarbamoyl-3-phenyl-2-pyrazolines. Eur. J. Med. Chem.. 2009;44(1):417-425.
[Google Scholar]

[6] Agwara M.O., Yufanyi M.D., Foba-Tendo J.N., Atamba M.A., Ndinteh D.T., . Assessment of methanolic extract of Marrubium vulgare for anti-inflammatory, analgesic and anti-microbiologic activities. J. Chem. Pharm. Res.. 2011;3(1):196-204.
[Google Scholar]

[7] Albaladejo M.J., Alonso F., . Synthesis of indolizines and heterocyclic chalcones catalyzed by supported copper nanoparticles. Chem. Eur. J.. 2013;19(17):5242-5245.
[Google Scholar]

[8] Ali I., Wani W.A., Khan A., Haque A., Ahmad A., Saleem K., Manzoor N., . Synthesis and synergistic antifungal activities of a pyrazoline based ligand and its copper(II) and nickel(II) complexes with conventional antifungals. Microb. Pathog.. 2012;53(2):66-73.
[Google Scholar]

[9] Ali M.A., Shaharyar M., Siddiqui A.A., . Synthesis, structural activity relationship and anti-tubercular activity of novel pyrazoline derivatives. Eur. J. Med. Chem.. 2007;42(2):268-275.
[Google Scholar]

[10] Al-Jibori M.N., Anaammajeedrasheed S., . Coordination modes of a new ligand derived from pyrazoline with Cr (III), Mn (II), Co (II), Ni (II), Cu (II) and Zn (II) metal ions: synthesis, identification and biological studies. Chem. Mater. Res.. 2013;3(1):1-11.
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Synthesis of 3-(pyridine-2-yl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamides and their copper(II) complexes

Abstract

Keywords

Copper(II) complexes

4,5-Dihydro-1H-pyrazole-1-thiocarboxamides

X-ray analysis

Voltammetry

1 Introduction

2 Experimental part

2.1 Materials and methods

2.1.1 Synthesis of 1-(N-phenylthiocarbamide) 2-pyrazolines

2.1.1.1 General procedure

2.1.2 Synthesis of coordination compounds

2.1.2.1 General procedure

3 Results and discussion

3.1 Synthesis of ligands and complexes

3.2 Electrochemistry

3.3 Cytotoxicity

4 Conclusions

Acknowledgments

References

Appendix A

Supplementary material

Appendix A

Supplementary material

Supplementary data 1

Supplementary data 2

Supplementary data 3

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