Next Article in Journal
Theoretical Studies on the Insertion Reaction of Polar Olefinic Monomers Mediated by a Scandium Complex
Previous Article in Journal
Silver Nanoparticle-Immobilized Cotton Fabric Serves as Flexible Surface-Enhanced Raman Scattering Substrate for Detection of Toxin
Previous Article in Special Issue
Investigating the Anticancer Properties of Novel Functionalized Platinum(II)–Terpyridine Complexes
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Inorganics
Volume 12
Issue 6
10.3390/inorganics12060171
inorganics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis of Cobalt(III) Complexes Derived from Pyridoxal: Structural Cleavage Evaluations and In Silico Calculations for Biological Targets

by
Liniquer André Fontana
1,
Francisco Mainardi Martins
2,
Josiéli Demetrio Siqueira
2,
Carlos Serpa
3,
Otávio Augusto Chaves
3,4,* and
Davi Fernando Back
2,*
1
Institute of Chemistry, University of Campinas, Rua Josué de Castro, Cidade Universitária Zeferino Vaz, Campinas 13083-970, SP, Brazil
2
Inorganic Materials Laboratory, Department of Chemistry, Center for Natural and Exact Sciences (CCNE), Federal University of Santa Maria (UFSM), Santa Maria 97105-900, RS, Brazil
3
Department of Chemistry, Coimbra Chemistry Centre—Institute of Molecular Science (CQC-IMS), University of Coimbra, Rua Larga s/n, 3004-535 Coimbra, Portugal
4
Laboratory of Immunopharmacology, Centro de Pesquisa, Inovação e Vigilância em COVID-19 e Emergências Sanitárias (CPIV), Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil
*
Authors to whom correspondence should be addressed.
Inorganics 2024, 12(6), 171; https://doi.org/10.3390/inorganics12060171
Submission received: 17 April 2024 / Revised: 11 June 2024 / Accepted: 16 June 2024 / Published: 18 June 2024
(This article belongs to the Special Issue Evaluation of the Potential Biological Activity of Metallo-Drugs)
Browse Figures
Versions Notes

Abstract

:
This study sought to investigate the synthesis of eight complexes constituted by a cobalt(III) (CoIII) metallic center coordinated to two units of iminic ligands LnC (n = 1–4, L1C–L4C), which are derivatives of pyridoxal hydrochloride and anilines with thioether function containing one to four carbons. Depending on the source of the cobalt ion and the addition (or not) of a non-coordinating counterion, complexes with distinct structures may form, being categorized into two series: [CoIII(LnC)(L0C)] (n = 1–4, C1’–C4’) with a LnC ligand and a ligand that has a thiolate function which cleaves the C-S(thioether) bond (L0C) and [CoIII(LnC)2]PF6 (n = 1–4, C1–C4) with two similar units of the same LnC ligand. The occurrence (or not) of cleavage in the eight complexes was observed by elucidating the solid-state structures by single crystal X-ray diffraction. This exciting method allows the synthesis of CoIII complexes without cleaving the C-S bonds from the ligands, thereby not requiring an inert atmosphere in the reaction systems. The synthesized complexes were evaluated by in silico calculations on viable biological targets such as deoxyribonucleic acid, superoxide dismutase enzyme, human serum albumin, and the structural spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the receptor binding domain (RBD) in both up and down conformations without and in complex with the cellular receptor angiotensin-converting enzyme 2 (ACE2). Overall, in silico results suggested that all the inorganic complexes under study are potential anticancer/antiviral agents; however, C4 and C4’ are the best candidates for future in vitro assays.

Graphical Abstract

1. Introduction

Carbon–sulfur bonds of specific organosulfur compounds, such as C(alkyl)-S and C(aryl)-S [1], can be catalytically activated by thiophilic metal ions and undergo cleavage and subsequent transformation [2]. This process can be led by transition metal centers and their compounds forming new sulfur molecules or sulfide-containing complexes [1]. These metal ion-mediated cleavages and transformation processes of C-S bonds are important in the oil and fuel industries [3], synthetic chemistry [4], and biological mechanisms [4], including the functioning of the enzyme methyl-coenzyme M reductase [5].
Recent reports have described the cleavage of C-S bonds by the action of different transition metal ions, such as palladium [6,7], iron [8], rhodium [1,9], copper [10], nickel [4], and cobalt [11,12,13,14,15]—a trace element essential for human life [16]. The catalytic action of cobalt as a constituent of cobalamin (vitamin B12) stands out [17], as it is a crucial part of DNA synthesis and cellular energy production [18]. In mammals, its forms containing methyl and adenosyl ligands are present as a cofactor of two enzymes: methionine synthase and methylmalonyl-CoA mutase [17,18,19]. Cobalt(II) (CoII) forms labile high-spin complexes with different possible coordination numbers. In contrast, cobalt(III) (CoIII) has octahedral coordination with high or low spin configurations, the latter being inert for ligand substitution and diamagnetic due to the d6 configuration [20].
To improve processes involving C-S bond activation, the rational design and synthesis of ligands are fundamental since their characteristics (e.g., size and coordinating capacities of these molecules) influence the properties of metallic centers [9]. Among the possibilities, there are Schiff base ligands—organic compounds with C=N (imine) bonds [21]. Thus, to coordinate with octahedral metallic centers (e.g., CoIII), an interesting iminic ligand can be obtained by condensing derivatized anilines and aldehydes [22,23], most notably pyridoxal. This vitamin B6 derivative has structural diversity [24,25] and groups that form possible intermolecular interactions [26] including coordination with different charges and Pearson’s absolute hardnesses, e.g., phenol/phenolate oxygen and imine nitrogen [27].
The design and development of drugs containing metal ions (metallodrugs) have gained significant attention in recent years for their potential applications in cancer and viral treatments [28,29]. One of the most well-known metallodrugs used in cancer therapy is cisplatin and its derivatives, carboplatin and oxaliplatin. These complexes have the capacity to bind to deoxyribonucleic acid (DNA), causing structural changes that inhibit cell division and promote apoptosis [30,31]. However, novel metallodrugs have been designed to also inhibit specific enzymes crucial for cancer cell survival and generate reactive oxygen species (ROS) to induce oxidative stress and apoptosis selectively, e.g., platinum- and palladium-based compounds [32,33,34,35,36,37]. Interestingly, some reports correlated the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with increasing probability of cancer development in different organs [38,39,40] and due to the unique mechanisms of action and the versatility of metallodrugs in interacting with biological molecules, e.g., targeting specific crucial steps for cancer cells and also interfering with the viral replication process, either by directly targeting viral components or by modulating host cellular mechanisms, metallodrugs might represent a promising frontier in both cancer and antiviral therapies [41,42]. In this sense, cobalt Schiff base complexes have gained attention, mainly due to their ability to induce apoptosis in cancer cells [43,44] and inhibit viral replication by targeting different viral enzymes [45,46], which offers a promising avenue for the development new therapies.
Thus, the present work reports the synthesis of a series of Schiff bases derived from pyridoxal and S-alkylated anilines containing different substituents, e.g., methyl, ethyl, propyl, and butyl, resulting in monomers containing CoIII cations. Depending on the conditions employed during the synthesis, bond cleavages between carbon and thioether atoms (C-sulfur) were observed. Additionally, molecular docking calculations were performed for [CoIII(LnC)2]PF6 (n = 1–4, C1–C4) and [CoIII(LnC)(L0C)] (n = 1–4, C1’–C4’) series complexes concerning their interactive profile with deoxyribonucleic acid (DNA), human serum albumin (HSA), and superoxide ions to preliminarily evaluate their anticancer profiles. Finally, the CoIII complexes were also in silico evaluated with the structural spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with receptor binding domain (RBD) in both up and down conformations without and in complex with the cellular receptor angiotensin-converting enzyme 2 (ACE2) due to the correlation between SARS-CoV-2 infection and oncogenesis [47]. The in silico results and their corresponding trends were compared with experimental data from the literature for other cobalt complexes. The novelty of this study lies in the relationship between the calculated in silico activity and the differentiation of the complexes that showed C-S(thioether) bond cleavage and those that did not.

2. Results and Discussion

2.1. [CoIII(LnC)(L0C)] Series Complexes (C1’–C4’)

The iminic ligands (L1C–L4C) were synthesized in an inert argon atmosphere using dry methanol, as summarized in the synthetic pathways in Scheme 1. On the other hand, the complexation reactions between ligands L1C–L4C and CoII acetate were done by bubbling atmospheric air every hour in the reactive medium, as summarized in the synthetic pathways in Scheme 2. In this case, a series of mononuclear complexes [CoIII(LnC)(L0C)] (n = 1–4, C1’–C4’) was obtained. The ORTEP-3.1 diagrams of the molecular structures of the [CoIII(LnC)(L0C)] series complexes (C1’–C4’) in the solid state are illustrated in Figure 1.
In this series of CoIII complexes, two distinct ligands coordinate with the cobalt cation were obtained. In the LnC form, coordination occurs by phenolate oxygen, imine nitrogen, and thioether sulfur atoms, being monoanionic species by the deprotonation of phenol. In the second form, L0C, the coordination occurs between a phenolate oxygen, imine nitrogen, and thiolate sulfur atom. The last highlighted organic function was formed in situ by the scission of the bond between carbon and thioether sulfur, which lost the aliphatic carbon chain. Thus, this thiolate anionic function with the charge of the phenolate oxygen makes L0C a dianionic ligand.
In the C1’–C4’ compounds, the coordination of the ligands LnC in the monoanionic form and L0C in the dianionic form led to the formation of a neutral complex, and the cobalt metallic centers presented a trivalent oxidation state of the O2N2S2 type. The bond length and angle values related to the coordination spheres of the C1’–C4’ complexes and their respective comparisons with values in the literature are summarized in Table 1. It was noted that the bond length values converged with each other for CoIII-N(imine), CoIII-O(phenolate), CoIII-S(thioether), and CoIII-S(thiolate) bonds.
The cleavage of C-S(thioether) bonds by cobalt ion was studied in hexadentate ligands derived from S-alkylated anilines containing two or three methylenes by different authors [11,12,13,14,15]. To obtain the C1’–C4’ complexes, a similar method as previously reported was employed [13,14,15], in which CoII acetate was used in the presence of dioxygen in the medium of the complexation reactions. An oxidative cleavage occurs in these cases, in which the carbon from methylene bonded to sulfur thioether is base-induced to activate, leading to its deprotonation and cleavage of the carbon–sulfur bond [15]. Recent evidence has suggested that oxygen is necessary in the reaction medium for the in situ oxidation of CoII to CoIII and cleavage of the C-S bond [13,14].
In these studies, the authors reported that the cleavage requires the formation of a stable five-membered metallacycle between cobalt and thioether sulfurs (-S-Co-S-). Thus, the cleavage occurs to avoid forming an unfavorable four-membered ring [14,15]. In the present work, we extended the study of these cleavages to S-alkylated anilines with monohaloalkanes in initially tridentate ligands that, in turn, do not form such -S-Co-S- metallacycles (Scheme 3).
Interestingly, under favorable synthesis conditions, the cleavage of the bond between carbon and sulfur thioether occurs mainly by electronic factors. With the formation and coordination of an anionic sulfur thiolate, a better σ-donor, there is a better stabilization of the CoIII center, probably with a low spin. Furthermore, in the ligand-to-metal charge transfer (LMCT), sulfur in the form of thiolate is favored when cobalt is trivalent [13]. As the cleavage occurs in only one of the two ligands in the monoanionic form coordinated to the same metallic center, this phenomenon leads to the formation of a third anionic charge to stabilize the CoIII ion in the form of a neutral hexacoordinated complex.
Furthermore, Rajsekhar and coworkers [13,14] showed that cleavage of the C-S bond of hexadentate imine ligands derived from salicylaldehydes and S-alkylated aniline with two methylenes also occurs using other CoII salts (i.e., hydrated chloride and sulfate). However, the authors found that the coordination reactions of the same ligands, although with NiII and ZnII acetates, divalent metal ions with restricted redox behavior, do not lead the cleavage of the C-S bond and the formation of coordinated sulfur thiolate. In these two later cases, the formation of neutral complexes occurs by the coordination of the hexadentate ligand in the dianionic form to the NiII and ZnII centers by sulfur thioether donor atoms [13,14].

2.2. [CoIII(LnC)(L0C)] Series Complexes (C1–C4)

A mononuclear [CoIII(LnC)2]PF6 (n = 1–4, C1–C4) complex series was obtained after the reactions between the same ligands L1C–L4C (Scheme 1) but with the dichlorobis(triphenylphosphine)cobalt(II) (CoIICl2(PPh3)2) complex as a source of cobalt cations and with the addition of potassium(I) hexafluorophosphate (KPF6) in methanol in an open atmosphere (Scheme 2). The ORTEP-3.1 diagrams of the molecular structures of the [CoIII(LnC)2]PF6 series complexes (C1–C4) in the solid state are shown in Figure 2.
In these four synthesized compounds, it was observed that two similar LnC ligands coordinated to the same metallic center via a phenolate oxygen atom, an imine nitrogen atom, and a thioether sulfur atom. Since thioether sulfur and imine nitrogen are neutral donor atoms and phenolic oxygen is deprotonated with (1-) charge, such LnC ligands are considered monoanionic.
Once the C1–C4 complexes are isolated in the form of KPF6 salt, a non-coordinating counterion with intense use in coordination chemistry, all complexes in this series can be denominated as monocationic complex ions. Thus, by the sum of the charges and coordination profile, it can be concluded that C1–C4 also present trivalent cobalt species and the O2N2S2 type.
Hence, in these cases, it is plausible that the air-stable phosphine–cobalt(II) complex [49] oxidizes from 2+ to 3+ in the reaction medium previously oxidized in the coordination to ligands L1C–L4C, preventing the cleavage of the carbon–sulfur bond and, consequently, without the formation of another anionic charge of the sulfur thiolate. The bond length and angle values related to the coordination spheres of the C1–C4 complexes and their respective comparisons with values in the literature are summarized in Table 2. It was noted that the bond length values converge with each other for CoIII-N(imine), CoIII-O(phenolate), CoIII-S(thioether), and CoIII-S(thiolate) bonds.

2.3. In Silico Calculations on Feasible Biological Targets for CoIII Complexes

In silico calculations by molecular docking approach have become one of the most used tools in hit finding and hit-to-lead optimization at evaluating the drug targets via an atomic point of view of the binding capacity [51,52]. In this sense, molecular docking calculations for C1–C4 and C1’–C4’ were performed with deoxyribonucleic acid (DNA), human serum albumin (HSA), and superoxide ions (O2−) to suggest feasible biological targets (as anticancer agents), comparing the obtained in silico trend with experimental data previously reported in the literature for other cobalt complexes.
Genetic changes can lead to cancer if they alter the way that cells grow and spread. Some compounds, e.g., platinum complexes, can bind covalently between two strands of DNA (interstrand crosslinking agents) and thereby prevent vital processes such as replication or transcription in dividing cancer cells, and for this reason these are the first-line chemotherapy treatment for many solid human cancers [53,54]. Since platinum resistance in the treatment of malignant diseases has already been reported [55], there is still a necessity to identify novel inorganic complexes that might interact with DNA.
Table 3 summarizes the docking score values for the interactions of DNA: C1–C4/C1’–C4’. The highest docking score values were obtained in the minor groove of DNA, suggesting that the CoIII complexes might interact with DNA strands via the minor groove. Interestingly, the increase of carbon in the S-alkyl moieties of CoIII complexes improved their interactive profile with DNA. The main intermolecular forces responsible for this interaction are the van der Waals force and hydrogen bonding. The number of connecting points is higher for C1’–C4’ than for C1–C4 with the corresponding lowest intermolecular distance (Table 4 and Figure 3). Thus, it is probable that C1’–C3’ interact more strongly than C1–C3 with DNA; however, the opposite trend was evidenced for C4 and C4’, probably due to the lack of additional stabilization in C4’ caused by the presence of just one S-alkyl group. Based on the reported literature [56], the CoIII complexes under study showed docking score values comparable with the experimental capacity of other cobalt complexes in interactions with DNA. In addition, the compounds C4 and C4’ showed better interactive profiles with DNA than the two reported water-soluble CoII double-stranded helicates, [CoII2L22][CoII(NCS)4]•9H2O and [CoII2 L42]Cl2•11H2O, where L2 and L4 are also derived from pyridoxal [56].
Reactive oxygen species (ROS) are critical determinants of cellular signaling and a strict balance of ROS levels must be maintained to ensure proper cellular function and survival. Notably, ROS are increased in cancer cells, and the essential physiological role that the enzyme superoxide dismutase (SOD) plays in mitigating deleterious effects of ROS during oxidative stress caused by cancer cells has been reported on for this reason [57]. SOD has this capacity due to its redox-active metal ions in the active site (Fe-, Mn- or Cu, and Zn-SODs) which can react with superoxide ions (O2−) [58].
Thus, since the CoIII complexes showed good in silico interactive profiles with DNA, molecular docking calculations were also explored to suggest the capacity of these complexes to also interact with O2− and probably act as SOD mimetics. Table 3 summarizes the distance between O2.− and the inorganic core of C1–C4/C1’–C4’, showing a distance in the 1.70–2.50 Å range that is inside the previously reported theoretical distance correlated with in silico and biological data for SOD-mimetic compounds [27,59]. Overall, beyond the good interactive profile of DNA: C1–C4/C1’–C4’, an inorganic core based on CoIII might interact with superoxide ions, also acting as a SOD mimetic. In this case, no trend based on the structural differences in the ligand structure was identified.
The most abundant globular protein in the human bloodstream is HSA (35–50 g/L), which is responsible for the delivery of both endogenous and exogenous compounds, e.g., fatty acids, hormones, metabolites, and commercial drugs, to their target [60,61]. Thus, since C1–C4 and C1’–C4’ are potential DNA binders and SOD mimetics, it is interesting to evaluate, even only by in silico calculations, the capacity of these CoIII complexes to interact with HSA to offer preliminary insights into their pharmacokinetic profiles.
The HSA structure has three main binding sites: subdomain IIA (site I), located in a hydrophobic binding pocket, where the main fluorophore Trp-214 residue can be found; subdomain IIIA (site II), also located in a hydrophobic binding pocket; and subdomain IB (site III), located on the surface of the albumin [62]. As summarized in Table 3, site II was not identified as a feasible binding pocket for CoIII complexes; however, despite the compounds possibly interacting with sites I and III, the highest docking score values were obtained in subdomain IB, suggesting site III as the main binding pocket for the evaluated compounds. Differently to DNA binding, a trend based on the number of carbon atoms in the S-alkyl moieties was not identified for HSA; however, it was suggested that C1’–C4’ have better interactive profiles than C1–C4 with HSA. Hydrogen bonding and van der Waals interactions are the main binding forces responsible for the stability of the interactions of HSA: C1–C4/C1’–C4’ (Table 4 and Figure 3).
Comparing the obtained docking score values with those previously reported of other inorganic complexes that also bind into subdomain IB [63,64,65], it is probable that CoIII complexes might present low metabolization and high residence time in the human bloodstream (moderate binding affinity). Additionally, the evaluated compounds showed better interactive profiles with HSA than the in silico data reported on the CoII double-stranded helicates [CoII2L22][CoII(NCS)4]•9H2O and [CoII2 L42]Cl2•11H2O, where L2 and L4 are also derived from pyridoxal [56], reinforcing C1–C4 and C1’–C4’ as interesting compounds for future in vitro assays as anticancer agents.
During the pandemic scenario of coronavirus disease 2019 (COVID-19), different reports showed diverse life-threatening effects due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Like many oncogenic viruses, it has been hypothesized that SARS-CoV-2 employs various strategies to cause cancer in different organs [38,39,40]. Thus, since C1–C4 and C1’–C4’ showed in silico capacity to act as anticancer agents and SARS-CoV-2 infection might increase the probability of causing cancer, molecular docking calculations were also carried out on the spike glycoprotein of SARS-CoV-2 (wild type) with the receptor binding domain (RBD) in both up and down conformations without and in complex with the cellular receptor ACE2 to explore all feasible possibilities of interactions. This target was chosen due to the reports of other CoIII complexes in interactions with the spike glycoprotein of SARS-CoV-2 [66,67,68] and this multi-approach is important to identify the possibility of CoIII complexes to act as anticancer/antiviral metallodrugs.
The spike glycoprotein of SARS-CoV-2 contains RBD, which is a critical target for antiviral compounds due to its capacity in recognizing the cellular receptor ACE2. Fundamentally, RBD includes two structural domains: the core (highly conserved) and the external subdomains arranged into three homologous chains (A, B, and C, Figure 4). There is conformational equilibrium between the down and up conformations of RBD in the spike glycoprotein, i.e., the active conformation to interact with ACE2 is the up form [69]. Since there are not any experimental data available for CoIII complexes that identify the main mechanisms of interaction between these inorganic complexes and the spike glycoprotein, this work evaluated all the possibilities in silico. As summarized in Table 3, there is an increase in the molecular docking score values from the spike glycoprotein complexed with ACE2 to the spike glycoprotein with the three RBD in down conformations, e.g., 36.0, 37.3, and 47.8 dimensionless to C1, suggesting that all CoIII complexes might interact preferentially via a competitive mechanism. Interestingly, as depicted in Figure 4, C1–C4 or C1’–C4’ interact with the three RBD chains that are in the down conformation; however, when chain B is in the up conformation, the CoIII complexes are dislocated, indicating that chain B might be the main structural motif that interacts with the inorganic complexes under study. Additionally, the electrostatic potential map of the spike glycoprotein (Figure 4) suggests that this might occur due to the capacity of CoIII complexes to interact with positive binding pockets. Overall, all the inorganic complexes under study are potential anticancer/antiviral agents; however, C4 and C4’ are the best candidates for in vitro evaluations.

3. Materials and Methods

3.1. Materials and General Instrumentation

All reagents were of commercial grade and used as received. The synthetic procedures of the S-alkylated anilines and imine ligands have already been reported elsewhere (except for the L1C ligand, described herein) and were performed in dry methanol in an inert argon atmosphere system [23]. The complexation reactions were carried out with methanol without purification in an open atmosphere system.
Infrared spectra (FT-IR) were recorded using a Bruker Tensor 27 spectrometer (Bruker Corporation, Billerica, MA, USA) with dry KBr pellets in the 4000–400 cm−1 range with band intensities expressed as w (weak), m (medium), s (strong), and br (broad). UV-Vis absorption spectra were recorded on a Shimadzu UV-2600 spectrometer (Shimadzu Scientific Instruments, Inc., Columbia, MD, USA) using a quartz cuvette (1.0 cm) in N,N-dimethylformamide (DMF) solutions. The 1H- and 13C-nuclear magnetic resonance spectra (1H- and 13C-NMR) were recorded on a Bruker DPX-400 spectrometer (Bruker Corporation, Billerica, MA, USA). Deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3) were used as solvents, and tetramethylsilane (TMS) was used as the internal reference. The chemical shifts were expressed in δ (ppm), and the coupling constants (J) in Hz. Multiplicities were expressed as s (singlet), t (triplet), q (quartet, quintet, or sextet), m (multiplet), and br (broad).

3.2. X-ray Crystallography

Data were collected on a Bruker D8 Venture diffractometer (Bruker Corporation, Billerica, MA, USA) equipped with an Incoatec IµS high brilliance Mo-Kα X-ray tube with two-dimensional Montel micro-focusing optics and a Photon 100 detector. Measurements (C2’, C3’, C1, C3, and C4) were made at low temperature (100 K–120K) using a Cryostream 800 unit from Oxford Cryosystems (Hanborough Business Park, Long Hanborough, UK). The structures were solved by direct methods using SHELXS [70]. Fourier-difference map analyses yielded the positions of the non-hydrogen atoms. Refinements were carried out with the SHELXL package version 2018/3 [71]. All refinements were made by full-matrix least squares on F2 with anisotropic displacement parameters for all non-hydrogen atoms. Hydrogen atoms were included in the refinement in calculated positions according to the molecular skeletons. Drawings were done using the software ORTEP-3.1 for Windows [72]. Crystal data and more details of the data collection and refinements of complexes C1’–C4’ and C1–C4 are contained in Tables S1 and S2 in the Supplementary Materials, respectively.

3.3. S-Alkylated Aniline Synthesis

S-alkylated anilines were synthesized using dry methanol in an inert argon atmosphere. 2-Aminothiophenol (2.0 mmol, 0.250 g) was dissolved in 15 mL of methanol in a 50 mL round bottom flask, followed by the addition of potassium hydroxide (KOH, 2.0 mmol, 0.112 g). The resulting mixture was heated at 50 °C and kept under constant magnetic stirring for 30 min. Afterward, a methanolic solution (10 mL) containing the respective haloalkane (2.0 mmol) (iodomethane, ethyl bromide, propyl bromide, or butyl bromide) was added dropwise and the resulting reaction mixture was stirred at room temperature for 3 h. Methanol was then evaporated and the reaction was extracted with dichloromethane, which was evaporated. The resulting oil was dissolved in 10 mL of methanol and treated with concentrated hydrochloric acid (Scheme 1). The solvent was evaporated and the resulting solid was washed several times with diethyl ether and recrystallized from methanol. The compounds 2-(ethylthio)benzenamine hydrochloride, 2-(propylthio)benzenamine hydrochloride, and 2-(butylthio)benzenamine hydrochloride have been already published in our previous work [23]. The NMR, FT-IR, and UV-Vis spectra of S-alkylated anilines are presented in the Supplementary Material.
2-(Methylthio)benzenamine hydrochloride. Yield: 57%. Anal. Calcd for C7H10NSCl(%): C 47.86; H 5.74; N 7.97. Found (%): C 47.79; H 5.72; N 7.91. M.p. 160–162 °C. FT-IR (KBr pellets, cm−1): 756 [m, ν(C-S)], 2865 [s, ν(C-NH3+)], 1512 [m, ν (C-NH3+)], 1566 [m, ν(C=Car)]. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 2.47 (s, CH3, 3H), 7.30 (m, C-Har, 2H), 7.53 (m, C-Har, 2H). 13C NMR (400 MHz, DMSO-d6, δ in ppm): 17.0, 122.9, 127.2, 127.5, 130.6, 131.0, 132.9.
2-(Ethylthio)benzenamine hydrochloride. Yield: 68%. Anal. Calcd for C8H12NSCl (%): C 50.65; H 6.38; N 7.38. Found (%): C 50.66; H 6.35; N 7.34. M.p. 157–158 °C. FT-IR (KBr pellets, cm−1): 751 [m, ν(C-S)], 2846 [s, ν(C-NH3+)], 1507 [m, ν (C-NH3+)], 1558 [m, ν(C=Car)]. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.17 (t, CH3, 3H), 2.91 (q, CH2, 2H), 5.53 (br, C-NH3+, 3H), 7.21 (m, C-Har, 1H), 7.31 (m, C-Har, 1H), 7.43 (m, C-Har, 1H), 7.50 (m, C-Har, 1H). 13C NMR (400 MHz, DMSO-d6, δ in ppm): 14.0, 28.3, 121.9, 125.9, 126.9, 128.1, 133.2, 136.0.
2-(Propylthio)benzenamine hydrochloride. Yield: 83%. Anal. Calcd for C9H14NSCl (%): C 53.06; H 6.93; N 6.88. Found (%): C 53.00; H 6.92; N 6.82. M.p. 150–153 °C. FT-IR (KBr pellets, cm−1): 748 [s, ν(C-S)], 2846 [s, ν(C-NH3+)], 1473 [m, ν(C-NH3+)], 1572 [m, ν(C=Car)]. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 0.93 (t, CH3, 3H), 1.54 (sextet, CH2, 2H), 2.87 (t, CH2-S, 2H), 5.25 (br, C-NH3+), 7.18 (m, C-Har, 1H,), 7.26 (m, C-Har, 1H), 7.41 (m, C-Har, 1H), 7.49 (m, C-Har, 1H). 13C NMR (400 MHz, DMSO-d6, δ in ppm): 12.9, 22.0, 36.2, 122.0, 126.0, 127.4, 128.0, 133.0, 135.8.
2-(Butylthio)benzenamine hydrochloride. Yield: 94%. Anal. Calcd for C10H16NSCl (%): C 55.16; H 7.41; N 6.43. Found (%): C 55.15; H 7.42; N 6.42. M.p. 141–143 °C. FT-IR (KBr pellets, cm−1): 761 [m, ν(C-S)], 2854 [s, ν(C-NH3+)], 1473 [m, ν(C-NH3+)], 1557 [m, ν(C=Car)]. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 0.84 (t, CH3, 3H), 1.36 (sextet, CH2, 2H), 1.50 (quintet, CH2, 2H), 2.91 (t, CH2-S, 2H), 5.31 (br, C-NH3+, 3H), 7.23 (m, C-Har, 1H), 7.28 (m, C-Har, 1H), 7.43 (m, C-Har, 1H), 7.51 (m, C-Har, 1H). 13C NMR (400 MHz, DMSO-d6, δ in ppm): 13.4, 21.2, 30.7, 33.8, 122.4, 126.5, 128.0, 132.8, 135.1.

3.4. Synthesis of Iminic Ligands L1C–L4C

Iminic ligands were synthesized in an inert argon atmosphere using dry methanol. Methanolic solutions (10 mL each) of pyridoxal hydrochloride (1.1 mmol, 0.224 g) and the respective S-alkylated aniline (1.0 mmol) were mixed in a 50 mL round bottom flask. The resulting mixture was refluxed for 2 h under magnetic stirring. Afterward, the reaction mixture was cooled to room temperature and a methanolic solution (10 mL) of potassium hydroxide (KOH, 2.1 mmol, 0.118 g) was added; the reaction was stirred at room temperature for another 15 min (Scheme 1). The methanol was then evaporated and the product was washed several times with water and then with ethyl ether and hexane. The resulting solid was filtered, recrystallized from methanol, and dried in a desiccator with calcium chloride (CaCl2). The ligands L2C, L3C, and L4C have been already published in our previous work [23]. The NMR, FT-IR, and UV-Vis spectra of the iminic ligands L1C–L4C are provided in the Supplementary Material.
Ligand L1C: 4-(2-(methylthio)phenylimino)methyl-5-(hydroxymethyl)-2-methylpyridin-3-ol. Yield: 52%. Anal. Calcd. for C15H16N2O2S (%): C 62.48; H 5.59; N 9.71. Found (%): C 62.46; H 5.60; N 9.73. M.p. 184–185 °C. FT-IR (KBr pellets, cm−1): 755 [m, ν(C-S)], 1606 [m, ν(C=N)], 1581 [w, ν(C=Car)], 1201 [s, ν(C-O)]. 1H NMR (400 MHz, CDCl3, δ in ppm): 2.52 (s, CH3, 3H), 2.60 (s, CH3, 3H), 4.89 (s, 2H, CH2-O), 7.21–7.36 (m, C-Har, 4H), 7.98 (s, C-Har, 1H), 9.19 (s, C(imine)-H, 1H). UV–Visible (DMF, λmax in nm; εmax in M−1.cm−1): 272 (15,150). The structure of the L1C ligand can be evaluated in the Supporting Information, Figure S27 and Table S3.
Ligand L2C: 4-(2-(ethylthio)phenylimino)methyl-5- (hydroxymethyl)-2-methylpyridin-3-ol. Yield: 87%. Anal. Calcd. for C16H18N2O2S (%): C 63.55; H 6.00; N 9.26. Found (%): C 63.52; H 6.02; N 9.25. M.p. 133–134 °C. FT-IR (KBr pellets, cm−1): 750 [m, ν(C-S)], 1606 [m, ν(C=N)], 1581 [m, ν(C=Car)], 1282 [s, ν(C-O)]. 1H NMR (400 MHz, CDCl3, δ in ppm): 1.39 (t, CH3, 3H), 2.60 (s, CH3, 3H), 2.99 (q, S-CH2, 2H), 4.88 (s, CH2-O, 2H), 7.21–7.41 (m, C-Har, 4H), 7.95 (s, C-Har, 1H), 9.16 (s, C(imine)-H, 1H). UV–Visible (DMF, λmax in nm; εmax in M−1.cm−1): 276 (11,390).
Ligand L3C: 4-(2-(propylthio)phenylimino)methyl-5- (hydroxymethyl)-2-methylpyridin-3-ol. Yield: 74%. Anal. Calcd. for C17H20N2O2S (%): C 64.53; H 6.37; N 8.85. Found (%): C 64.58; H 6.44; N 8.77. M.p. 131–132 °C. FT- IR (KBr pellets, cm−1): 754 [m, ν (C-S)], 1607 [m, ν(C=N)], 1582 [w, ν(C=Car)], 1286 [m, ν(C-O)]. 1H NMR (400 MHz, CDCl3, δ in ppm): 1.09 (t, CH3, 3H), 1.78 (sextet, CH2, 2H), 2.61 (s, CH3, 3H), 2.96 (t, CH2-S, 2H), 4.88 (s, O-CH2, 2H), 7.23–7.42 (m, C-Har, 4H), 7.94 (s, C-Har, 1H), 9.19 (s, C(imine)-H, 1H). UV–Visible (DMF, λmax in nm; εmax in M−1.cm−1): 276 (13,370).
Ligand L4C: 4-(2-(butylthio)phenylimino)methyl-5- (hydroxymethyl)-2-methylpyridin-3-ol. Yield: 63%. Anal. Calcd. for C18H22N2O2S (%): C 65.42; H 6.71; N 8.48. Found (%): C 65.44; H 6.77; N 8.40. M.p. 124–125 °C. FT- IR (KBr pellets, cm−1): 754 [m, ν(C-S)], 1607 [m, ν(C=N)], 1582 [m, ν(C=Car)], 1287 [m, ν(C-O)]. 1H NMR (400 MHz, CDCl3, δ in ppm): 0.97 (t, CH3, 3H), 1.52 (sextet, CH2, 2H), 1.73 (quintet, CH2, 2H), 2.62 (s, CH3, 3H), 2.98 (t, CH2-S, 2H), 4.88 (s, O-CH2, 2H), 7.23–7.41 (m, C-Har, 4H), 7.96 (s, C-Har, 1H), 9.18 (s, C(imine)-H, 1H). UV–visible (DMF, λmax in nm; εmax in M−1.cm−1): 274 (16,770).

3.5. Synthesis of [CoIII(LnC)(L0C)] Series Complexes (C1’–C4’)

3.5.1. Conventional Method

The complexation reactions were carried out in an open atmosphere using methanol without purification. Then, 0.10 mmol of the ligand (L1C, 0.029 g; L2C, 0.030 g; L3C, 0.032 g; L4C, 0.033 g) was dissolved in 15 mL of methanol in a 50 mL round bottom flask, and triethylamine (0.10 mmol, 0.010 g, 14 µL) was added to the solution. Cobalt(II) acetate (CoII(CH3COO)2), 0.05 mmol, 0.009 g) was then added and the resulting solution was kept under magnetic stirring at 60 °C for 3 h. During this period, air was bubbled into the reaction mixture every hour using an electric pump (Scheme 2). Subsequently, the resulting solution was filtered by simple filtration using filter paper; tetrahydrofuran and acetonitrile (5 mL each) were added to the solution in the C2’ and C4’ complexes, respectively.
After slow evaporation of the solvents at room temperature, dark red single crystals suitable for X-ray diffraction were obtained. The crystals were washed with small portions of water and chloroform and then dried in a desiccator with CaCl2. The FT-IR and UV-Vis spectra of the iminic complexes C1’–C4’ are demonstrated in the Supplementary Material. Similar results were obtained in a one-pot version of these reactions (Section 3.5.2).

3.5.2. Alternative One-Pot Synthesis

In a round bottom flask containing methanol (15 mL), pyridoxal (0.10 mmol) and the corresponding amine (0.10 mmol) were added. The resulting mixture was heated to 60 °C and kept under magnetic stirring for 30 min. After this period, upon the addition of triethylamine (0.30 mmol, 0.030 g, 42 µL) an intense yellow coloration appeared, which changed to dark brown upon addition of cobalt(II) acetate (CoII(CH3COO)2, 0.05 mmol, 0.009 g). The resulting solution was kept under magnetic stirring at 60 °C for 3 h. During this period, air was bubbled into the reaction mixture every hour (during 5 min) by an electric pump. Subsequently, the resulting solution was filtered by simple filtration through filter paper. Specifically, in the C2’ and C4’ complexes, 5 mL of tetrahydrofuran and 5 mL of acetonitrile, respectively, were added to the solution. After slow evaporation of the solvents at room temperature, dark red single crystals suitable for X-ray diffraction were obtained. The crystals were washed with small portions of water and chloroform, and then dried in a desiccator with CaCl2.
Complex [CoIII(L1C)(L0C)]∙4H2O (C1’): Crystalline material yield: 25%. MP > 350 °C (decomposition). Elem. Anal. for C29H27CoN4O4S2·4H2O (690.66 g mol−1): Calc. (%): C, 50.43; H, 5.11; N, 8.11. Found (%): C, 50.33; H, 5.03; N, 8.07. FT-IR (KBr, cm−1): 3245 [br, ν(O–H)alcohol], 3002 [w, ν(C–H)aromatic], 2915 [w, ν(C–H)aliphatic], 1602 [s, ν(C=N)imine], 1573 [w, ν(C=C)aromatic], 1266 [m, ν(C-O)aromatic], and 764 [m, ν(C-S)]. UV-Vis, λmax (DMF, ε in M−1 cm−1): 272 nm (ε = 38,900).
Complex [CoIII(L2C)(L0C)]∙THF∙CH3CN (C2’): Crystalline material yield: 17%. MP ≈ 315 °C (decomposition). Elem. Anal. for C30H29CoN4O4S2·THF∙CH3CN (745.78 g mol−1): Calc. (%): C, 57.98; H, 5.41; N, 9.39. Found (%): C, 57.35; H, 5.30; N, 9.35. FT-IR (KBr, cm−1): 3185 [br, ν(O–H)alcohol], 3056 [w, ν(C–H)aromatic], 1604 [m, ν(C=N)imine], 1574 [w, ν(C=C)aromatic], 1265 [m, ν(C-O)aromatic], and 756 [m, ν(C-S)]. UV-Vis, λmax (DMF, ε in M−1 cm−1): 272 nm (ε = 43,350).
Complex [CoIII(L3C)(L0C)]∙MeOH (C3’): Crystalline material yield: 15%. MP ≈ 240 °C (decomposition). Elem. Anal. for C31H31CoN4O4S2·MeOH (678.69 g mol−1): Calc. (%): C, 56.63; H, 5.20; N, 8.25. Found (%): C, 56.69; H, 5.21; N, 8.20. FT-IR (KBr, cm−1): 3202 [br, ν(O–H)alcohol], 2960 [w, ν(C–H)aliphatic], 1604 [m, ν(C=N)imine], 1574 [w, ν(C=C)aromatic], 1267 [w, ν(C–O)aromatic], and 754 [m, ν(C-S)]. UV-Vis, λmax (DMF, ε in M−1 cm−1): 266 nm (ε = 47,540).
Complex [CoIII(L4C)(L0C)] (C4’): Crystalline material yield: 15%. MP > 350 °C. Elem. Anal. for C32H33CoN4O4S2·4H2O(660.67 g mol−1): Calc. (%): C, 58.17; H, 5.03; N, 8.48. Found (%): C, 58.16; H, 4.95; N, 8.45. FT-IR (KBr, cm−1): 3218 [br, ν(O–H)alcohol], 2955 [w, ν(C–H)aliphatic], 1604 [s, ν(C=N)imine], 1574 [w, ν(C=C)aromatic], 1267 [m, ν(C-O)aromatic], and 755 [m, ν(C-S)]. UV-Vis, λmax (DMF, ε in M−1 cm−1): 266 nm (ε = 44,120).

3.6. Synthesis of [CoIII(LnC)2]PF6 Series Complexes (C1–C4)

3.6.1. Conventional Method

The complexation reactions were conducted in an open atmosphere using methanol without purification. Then, 0.10 mmol of the ligand (L1C, 0.029 g; L2C, 0.030 g; L3C, 0.032 g; L4C, 0.033 g) was dissolved in 15 mL of methanol in a 50 mL round bottom flask, and triethylamine (0.10 mmol, 0.010 g, 14 µL) was added to the solution. The precursor complex dichlorobis(triphenylphosphane)cobalt(II) (CoIICl2(PPh3)2, 0.05 mmol, 0.033 g) and potassium(I) hexafluorophosphate (KPF6, 0.10 mmol, 0.018 g) were then added. The resulting solution was kept under magnetic stirring at 60 °C for 2 h (Scheme 2). After the reaction, the resulting solution was filtered by simple filtration using filter paper.
In the C4 complex, ethanol and acetonitrile (2 and 5 mL, respectively) were added to the solution. After slow evaporation of the solvents at room temperature, dark red single crystals suitable for X-ray diffraction were acquired. The crystals were washed with small portions of water and dichloromethane and dried in a desiccator with CaCl2. The FT-IR and UV/Vis spectra of the iminic complexes C1’–C4’ are demonstrated in the Supplementary Material. Similar results were obtained in a one-pot version of these reactions (Section 3.6.2).

3.6.2. Alternative One-Pot Synthesis

In a round bottom flask containing methanol (15 mL), pyridoxal (0.10 mmol) and the corresponding amine (0.10 mmol) were added. The resulting mixture was heated to 60 °C and kept under magnetic stirring for 30 min. After this period, triethylamine (0.30 mmol, 0.030 g, 42 µL) was added, followed by addition of the precursor complex dichlorobis(triphenylphosphane)cobalt(II) (CoIICl2(PPh3)2, 0.05 mmol, 0.033 g) and potassium(I) hexafluorophosphate (KPF6, 0.10 mmol, 0.018 g). The resulting solution was kept under magnetic stirring at 60 °C for 2 h. After the reaction, the resulting solution was filtered by simple filtration through filter paper. Specifically, in the C4 complex, 2 mL of ethanol and 5 mL of acetonitrile were added to the solution. After slow evaporation of the solvents at room temperature, dark red single crystals suitable for X-ray diffraction were obtained. The crystals were washed with small portions of water and dichloromethane, and then dried in a desiccator with calcium(II) chloride.
Complex [CoIII(L1C)2]PF6∙H2O·MeOH·2(C7H9NS) (C1): Crystalline material yield: 71%. MP > 350 °C. Elem. Anal. for C30H30CoF6N4O4PS2·H2O·MeOH·2(C7H9NS) (1107.08 g mol−1): Calc. (%): C, 48.87; H, 4.92; N, 7.59. Found (%): C, 48.88; H, 4.95; N, 7.45. FT-IR (KBr, cm−1): 2980 [w, ν(C–H)aliphatic], 1604 [m, ν(C=N)imine], 1574 [w, ν(C=C)aromatic], 1273 [m, ν(C-O)aromatic], 842 [s, ν(PF6−)], and 770 [w, ν(C-S)]. UV-Vis, λmax (DMF, ε in M−1 cm−1): 274 nm (ε = 37,910).
Complex [CoIII(L2C)2]PF6 (C2): Crystalline material yield: 78%. MP ≈ 287 °C (decomposition). Elem. Anal. for C32H34CoF6N4O4PS2 (806.65 g mol−1): Calc. (%): C, 47.65; H, 4.25; N, 6.95 Found (%): C, 47.61; H, 4.22; N, 6.95. FT-IR (KBr, cm−1): 2929 [w, ν(C–H)aliphatic], 1605 [s, ν(C=N)imine], 1573 [w, ν(C=C)aromatic], 1266 [m, ν(C-O)aromatic], 845 [s, ν(PF6−)], and 771 [m, ν(C-S)]. UV-Vis, λmax (DMF, ε in M−1 cm−1): 266 nm (ε = 37,830).
Complex [CoIII(L3C)2]PF6 (C3): Crystalline material yield: 86%. MP > 350 °C. Elem. Anal. for C34H38CoF6N4O4PS2 (834.70 g mol−1): Calc. (%): C, 48.92; H, 4.59; N, 6.71 Found (%): C, 48.89.; H, 4.05; N, 6.66. FT-IR (KBr, cm−1): 2965 [w, ν(C–H)aliphatic], 1605 [s, ν(C=N)imine], 1574 [w, ν(C=C)aromatic], 1266 [m, ν(C-O)aromatic], 840 [s, ν(PF6−)], and 771 [w, ν(C-S)]. UV-Vis, λmax (DMF, ε in M−1 cm−1): 274 nm (ε = 35,560).
Complex [CoIII(L4C)2]PF6∙EtOH∙CH3CN (C4): Crystalline material yield: 90%. MP ≈ 250 °C (decomposition). Elem. Anal. for C38H43CoF6N4O4PS2·CH3CN·EtOH (948.87 g mol−1): Calc. (%): C, 50.58; H, 5.41; N, 7.37 Found (%): C, 50.59; H, 5.40; N, 7.39. FT-IR (KBr, cm−1): 2960 [w, ν(C–H)aliphatic], 1604 [s, ν(C=N)imine], 1574 [m, ν(C=C)aromatic], 1267 [m, ν(C-O)aromatic], 841 [s, ν(PF6−)], and 770 [w, ν(C-S)]. UV-Vis, λmax (DMF, ε in M−1 cm−1): 276 nm (ε = 43,850).

3.7. In Silico Calculations

The crystallographic structure of DNA and HSA were obtained from Protein Data Bank (PDB) with access codes 1BNA and 1N5U, respectively [73,74]. The three-dimensional structural spike glycoprotein of SARS-CoV-2 (wild type) with the three RBD in down conformation, one in up conformation, and in complex with the cellular ACE2 were also obtained from the PDB with the access codes 6VXX, 6VYB, and 7KJ2, respectively. The chemical structure of C1’–C4’ and C1–C4 were obtained from the experimental X-ray data, while the superoxide ions (O2−) were built and energy minimized with the Density Functional Theory (DFT) method with Becke-3-Lee Yang Parr (B3LYP) and standard 6–31G* basis set, available in the Spartan’18 software (Wavefunction, Inc., Irvine, CA, USA).
The molecular docking calculations were performed with GOLD 2020.2 software (Cambridge Crystallographic Data Center Software Ltd., Cambridge, UK). Hydrogen atoms were added to the biomacromolecules following tautomeric states and ionization data inferred by the software. The DNA structure has two possible binding sites (major and minor groove), which were explored in the docking calculation (8.0 Å spherical cavity around each region) [56,75]. On the other hand, the HSA structure presents three main binding pockets, which were also explored by in silico calculations (8.0 Å spherical cavity around subdomains IIA, IIIA, and IB) [76], while for the superoxide dismutase mimetic activity (complexes C1’–C4’ and C1–C4), a 5.0 Å spherical cavity around CoIII was defined, and for RBD of SARS-CoV-2 a 10 Å spherical cavity was delimitated around the three domains. The number of genetic operations (crossing, migration, and mutation) during the search procedure was set as 100,000. For the scoring function, ChemPLP was used, which is a default function of the GOLD 2020.2 software. The figures of the docking poses for the largest docking score values were generated with the PyMOL Delano Scientific LLC software (DeLano Scientific LLC: San Carlos, CA, USA).

4. Conclusions

Derivatizations of the thiol functions of 2-aminothiophenol through alkylation reactions using different haloalkanes (iodomethane, bromoethane, 1-bromopropane, and 1-bromobutane) in an alkaline medium were done to obtain S-alkylated anilines with the thioether function bonded to aliphatic chains with one to four carbons. Afterward, these compounds had their amine functions condensed with pyridoxal hydrochloride to obtain four iminic organic ligands (L1C–L4C). The ligands L1C–L4C showed tridentate chelating behavior due to the presence of phenolate oxygen (after deprotonation), imine nitrogen, and thioether sulfur atoms that acted as donor atoms. Thus, when reacting such ligands with cobalt cations in a 2:1 ratio (ligand/cobalt), octahedral complexes were formed by the coordination of two units of the tridentate ligands to the CoIII metallic center.
By using CoII acetate, the formation of a series [CoIII(LnC)(L0C)] (n = 1–4, C1’–C4’) was observed, with the coordination of a ligand unit presenting scission of the C-S bond and, consequently, a thiolate function (L0C) resulting in neutral CoIII complexes. Nevertheless, when the reaction was carried out using the CoCl2(PPh3)2 complex and adding KPF6, no scission of the C-S bonds occurred, forming a series [CoIII(LnC)2]PF6 (n = 1–4, C1–C4) composed of ionic CoIII complexes in the form of a KPF6 salt. Overall, this exciting method allows the synthesis of CoIII complexes without cleavage of the C-S bonds from the ligands, thereby not requiring an inert atmosphere in the reaction systems. Given our findings, it is highly suggested to extend this study to iminic ligands derived from 2-aminothiophenol derivatized with branched aliphatic chains, including tert-butyl, to observe the possible occurrence of C-S cleavage in these derivatives and evaluate the effectiveness of using CoCl2(PPh3)2 to avoid this possible cleavage behavior in these cases.
The best docking score values for DNA were obtained into the minor groove, suggesting that CoIII complexes can interact with DNA not via intercalative behavior. Unexpectedly, the increase in carbon in the S-alkyl portions of the CoIII complexes improved their DNA interaction profile (C4 and C4’). However, based on the literature, the CoIII complexes under study showed docking score values comparable with the experimental capacity of other cobalt complexes to interact with DNA. Additionally, there was a good correlation between the binding capacity of the inorganic complexes with DNA and their SOD-mimetic capability (interaction with O2.−). Finally, all CoIII complexes might be biodistributed in the human bloodstream by has, and mainly C4 and C4’ showed a feasible trend of interaction with the spike glycoprotein of SARS-CoV-2 with RBD in a down conformation, suggesting the possibility of CoIII complexes to act as anticancer/antiviral metallodrugs.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/inorganics12060171/s1, Table S1. Crystal data and data collection and refinements of complexes C1’–C4’; Table S2. Crystal data and data collection and refinements of complexes C1–C4; Figure S1. 1H NMR spectra of the 2-(Methylthio)aniline hydrochloride (DMSO-d6, 400 MHz, 25 °C). Figure S2. 13C NMR spectra of the 2-(Methylthio)aniline hydrochloride (DMSO-d6, 100 MHz, 25 °C). Figure S3. 1H NMR spectra of the 2-(Ethylthio)benzenamine hydrochloride (DMSO-d6, 400 MHz, 25 °C). Figure S4. 13C NMR spectra of the 2-(Ethylthio)benzenamine hydrochloride (DMSO-d6, 100 MHz, 25 °C). Figure S5. 1H NMR spectra of the 2-(Propylthio)benzenamine hydrochloride (DMSO-d6, 400 MHz, 25 °C). Figure S6. 13C NMR spectra of the 2-(Propylthio)benzenamine hydrochloride (DMSO-d6, 100 MHz, 25 °C). Figure S7. 1H NMR spectra of the 2-(Butylthio)benzenamine hydrochloride (DMSO-d6, 400 MHz, 25 °C). Figure S8. 13C NMR spectra of the 2-(Butylthio)benzenamine hydrochloride (DMSO-d6, 100 MHz, 25 °C). Figure S9. 1H NMR spectra of the ligand L1C (CDCl3, 400 MHz, 25 °C). Impurities: 5.30 (dichloromethane); 3.46 (methanol) and 1.61 (residual water). Figure S10. 1H NMR spectra of the ligand L2C (CDCl3, 400 MHz, 25 °C). Impurities: 5.30 (dichloromethane) and 1.64 (residual water). Figure S11. 1H NMR spectra of the ligand L3C (CDCl3, 400 MHz, 25 °C). Figure S12. 1H NMR spectra of the ligand L4C (CDCl3, 400 MHz, 25 °C). Figure S13. Steady state UV-Vis spectra of ligand L1C, complex C1’ and complex C1 (Experimental conditions: DMF, room temperature, 10−5 M range). Figure S14. Steady state UV-Vis spectra of ligand L2C, complex C2’ and complex C2 (Experimental conditions: DMF, room temperature, 10−5 M range). Figure S15. Steady state UV-Vis spectra of ligand L3C, complex C3’ and complex C3 (Experimental conditions: DMF, room temperature, 10−5 M range). Figure S16. Steady state UV-Vis spectra of ligand L4C, complex C4’ and complex C4 (Experimental conditions: DMF, room temperature, 10−5 M range). Figure S17. Infrared spectra (FTIR) of the S-alkylated aniline 2-(methylthio)aniline hydrochloride. Figure S18. Infrared spectra (FTIR) of the ligand L1C. Figure S19. Infrared spectra (FTIR) of the complex C1’. Figure S20. Infrared spectra (FTIR) of the complex C2’. Figure S21. Infrared spectra (FTIR) of the complex C3’. Figure S22. Infrared spectra (FTIR) of the complex C4’. Figure S23. Infrared spectra (FTIR) of the complex C1. Figure S24. Infrared spectra (FTIR) of the complex C2. Figure S25. Infrared spectra (FTIR) of the complex C3. Figure S26. Infrared spectra (FTIR) of the complex C4. Figure S27. ORTEP-3.1 projection of the molecular structures of the ligand L1C in the solid state. Ellipsoids were calculated at 50% probability. Table S3. Crystal data and data collection and refinements of ligand L1C. Supplementary data: CCDC 2245356–2245359, 2245360–2245362, 2245364, and 2245365 contain the supplementary crystallographic data for complexes C1’–C4’, C1–C3, C4 and, LC1 respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, accessed on 6 June 2024, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223–336–033; or e–mail: [email protected].

Author Contributions

Conceptualization, O.A.C. and D.F.B.; methodology, L.A.F., F.M.M., J.D.S., O.A.C. and D.F.B.; software, O.A.C. and C.S.; validation, O.A.C. and D.F.B.; formal analysis, L.A.F., F.M.M., J.D.S., O.A.C. and D.F.B.; investigation, L.A.F., F.M.M., J.D.S., O.A.C. and D.F.B.; resources, D.F.B.; data curation, O.A.C. and D.F.B.; writing—original draft preparation, D.F.B.; writing—review and editing, C.S., O.A.C. and D.F.B.; visualization, D.F.B.; supervision, D.F.B.; project administration, D.F.B.; funding acquisition, D.F.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Brazilian Research Councils, Conselho Nacional do Desenvolvimento Científico e Tecnológico (CNPq, Edital PQ 06/2019 and 309482/2019-4) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-PROEX, 001). This research was also funded by the Portuguese Agency for Scientific Research, Fundação para a Ciência e a Tecnologia (FCT), through the projects UIDB/00313/2020 (https://doi.org/10.54499/UIDB/00313/2020, accessed on 15 February 2024) and UIDP/00313/2020 (https://doi.org/10.54499/UIDP/00313/2020, accessed on 15 February 2024).

Data Availability Statement

Data are contained within the article.

Acknowledgments

The authors acknowledge Atlas Assessoria Linguística (Santa Maria, RS, Brazil) for the language editing. O.A.C. also thanks FCT for his PhD fellowship 2020.07504.BD (https://doi.org/10.54499/2020.07504.BD, accessed on 15 February 2024).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Biswas, S.; Kumar Manna, C.; Naskar, R.; Das, A.; Mondal, T.K. Synthesis of new rhodium(III) complex by benzylic CS bond cleavage of thioether containing NNS donor Schiff base ligand: Investigation of catalytic activity towards transfer hydrogenation of ketones. Inorg. Chim. Acta 2021, 515, 120096. [Google Scholar] [CrossRef]
  2. Wang, L.; He, W.; Yu, Z. Transition-metal mediated carbon–sulfur bond activation and transformations. Chem. Soc. Rev. 2013, 42, 599–621. [Google Scholar] [CrossRef] [PubMed]
  3. Lou, J.; Wang, Q.; Wu, P.; Wang, H.; Zhou, Y.-G.; Yu, Z. Transition-metal mediated carbon–sulfur bond activation and transformations: An update. Chem. Soc. Rev. 2020, 49, 4307–4359. [Google Scholar] [CrossRef] [PubMed]
  4. Bag, J.; Barman, S.; Maiti, B.K.; Pal, K. M(II) (M=Cu, Ni) Assisted C−S bond cleavage and oxidative dehydrogenation of amine on non-innocent salen type ligand platforms by varying nitrogen vs. sulfur coordination atoms. Eur. J. Inorg. Chem. 2022, 11, e202101107. [Google Scholar] [CrossRef]
  5. Wongnate, T.; Ragsdale, S.W. The reaction mechanism of methyl-coenzyme M reductase. J. Biol. Chem. 2015, 290, 9322–9334. [Google Scholar] [CrossRef] [PubMed]
  6. Pattanayak, P.; Patra, D.; Brandão, P.; Mal, D.; Felix, V. Synthesis and characterization of palladium(II) complex of Schiff base ligand: CS bond cleavage and catalytic activity. Inorg. Chem. Commun. 2015, 53, 68–71. [Google Scholar] [CrossRef]
  7. Biswas, S.; Roy, P.; Mondal, T.K. Synthesis of palladium(II) complex with NNS donor Schiff base ligand via C S bond cleavage: X-ray structure, electrochemistry and DFT computation. J. Mol. Struct. 2017, 1142, 110–115. [Google Scholar] [CrossRef]
  8. Elsby, M.R.; Ghostine, K.; Das, U.K.; Gabidullin, B.M.; Baker, R.T. Iron-SNS and -CNS complexes: Selective caryl–S bond cleavage and amine-borane dehydrogenation catalysis. Organometallics 2019, 38, 3844–3851. [Google Scholar] [CrossRef]
  9. Roy, P.; Manna, C.K.; Naskar, R.; Mondal, T.K. Synthesis of a rhodium(III) triphenylphosphine complex via C S bond cleavage of an azo-thioether ligand: X-ray structure, electrochemistry and catalysis towards transfer hydrogenation of ketones. Polyhedron 2019, 158, 208–214. [Google Scholar] [CrossRef]
  10. Majouga, A.G.; Beloglazkina, E.K.; Moiseeva, A.A.; Shilova, O.V.; Manzheliy, E.A.; Lebedeva, M.A.; Davies, E.S.; Khlobystov, A.N.; Zyk, N.V. Cleavage of the C–S bond with the formation of a binuclear copper complex with 2-thiolato-3-phenyl-5-(pyridine-2-ylmethylene)-3,5-dihydro-4H-imidazole-4-one. A new mimic of the active site of N2O reductase. Dalton Trans. 2013, 42, 6290. [Google Scholar] [CrossRef]
  11. Chakraborty, P.; Chandra, S.K.; Chakravorty, A. Ring-size specific transformations of cobalt(III)-thioether chelates activated by base. Co-C formation or C-S cleavage? Organometallics 1993, 12, 4726–4727. [Google Scholar] [CrossRef]
  12. Chakraborty, P.; Karmakar, S.; Chandra, S.K.; Chakravorty, A. New cobalt complexes incorporating thioether chelation and base-induced homolog-selective transformations thereof. Inorg. Chem. 1994, 33, 816–822. [Google Scholar] [CrossRef]
  13. Rajsekhar, G.; Rao, C.P.; Saarenketo, P.K.; Kolehmainen, E.; Rissanen, K. C–S bond cleavage by cobalt: Synthesis, characterization and crystal structure determination of 1,2-di-(o-salicylaldiminophenylthio)ethane and its Co(III) product with C–S bond cleaved fragments. Inorg. Chem. Commun. 2002, 5, 649–652. [Google Scholar] [CrossRef]
  14. Rajsekhar, G.; Rao, C.P.; Saarenketo, P.; Nättinen, K.; Rissanen, K. Complexation behaviour of hexadentate ligands possessing N2O4 and N2O2S2 cores: Differential reactivity towards Co(II), Ni(II) and Zn(II) salts and structures of the products. New J. Chem. 2004, 28, 75–84. [Google Scholar] [CrossRef]
  15. Singh, A.K.; Mukherjee, R. Cobalt(II) and cobalt(III) complexes of thioether-containing hexadentate pyrazine amide ligands: C–S bond cleavage and cyclometallation reaction. Dalton Trans. 2008, 14, 260–270. [Google Scholar] [CrossRef] [PubMed]
  16. Cleave, C.V.; Crans, D.C. The first-row transition metals in the periodic table of medicine. Inorganics 2019, 7, 111. [Google Scholar] [CrossRef]
  17. Osman, D.; Cooke, A.; Young, T.R.; Deery, E.; Robinson, N.J.; Warren, M.J. The requirement for cobalt in vitamin B12: A paradigm for protein metalation. Biochim. Biophys. Acta Mol. Cell Res. 2021, 1868, 118896. [Google Scholar] [CrossRef] [PubMed]
  18. Ge, Y.; Zadeh, M.; Mohamadzadeh, M. Vitamin B12 regulates the transcriptional, metabolic, and epigenetic programing in human ileal epithelial cells. Nutrients 2022, 14, 2825. [Google Scholar] [CrossRef] [PubMed]
  19. Froese, D.S.; Fowler, B.; Baumgartner, M.R. Vitamin B12, folate, and the methionine remethylation cycle—Biochemistry, pathways, and regulation. J. Inherit. Metab. Dis. 2019, 42, 673–685. [Google Scholar] [CrossRef]
  20. Renfrew, A.K.; O’Neill, E.S.; Hambley, T.W.; New, E.J. Harnessing the properties of cobalt coordination complexes for biological application. Coord. Chem. Rev. 2018, 375, 221–233. [Google Scholar] [CrossRef]
  21. Acharyya, K.; Mukherjee, P.S. Organic imine cages: Molecular marriage and applications. Angew. Chem. Int. Ed. 2019, 58, 8640–8653. [Google Scholar] [CrossRef]
  22. Basak, D.; van Leusen, J.; Gupta, T.; Kögerler, P.; Bertolasi, V.; Ray, D. Unusually distorted pseudo-octahedral coordination environment around CoII from thioether Schiff base ligands in dinuclear [CoLn] (Ln = La, Gd, Tb, Dy, Ho) complexes: Synthesis, structure, and understanding of magnetic behavior. Inorg. Chem. 2020, 59, 2387–2405. [Google Scholar] [CrossRef]
  23. Fontana, L.A.; Stüker, M.; Oliveira, G.M.; Iglesias, B.A.; Back, D.F. Pro-oxidant activity of nickel (II) pyridoxal complexes. Synthesis, characterization and peroxidase activity assays. Inorg. Chem. Commun. 2015, 62, 55–59. [Google Scholar] [CrossRef]
  24. Rocha, J.F.; Pina, A.F.; Sousa, S.F.; Cerqueira, N.M.F.S.A. PLP-dependent enzymes as important biocatalysts for the pharmaceutical, chemical and food industries: A structural and mechanistic perspective. Catal. Sci. Technol. 2019, 9, 4864–4876. [Google Scholar] [CrossRef]
  25. Casas, J.S.; Couce, M.D.; Sordo, J. Coordination chemistry of vitamin B6 and derivatives: A structural overview. Coord. Chem. Rev. 2012, 256, 3036–3062. [Google Scholar] [CrossRef]
  26. Naskar, S.; Naskar, S.; Butcher, R.J.; Chattopadhyay, S.K. Synthesis, X-ray crystal structures and spectroscopic properties of two Ni(II) complexes of pyridoxal Schiff’s bases with diamines: Importance of steric factor in stabilization of water helices in the lattices of metal complex. Inorg. Chim. Acta 2010, 363, 404–411. [Google Scholar] [CrossRef]
  27. Siqueira, J.D.; de Pellegrin, S.F.; dos Santos, S.S.; Iglesias, B.A.; Piquini, P.C.; Arantes, L.P.; Soares, F.A.; Chaves, O.A.; Neves, A.; Back, D.F. SOD activity of new copper II complexes with ligands derived from pyridoxal and toxicity in Caenorhabditis elegans. J. Inorg. Biochem. 2020, 204, 110950. [Google Scholar] [CrossRef]
  28. Anthony, E.J.; Bolitho, E.M.; Bridgewater, H.E.; Carter, O.W.L.; Donnelly, J.M.; Imberti, C.; Lant, E.C.; Lermyte, F.; Needham, R.J.; Palau, M.; et al. Metallodrugs are unique: Opportunities and challenges of discovery and development. Chem. Sci. 2020, 11, 12888–12917. [Google Scholar] [CrossRef]
  29. Kabir, E.; Noyan, M.R.O.K.; Hossain, M.A. Synthesis, biological and medicinal impacts of metallodrugs: A study. Res. Chem. 2023, 5, 100935. [Google Scholar] [CrossRef]
  30. Szefler, B.; Czeleń, P. Will the Interactions of Some Platinum (II)-Based Drugs with B-Vitamins Reduce Their Therapeutic Effect in Cancer Patients? Comparison of Chemotherapeutic Agents such as Cisplatin, Carboplatin and Oxaliplatin—A Review. Int. J. Mol. Sci. 2023, 24, 1548. [Google Scholar] [CrossRef]
  31. Zhang, C.; Xu, C.; Gao, X.; Yao, Q. Platinum-based drugs for cancer therapy and anti-tumor strategies. Theranostics 2022, 12, 2115–2132. [Google Scholar] [CrossRef]
  32. Komlyagina, V.I.; Romashev, N.F.; Besprozvannykh, V.K.; Arakelyan, J.; Wu, C.; Chubarov, A.S.; Bakaev, I.V.; Soh, Y.K.; Abramov, P.A.; Cheung, K.L.; et al. Effects of bis(imino)acenaphthene (bian)-derived ligands on the cytotoxicity, DNA interactions, and redox activity of palladium(II) bipyridine complexes. Inorg. Chem. 2023, 62, 11541–11553. [Google Scholar] [CrossRef]
  33. Bian, M.; Fan, R.; Yang, Z.; Chen, Y.; Xu, Z.; Lu, Y.; Liu, W. Pt(II)-NHC complex induces ROS-ERS-related DAMP balance to harness immunogenic cell death in hepatocellular carcinoma. J. Med. Chem. 2022, 65, 1848–1866. [Google Scholar] [CrossRef]
  34. Phan, T.T.V.; Huynh, T.-C.; Manivasagan, P.; Mondal, S.; Oh, J. An up-to-date review on biomedical applications of palladium nanoparticles. Nanomaterials 2020, 10, 66. [Google Scholar] [CrossRef]
  35. Mirzaei, S.; Hushmandi, K.; Zabolian, A.; Saleki, H.; Torabi, S.M.R.; Ranjbar, A.; SeyedSaleh, S.; Sharifzadeh, S.O.; Khan, H.; Ashrafizadeh, M.; et al. Elucidating role of reactive oxygen species (ROS) in cisplatin chemotherapy: A focus on molecular pathways and possible therapeutic strategies. Molecules 2021, 26, 2382. [Google Scholar] [CrossRef]
  36. Perillo, B.; Di Donato, M.; Pezone, A.; Di Zazzo, E.; Giovannelli, P.; Galasso, G.; Castoria, G.; Migliaccio, A. ROS in cancer therapy: The bright side of the moon. Exp. Mol. Med. 2020, 52, 192–203. [Google Scholar] [CrossRef]
  37. Carneiro, T.J.; Martins, A.S.; Marques, M.P.M.; Gil, A.M. Metabolic aspects of palladium(II) potential anti-cancer drugs. Front. Oncol. 2020, 12, 590970. [Google Scholar] [CrossRef]
  38. Jahankhani, K.; Ahangari, F.; Adcock, I.M.; Mortaz, E. Possible cancer-causing capacity of COVID-19: Is SARS-CoV-2 an oncogenic agent? Biochimie 2023, 213, 130–138. [Google Scholar] [CrossRef]
  39. Li, J.; Bai, H.; Qiao, H.; Du, C.; Yao, P.; Zhang, Y.; Cai, Y.; Jia, Y.; Wei, X.; Li, C.; et al. Causal effects of COVID-19 on cancer risk: A Mendelian randomization study. J. Med. Virol. 2023, 95, e28722. [Google Scholar] [CrossRef]
  40. Ghosh, M.K.; Kumar, S.; Ganguly, K.K.; Ghosh, P.; Tabassum, S.; Basu, B.; Basu, M. COVID-19 and cancer: Insights into their association and influence on genetic and epigenetic landscape. Epigenomics 2023, 15, 227–248. [Google Scholar] [CrossRef]
  41. Casini, A.; Pothig, A. Metals in cancer research: Beyond platinum metallodrugs. ACS Cent. Sci. 2024, 10, 242–250. [Google Scholar] [CrossRef] [PubMed]
  42. Yousuf, I.; Bashir, M.; Arjmand, F.; Tabassum, S. Advancement of metal compounds as therapeutic and diagnostic metallodrugs: Current frontiers and future perspectives. Coord. Chem. Rev. 2021, 445, 214104. [Google Scholar] [CrossRef]
  43. Kar, K.; Ghosh, D.; Kabi, B.; Chandra, A. A concise review on cobalt Schiff base complexes as anticancer agents. Polyhedron 2022, 222, 115890. [Google Scholar] [CrossRef]
  44. Smilowicz, D.; Metzler-Nolte, N. Bioconjugates of Co(III) complexes with Schiff base ligands and cell penetrating peptides: Solid phase synthesis, characterization and antiproliferative activity. J. Inorg. Biochem. 2020, 206, 111041. [Google Scholar] [CrossRef] [PubMed]
  45. Kaushik, S.; Paliwal, S.K.; Iyer, M.R.; Patil, V.M. Promising Schiff bases in antiviral drug design and discovery. Med. Chem. Res. 2023, 32, 1063–1076. [Google Scholar] [CrossRef] [PubMed]
  46. Chang, E.L.; Simmers, C.; Knight, D.A. Cobalt complexes as antiviral and antibacterial agents. Pharmaceuticals 2010, 3, 1711–1728. [Google Scholar] [CrossRef] [PubMed]
  47. Costanzo, M.; de Giglio, M.A.R.; Roviello, G.N. Deciphering the relationship between SARS-CoV-2 and cancer. Int. J. Mol. Sci. 2023, 24, 7803. [Google Scholar] [CrossRef] [PubMed]
  48. Tyler, L.A.; Olmstead, M.M.; Mascharak, P.K. Conversion of azomethine moiety to carboxamido group at cobalt(III) center in model complexes of Co-containing nitrile hydratase. Inorg. Chem. 2001, 40, 5408–5414. [Google Scholar] [CrossRef] [PubMed]
  49. Yang, F.; Zhou, Q.; Zhang, Y.; Zeng, G.; Li, G.; Shi, Z.; Wang, B.; Feng, S. Inspiration from old molecules: Field-induced slow magnetic relaxation in three air-stable tetrahedral cobalt(ii) compounds. Chem. Commun. 2013, 49, 5289. [Google Scholar] [CrossRef]
  50. Pattanayak, P.; Pratihar, J.L.; Patra, D.; Lin, C.-H.; Paul, S.; Chakraborty, K. Synthesis, characterization, structure, redox property, antibacterial and catalytic activity of tridentate Schiff base cobalt(III), nickel(II) and palladium(II) complexes. Polyhedron 2013, 51, 275–282. [Google Scholar] [CrossRef]
  51. Chaves, O.A.; Rodrigues-Santos, C.E.; Echevarria, Á.; Sacramento, C.Q.; Fintelman-Rodrigues, N.; Temerozo, J.R.; Castro-Faria-Neto, H.C.; E Souza, T.M.L. Fluorine atoms on C6H5-corrole affect the interaction with Mpro and PLpro proteases of SARS-CoV-2: Molecular docking and 2D-QSAR approaches. Int. J. Mol. Sci. 2022, 23, 10936. [Google Scholar] [CrossRef]
  52. Enyedy, I.J.; Egan, W.J. Can we use docking and scoring for hit-to-lead optimization? J. Comput. Aided Mol. Des. 2008, 22, 161–168. [Google Scholar] [CrossRef]
  53. Basourakos, S.P.; Li, L.; Aparicio, A.M.; Corn, P.G.; Kim, J.; Thompson, T.C. Combination platinum-based and DNA damage response-targeting cancer therapy: Evolution and future directions. Curr. Med. Chem. 2017, 24, 1586–1606. [Google Scholar] [CrossRef]
  54. Brulikova, J.; Hlavac, J.; Hradil, P. DNA interstrand cross-linking agents and their chemotherapeutic potential. Curr. Med. Chem. 2012, 19, 364–385. [Google Scholar] [CrossRef]
  55. Martin, L.P.; Hamilton, T.C.; Schilder, R.J. Platinum resistance: The role of DNA repair pathways. Clin. Cancer Res. 2008, 14, 1291–1295. [Google Scholar] [CrossRef]
  56. Martins, F.M.; Siqueira, J.D.; Iglesias, B.A.; Chaves, O.A.; Back, D.F. Pyridoxal water-soluble cobalt(II) helicates: Synthesis, structural analysis, and interactions with biomacromolecules. J. Inorg. Biochem. 2022, 233, 111854. [Google Scholar] [CrossRef]
  57. Griess, B.; Tom, E.; Domann, F.; Teoh-Fitzgerald, M. Extracellular superoxide dismutase and its role in cancer. Free Rad. Biol. Med. 2017, 112, 464–479. [Google Scholar] [CrossRef]
  58. Sheng, Y.; Abreu, I.A.; Cabell, D.E.; Maroney, M.J.; Miller, A.-F.; Teixeira, M.; Valentine, J.S. Superoxide dismutases and superoxide reductases. Chem. Rev. 2014, 114, 3854–3918. [Google Scholar] [CrossRef]
  59. Siqueira, J.D.; de Pellegrin, S.F.; Fontana, L.A.; Iglesias, B.A.; Sagrillo, M.R.; Oliveira, P.S.; Rossato, A.; da Silva Silveira, L.; Neves, A.; Chaves, O.A.; et al. Copper (II) complexes derived from pyridoxal: Structural correlations, cytotoxic activities, and molecular docking. Inorg. Chim. Acta 2021, 526, 120530. [Google Scholar] [CrossRef]
  60. Chaves, O.A.; Iglesias, B.A.; Serpa, C. Biophysical characterization of the interaction between a transport human plasma protein and the 5,10,15,20-tetra(pyridine-4-yl)porphyrin. Molecules 2022, 27, 5341. [Google Scholar] [CrossRef]
  61. Naveenraj, S.; Anandan, S. Binding of serum albumins with bioactive substances–Nanoparticles to drugs. J. Photochem. Photobiol. C 2013, 14, 53–71. [Google Scholar] [CrossRef]
  62. Chaves, O.A.; Acunha, T.V.; Iglesias, B.A.; Jesus, C.S.H.; Serpa, C. Effect of peripheral platinum(II) bipyridyl complexes on the interaction of tetra-cationic porphyrins with human serum albumin. J. Mol. Liq. 2020, 301, 112466. [Google Scholar] [CrossRef]
  63. Da Silveira, C.H.; Chaves, O.A.; Marques, A.C.; Rosa, N.M.P.; Costa, L.A.S.; Iglesias, B.A. Synthesis, photophysics, computational approaches, and biomolecule interactive studies of metalloporphyrins containing pyrenyl units: Influence of the metal center. Eur. J. Inorg. Chem. 2022, 12, e202200075. [Google Scholar] [CrossRef]
  64. Sarmento, C.O.; Pinheiro, B.F.A.; Abrahão, J.; Chaves, O.A.; Moreira, M.B.; Nikolaou, S. Interactions of a ruthenium-ketoprofen compound with human serum albumin and DNA: Insights from spectrophotometric titrations and molecular docking calculations. ChemistrySelect 2022, 7, e202104020. [Google Scholar] [CrossRef]
  65. Tisoco, I.; Donatoni, M.C.; Victória, H.F.V.; de Toledo, J.R.; Krambrock, K.; Chaves, O.A.; de Oliveira, K.T.; Iglesias, B.A. Photophysical, photooxidation, and biomolecule-interaction of meso-tetra(thienyl)porphyrins containing peripheral Pt(II) and Pd(II) complexes. Insights for photodynamic therapy applications. Dalton Trans. 2022, 51, 1646–1657. [Google Scholar] [CrossRef] [PubMed]
  66. Parvarinezhad, S.; Salehi, M.; Kubicki, M.; Malekshah, R.E. Experimental and theoretical studies of new Co(III) complexes of hydrazide derivatives proposed as multi-target inhibitors of SARS-CoV-2. Appl. Organomet. Chem. 2022, 36, e6836. [Google Scholar] [CrossRef] [PubMed]
  67. Ioannou, K.; Vlasiou, M.C. Metal-based complexes against SARS-CoV-2. Biometals 2022, 35, 639–652. [Google Scholar] [CrossRef] [PubMed]
  68. El-Lateef, H.M.A.; El-Dabea, T.; Khalaf, M.M.; Abu-Dief, A.M. Development of metal complexes for treatment of coronaviruses. Int. J. Mol. Sci. 2022, 23, 6418. [Google Scholar] [CrossRef] [PubMed]
  69. Yan, R.; Zhang, Y.; Li, Y.; Ye, F.; Guo, Y.; Xia, L.; Zhong, X.; Chi, X.; Zhou, Q. Structural basis for the different states of the spike protein of SARS-CoV-2 in complex with ACE2. Cell Res. 2021, 31, 717–719. [Google Scholar] [CrossRef]
  70. Sheldrick, G.M. A short history of SHELX. Acta Cryst. 2008, 64, 112–122. [Google Scholar] [CrossRef]
  71. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Cryst. 2015, 71, 3–8. [Google Scholar]
  72. Farrugia, L.J. ORTEP-3 for Windows—A version of ORTEP-III with a Graphical User Interface (GUI). J. Appl. Cryst. 1997, 30, 565. [Google Scholar] [CrossRef]
  73. Drew, H.R.; Wing, R.M.; Takano, T.; Broka, C.; Tanaka, S.; Itakura, K.; Dickerson, R.E. Structure of a B-DNA dodecamer: Conformation and dynamics. Proc. Natl. Acad. Sci. USA 1981, 78, 2179–2183. [Google Scholar] [CrossRef] [PubMed]
  74. Wardell, M.; Wang, Z.; Ho, J.X.; Robert, J.; Ruker, F.; Ruble, J.; Carter, D.C. The atomic structure of human methemalbumin at 1.9 Å. Biochem. Biophys. Res. Commun. 2002, 291, 813–819. [Google Scholar] [CrossRef] [PubMed]
  75. Siqueira, J.D.; de Pellegrin, S.F.; Fioravanço, L.P.; Fontana, L.A.; Iglesias, B.A.; Chaves, O.A.; Back, D.F. Self-association synthesis with ortho-vanillin to promote mono- and heptanuclear complexes and their evaluation as antioxidant agents. J. Mol. Struct. 2022, 1256, 132480. [Google Scholar] [CrossRef]
  76. Soares, M.A.G.; de Aquino, P.A.; Costa, T.; Serpa, C.; Chaves, O.A. Insights into the effect of glucose on the binding between human serum albumin and the nonsteroidal anti-inflammatory drug nimesulide. Int. J. Biol. Macromol. 2024, 265, 131148. [Google Scholar] [CrossRef]
Inorganics 12 00171 sch001
Scheme 1. General representation for the synthesis of S-alkylated anilines and L1C–L4C ligands.
Scheme 1. General representation for the synthesis of S-alkylated anilines and L1C–L4C ligands.
Inorganics 12 00171 sch001
Inorganics 12 00171 sch002
Scheme 2. Synthesis of cobalt complexes of the series [CoIII(LnC)(L0C)] (n = 1–4, C1’–C4’) and [CoIII(LnC)2]PF6 (n = 1–4, C1–C4) from L1C–L4C ligands according to the reagents used. For better interpretation the crystallization solvates were not shown.
Scheme 2. Synthesis of cobalt complexes of the series [CoIII(LnC)(L0C)] (n = 1–4, C1’–C4’) and [CoIII(LnC)2]PF6 (n = 1–4, C1–C4) from L1C–L4C ligands according to the reagents used. For better interpretation the crystallization solvates were not shown.
Inorganics 12 00171 sch002
Inorganics 12 00171 g001
Figure 1. ORTEP-3.1 projection of the molecular structures of the [CoIII(LnC)(L0C)] series complexes (C1’–C4’) in the solid state. Ellipsoids were calculated at 50% probability, and hydrogens and crystallization solvate are omitted for better visualization. In the case of the C1’ complex, solvates from the starting material are not represented.
Figure 1. ORTEP-3.1 projection of the molecular structures of the [CoIII(LnC)(L0C)] series complexes (C1’–C4’) in the solid state. Ellipsoids were calculated at 50% probability, and hydrogens and crystallization solvate are omitted for better visualization. In the case of the C1’ complex, solvates from the starting material are not represented.
Inorganics 12 00171 g001
Inorganics 12 00171 sch003
Scheme 3. (A) Carbon–sulfur bond cleavage in inorganic complexes from the literature in which there are five-membered -S-Co-S- metallacycles. (B) Carbon–sulfur bond cleavage in C1’–C4’ complexes without the formation of the same -S-Co-S- metallacycles.
Scheme 3. (A) Carbon–sulfur bond cleavage in inorganic complexes from the literature in which there are five-membered -S-Co-S- metallacycles. (B) Carbon–sulfur bond cleavage in C1’–C4’ complexes without the formation of the same -S-Co-S- metallacycles.
Inorganics 12 00171 sch003
Inorganics 12 00171 g002
Figure 2. ORTEP-3.1 projection of the molecular structures of the [CoIII(LnC)2]PF6 series complexes (C1–C4) in the solid state. Ellipsoids were calculated at 50% probability and hydrogens, crystallization solvates, hexafluorophosphate counterions (PF6−), and aniline molecules are omitted for better visualization.
Figure 2. ORTEP-3.1 projection of the molecular structures of the [CoIII(LnC)2]PF6 series complexes (C1–C4) in the solid state. Ellipsoids were calculated at 50% probability and hydrogens, crystallization solvates, hexafluorophosphate counterions (PF6−), and aniline molecules are omitted for better visualization.
Inorganics 12 00171 g002
Inorganics 12 00171 g003
Figure 3. Top views and the corresponding identifications of the main nitrogenated bases that interact with (A) DNA: C1–C4 and (B) DNA: C1’–C4’ in the minor groove. (C) The representative distance between the superoxide ion and each CoIII complex. Best docking pose and the corresponding zoom representation for the interactions of (D) HSA: C1–C4 and (E) HSA: C1’–C4’ with subdomain IB (site III). Elements’ color: hydrogen, nitrogen, oxygen, sulfur, and CoIII are in white, dark blue, red, yellow, and beige, respectively. In the case of SOD mimetics, the ion CoIII is represented in green.
Figure 3. Top views and the corresponding identifications of the main nitrogenated bases that interact with (A) DNA: C1–C4 and (B) DNA: C1’–C4’ in the minor groove. (C) The representative distance between the superoxide ion and each CoIII complex. Best docking pose and the corresponding zoom representation for the interactions of (D) HSA: C1–C4 and (E) HSA: C1’–C4’ with subdomain IB (site III). Elements’ color: hydrogen, nitrogen, oxygen, sulfur, and CoIII are in white, dark blue, red, yellow, and beige, respectively. In the case of SOD mimetics, the ion CoIII is represented in green.
Inorganics 12 00171 g003
Inorganics 12 00171 g004
Figure 4. Superposition of the best docking pose for the compounds (A) C1–C4 and (B) C1’–C4’ into the RBD (all in down conformations) of the spike glycoprotein from SARS-CoV-2. Superposition of the best docking pose for the compounds (C) C1–C4 and (D) C1’–C4’ into the RBD (two in down and one in up conformation) of the spike glycoprotein from SARS-CoV-2. Superposition of the best docking pose for the compounds (E) C1–C4 and (F) C1’–C4’ into the RBD (two in down and one in up conformation in complex with ACE2) of the spike glycoprotein from SARS-CoV-2. The corresponding electrostatic potential map for the protein is represented below the zoom representation of each superposition. Elements’ color: nitrogen, oxygen, sulfur, and CoIII are in dark blue, red, yellow, and beige, respectively. Hydrogen atoms are omitted for better interpretation.
Figure 4. Superposition of the best docking pose for the compounds (A) C1–C4 and (B) C1’–C4’ into the RBD (all in down conformations) of the spike glycoprotein from SARS-CoV-2. Superposition of the best docking pose for the compounds (C) C1–C4 and (D) C1’–C4’ into the RBD (two in down and one in up conformation) of the spike glycoprotein from SARS-CoV-2. Superposition of the best docking pose for the compounds (E) C1–C4 and (F) C1’–C4’ into the RBD (two in down and one in up conformation in complex with ACE2) of the spike glycoprotein from SARS-CoV-2. The corresponding electrostatic potential map for the protein is represented below the zoom representation of each superposition. Elements’ color: nitrogen, oxygen, sulfur, and CoIII are in dark blue, red, yellow, and beige, respectively. Hydrogen atoms are omitted for better interpretation.
Inorganics 12 00171 g004
Table 1. The bonds’ length and angle values related to the coordination spheres of the [CoIII(LnC)(L0C)] (C1’–C4’) complex series and their respective comparisons with values found in the literature.
Table 1. The bonds’ length and angle values related to the coordination spheres of the [CoIII(LnC)(L0C)] (C1’–C4’) complex series and their respective comparisons with values found in the literature.
ParameterCoIII-Donor AtomC1’C2’C3’C4’Literature
Bonds lengths (Å)CoIII-N(iminic)1.911 (3)
1.919 (3)		1.915 (4)
1.918 (4)		1.924 (2)
1.936 (2)		1.897 (5)
1.904 (5)		1.913 (3) [14]
1.926 (2) [14]
1.903 (2) [48]
1.910 (2) [48]
CoIII-O(phenolate)1.900 (3)
1.920 (3)		1.916 (3)
1.917 (3)		1.9187 (19)
1.9311 (19)		1.903 (3)
1.927 (3)		1.894 (2) [14]
1.914 (2) [14]
CoIII-S(thioether)2.2193 (12)2.2444 (14)2.2485 (10)2.2379 (15)2.2274 (9) [14]
CoIII-S(thiolate)2.2345 (13)2.2330 (14)2.2504 (10)2.2377 (16)2.2384 (9) [14]
2.237 (2) [48]
2.243 (1) [48]
ParameterDonor Atom-CoIII-Donor AtomC1’C2’C3’C4’
Bonds angles (°)O(phenolate)-CoIII-N(imine)86.83 (13)86.77 (13)88.26 (9)88.33 (15)
87.89 (13)87.44 (14)89.53 (9)88.35 (17)
92.60 (14)94.05 (14)92.40 (9)92.00 (17)
93.09 (13)94.10 (14)93.24 (9)93.37 (17)
O(phenolate)-CoIII-O(phenolate)89.07 (13)87.65 (12)86.45 (8)88.22 (14)
N(imine)-CoIII-N(imine)178.86 (15)178.31 (14)177.19 (9)178.27 (17)
O(phenolate)-CoIII-S(thioether)94.27 (9)93.72 (10)93.11 (7)93.40 (11)
176.35 (10)177.68 (10)178.00 (6)178.36 (11)
N(imine)-CoIII-S(thioether)88.57 (10)87.83 (10) 85.64 (7) 86.45 (14)
90.48 (11)91.26 (10)93.72 (8)91.83 (13)
O(phenolate)-CoIII-S(thiolate)92.13 (10) 94.64 (10) 93.11 (7) 93.12 (11)
178.76 (9)176.92 (10)179.42 (6)178.49 (12)
N(imine)-CoIII-S(thiolate)87.74 (12)88.15 (10) 87.12 (8) 87.34 (14)
92.81 (11)90.34 (10)90.11 (7)92.27 (14)
S(thioether)-CoIII-S(thiolate)84.53 (5)84.06 (6)87.31 (4)85.26 (6)
Table 2. The bonds’ length and angle values related to the coordination spheres of the [CoIII(LnC)2]PF6 (C1–C4) complex series and their respective comparisons with values found in the literature.
Table 2. The bonds’ length and angle values related to the coordination spheres of the [CoIII(LnC)2]PF6 (C1–C4) complex series and their respective comparisons with values found in the literature.
ParameterCoIII-Donor AtomC1C2C3C4Literature
Bond lengths (Å)CoIII-N(iminic)1.925 (3)1.916 (3)1.9164 (13)1.913 (3)1.9224 (18) [50]
1.927 (3)1.923 (3)1.9187 (13)1.913 (4)1.9248 (18) [50]
CoIII-O(phenolate)1.878 (3)1.883 (3)1.8793 (11)1.873 (3)1.8809 (15) [50]
1.880 (3)1.883 (3)1.8893 (10)1.876 (3)1.8870 (15) [50]
CoIII-S(thioether)2.2423 (14)2.2780 (15)2.2684 (4)2.2253 (13)2.2494 (7) [50]
2.2472 (14)2.2840 (14)2.2698 (4)2.2456 (12)2.2630 (6) [50]
ParameterDonor Atom-CoIII-Donor AtomC1C2C3C4
Bonds angles (°)O(phenolate)-CoIII-N(imine)86.23 (13)89.61 (12)90.49 (5)86.10 (13)
86.97 (13)89.82 (12)90.79 (5) 86.85 (14)
93.89 (13)91.35 (13)91.95 (5)93.83 (13)
94.40 (13)91.81 (12)92.41 (5)94.20 (14)
O(phenolate)-CoIII-O(phenolate)88.92 (13)89.28 (12)87.83 (5)89.03 (13)
N(imine)-CoIII-N(imine)178.62 (14)178.12 (13)176.08 (5)179.26 (15)
O(phenolate)-CoIII-S(thioether)92.03 (10)90.94 (9)91.32 (3)91.44 (10)
92.59 (10)91.99 (9)92.92 (4)92.82 (10)
177.41 (9) 176.82 (9) 177.15 (4)177.35 (9)
178.40 (9)177.45 (9)177.65 (4)178.12 (10)
N(imine)-CoIII-S(thioether)87.45 (11) 85.48 (11)84.88 (4)87.64 (11)
87.79 (11)85.98 (9)85.83 (4)88.19 (11)
90.83 (11)92.36 (10)91.39 (4) 91.12 (12)
92.42 (10)93.55 (10)92.26 (4)92.06 (10)
S(thioether)-CoIII-S(thiolate)86.50 (6)87.92 (4)88.026 (15)86.77 (5)
Table 3. Molecular docking score values (dimensionless) for the interactions between the inorganic complexes C1–C4/C1’–C4’ and DNA/HSA/spike and distances between O2.− and C1–C4/C1’–C4’.
Table 3. Molecular docking score values (dimensionless) for the interactions between the inorganic complexes C1–C4/C1’–C4’ and DNA/HSA/spike and distances between O2.− and C1–C4/C1’–C4’.
DNAHSASOD MimeticSpike Glycoprotein
SampleMajor GrooveMinor GrooveSite
I		Site
II		Site
III		Distance
Complex: O2− (Å)		Down
Conformation		Up
Conformation		Complex
ACE2
C136.838.320.1-----24.61.7047.837.336.0
C237.641.5----------24.91.8043.641.837.5
C340.644.510.3-----17.22.0046.642.842.1
C441.147.1----------29.81.8054.151.144.6
C1’36.343.142.5-----59.42.1046.844.040.5
C2’36.244.425.3-----53.52.5045.442.738.5
C3’40.445.228.9-----51.02.1049.446.439.9
C4’41.545.723.4-----54.62.0053.449.545.9
Table 4. Molecular docking results for the interactions between the inorganic complexes C1–C4/C1’–C4’ and DNA/HSA.
Table 4. Molecular docking results for the interactions between the inorganic complexes C1–C4/C1’–C4’ and DNA/HSA.
SampleConnected PointsInteractionsDistance (Å)
DG-04Hydrogen bonding2.80
DNA: C1–C4DC-21Hydrogen bonding3.10
DG-22Van der Waals3.30
DC-03Van der Waals3.60
DNA: C1’–C4’DG-04Hydrogen bonding2.00
DA-05Van der Waals2.50
DG-22Van der Waals1.70
Arg-117Hydrogen bonding1.70
Pro-118Van der Waals2.60
Tyr-138Van der Waals1.30
HSA: C1–C4Pro-146Van der Waals3.00
Phe-165Van der Waals2.10
Leu-182Van der Waals3.00
Arg-186Van der Waals3.70
Pro-118Van der Waals2.40
Tyr-138Van der Waals3.60
Ile-142Van der Waals1.00
HSA: C1’–C4’Tyr-161Hydrogen bonding2.00
Phe-165Van der Waals2.80
Leu-182Van der Waals2.70
Arg-186Hydrogen bonding2.20
Lys-190Van der Waals2.40
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Fontana, L.A.; Martins, F.M.; Siqueira, J.D.; Serpa, C.; Chaves, O.A.; Back, D.F. Synthesis of Cobalt(III) Complexes Derived from Pyridoxal: Structural Cleavage Evaluations and In Silico Calculations for Biological Targets. Inorganics 2024, 12, 171. https://doi.org/10.3390/inorganics12060171

AMA Style

Fontana LA, Martins FM, Siqueira JD, Serpa C, Chaves OA, Back DF. Synthesis of Cobalt(III) Complexes Derived from Pyridoxal: Structural Cleavage Evaluations and In Silico Calculations for Biological Targets. Inorganics. 2024; 12(6):171. https://doi.org/10.3390/inorganics12060171

Chicago/Turabian Style

Fontana, Liniquer André, Francisco Mainardi Martins, Josiéli Demetrio Siqueira, Carlos Serpa, Otávio Augusto Chaves, and Davi Fernando Back. 2024. "Synthesis of Cobalt(III) Complexes Derived from Pyridoxal: Structural Cleavage Evaluations and In Silico Calculations for Biological Targets" Inorganics 12, no. 6: 171. https://doi.org/10.3390/inorganics12060171

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop