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Article

Synthesis, Structural Characterization, and In Silico Antiviral Prediction of Novel DyIII-, YIII-, and EuIII-Pyridoxal Helicates

by
Francisco Mainardi Martins
1,
Yuri Clemente Andrade Sokolovicz
1,
Morgana Maciél Oliveira
1,
Carlos Serpa
2,
Otávio Augusto Chaves
2,3,* and
Davi Fernando Back
1,*
1
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
2
Department of Chemistry, Coimbra Chemistry Centre—Institute of Molecular Science (CQC-IMS), University of Coimbra, Rua Larga s/n, 3004-535 Coimbra, Portugal
3
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 2025, 13(8), 252; https://doi.org/10.3390/inorganics13080252
Submission received: 24 June 2025 / Revised: 15 July 2025 / Accepted: 18 July 2025 / Published: 23 July 2025
(This article belongs to the Special Issue Metal-Based Compounds: Relevance for the Biomedical Field, 2nd Edition)
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Abstract

The synthesis and structural characterization of three new triple-stranded helical complexes ([Dy2(L2)3]2Cl∙15H2O (C1), [Y2(L2)3]3(NO3)Cl∙14H2O∙DMSO (C2), and [Eu2(L4)3]∙12H2O (C3), where L2 and L4 are ligands derived from pyridoxal hydrochloride and succinic or adipic acid dihydrazides, respectively, were described. The X-ray data, combined with spectroscopic measurements, indicated that L2 and L4 act as bis-tridentate ligands, presenting two tridentate chelating cavities O,N,O to obtain the dinuclear complexes C1–C3. Their antiviral profile was predicted via in silico calculations in terms of interaction with the structural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein in the down- and up-states and complexed with the cellular receptor angiotensin-converting enzyme 2 (ACE2). The best affinity energy values (−9.506, −9.348, and −9.170 kJ/mol for C1, C2, and C3, respectively) were obtained for the inorganic complexes docked in the model spike-ACE2, with C1 being suggested as the most promising candidate for a future in vitro validation. The obtained in silico antiviral trend was supported by the prediction of the electronic and physical–chemical properties of the inorganic complexes via the density functional theory (DFT) approach, representing an original and relevant contribution to the bioinorganic and medicinal chemistry fields.

1. Introduction

The peculiar electronic structures of lanthanide series, presenting 4f orbitals shielded by 5s and 5p electrons, give them unique catalytic, magnetic, and electronic properties [1,2]. Such 4fn−15d16s2 or 4fn6s2 outer-electron configurations, as well as that of yttrium ([Kr]4d15s2), cause rare earths to have stable trivalent oxidation states [2]. An interesting feature of lanthanoids ions is their chemical similarity to calcium(II) ions, especially regarding ionic radius and coordination chemistry. Due to their higher electropositivities, lanthanoids often exhibit a higher binding affinity for certain proteins than Ca2+ [3]. Interestingly, lanthanoids, specifically cerium(III), are essential cofactors of the homodimeric methanol dehydrogenase enzyme from Methylacidiphilum fumariolicum SolV, an extremely acidophilic methanotrophic microorganism [4].
Presenting a wide structural coordination chemistry [5], lanthanide complexes are developed and studied, among other purposes, for their possible cytotoxic potentials [6] and for their ability to interact and/or hydrolytically cleave deoxyribonucleic acid (DNA) [7,8,9]. Additionally, gadolinium(III) chelate complexes have been utilized for over three decades as contrast agents for magnetic resonance imaging (MRI) due to the paramagnetic properties of this metal, specifically the presence of seven unpaired electrons in a 4f spherically symmetric orbital [10,11]. In the field of nuclear medicine, some compounds containing a lutetium isotope (177Lu, a purely β– radiation emitter with low-energy electrons) have received approval from the U.S. Food and Drug Administration (FDA) as radiopharmaceuticals, namely 177Lu-DOTATATE (LutatheraTM) for the treatment of some cases of midgut carcinoid tumors and 177Lu-vipivotide tetraxetan (PluvictoTM) for the treatment of metastatic prostate cancer [12,13].
Coordination-driven self-assembly processes employ metal–ligand coordination as the driving force for the formation of supramolecular structures [14,15]. These processes can lead to the formation of well-defined structures in a spontaneous and directed manner [16]. Discrete (finite) and structurally well-defined examples of these architectures are helical complexes, also called helicates, which are chiral complexes composed of two or more organic ligands coordinated to the metal centers, which form an axis of helicity [17]. Helical complexes are studied in biological chemistry for their possible applications in host–guest chemistry [18] and possible interactions with biomolecules, such as DNA [19,20,21], serum albumins [22,23], nucleic acids three-way junctions [24,25], and the trans-activation response (TAR) region of ribonucleic acid from human immunodeficiency virus 1 (HIV-1 RNA) [26,27].
Despite the FDA only approving small organic compounds for the treatment of coronavirus disease (COVID-19), e.g., molnupiravir (LagevrioTM), remdesivir (VekluryTM), and the combination of nirmatrelvir with ritonavir (PaxlovidTM) [28,29], metallodrugs have been considered a feasible emerging area of research in the fight against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections [30,31,32]. In this sense, there are reports highlighting selenium- and tellurium-containing zidovudine (AZT) derivatives as promising SARS-CoV-2 inhibitors targeting the viral RNA-dependent RNA polymerase (RdRp) [33]; gold metallodrugs, including auranofin, were reported as efficient inhibitors of the papain-like protease (PLpro) SARS-CoV-2 [34], while ranitidine bismuth citrate exhibited low cytotoxicity and protected SARS-CoV-2-infected cells with a high selectivity index of 975 targeting the viral helicase [35]. Additionally, mononuclear titanocene dichloride and polyoxidometalates (POMs), more specifically POM-6 (Rb5.5Na4.5[{(p-tolyl)-Sb}4(PW9O34)2]∙40H2O), POM-7 (Rb6Na6[{(p-tolyl)Sb}4(GeW9O34)2]∙40H2O), and POM-11 ([Pd16Na2O26(OH)3Cl3((CH3)2As)8]∙0.25Na(CH3)2AsO2∙17H2O), were identified as binders of the structural SARS-CoV-2 spike glycoprotein, inhibiting the interaction with the cellular receptor angiotensin-converting enzyme 2 (ACE2) with potency of 3.9 ± 0.3, 0.2 ± 0.1, 0.3 ± 0.1, and 2.5 ± 0.3 µM, respectively [36]. This reinforces the versatility and applicability of metallodrugs, including helical complexes, as potential anti-SARS-CoV-2 candidates.
There are few reports on the antiviral profile of helical complexes, mainly those coordinated with rare earth metal centers. The formation of helical complexes systematically depends on the characteristics of the ligands and metal centers employed, especially regarding their preferred coordination geometries [37]. Although rare earth metal centers present the possibility of higher coordination numbers, such as 9- or 12-coordinate, the predictability of the coordination chemistry of such elements is low due to the absence of a strong ligand field effect, which leads to low energy differences between coordination numbers and arrangements [5,38].
In this context, the nature of the ligands used influences the coordination behavior of the complexes formed, with coordination saturation and intraligand repulsions being relevant factors for the stabilization of a given geometry [39]. Bis-tridentate ligands, such as those bis-iminic obtained by the condensation of succinic or adipic acid dihydrazides with aldehydes, can lead to the formation of dinuclear complexes with different numbers of units of the same ligand. Generally, these ligands can lead to the formation of monomeric complexes with oxophilic metallic centers, such as vanadium(V) [40,41] and molybdenum(VI) [42,43]; dinuclear double-stranded helicates with octahedral metallic centers, such as cobalt(II) [19,23], nickel(II) [22], or iron(III) [44,45]; or even triple-stranded helicates with rare earths metallic centers [37,46,47,48]. Furthermore, with rare earths, it is possible to form coordinatively unsaturated double-stranded (instead of triple-stranded) helicates, presenting coligands (such as water or nitrate) in place of a third strand for the stabilization of the metallic center with a higher coordination number [49]. In these dihydrazide-derived ligands, salicylaldehydes containing 3-methoxy (orto-vanillin) or 3-ethoxy substituents are widely used because their ether oxygen atoms can act as hard donor atoms for coordination with rare earths or even metal centers with other characteristics, such as copper(II), allowing for the formation of complexes with higher nuclearities [47,48,50,51]. The aldehyde derivative of the vitamin B6 group, pyridoxal, is a particularly interesting choice due to its defined structural and biological chemistries [52,53,54,55,56,57]. Despite this, there are still a few studies [58,59,60,61] reporting crystallographic structures of pyridoxal-containing ligands coordinated to rare earth metal centers.
Considering the biological and structural background presented above, the present work reports the synthesis and structural characterization of three novel triple-stranded helical complexes: [Dy2(L2)3]2Cl∙15H2O (C1), [Y2(L2)3]3(NO3)Cl∙14H2O∙DMSO (C2), and [Eu2(L4)3]∙12H2O (C3). These inorganic complexes present bis-iminic bis-tridentate hydrazone ligands derived from pyridoxal hydrochloride and succinic (L2) or adipic acid (L4) dihydrazides. Together with the solid-state structures obtained by single-crystal X-ray diffraction, these complexes were characterized using infrared vibrational spectroscopies (FT-IR), as well as UV-Vis electronic absorption spectroscopy (DMSO and DMF). Through in silico molecular docking calculations, C1–C3 had their antiviral profiles predicted in terms of interactions with the structural spike glycoprotein from SARS-CoV-2. The three possible dynamics of the viral receptor binding domain (RBD) were considered: close-state, up-state, and in complex with ACE2 [62], giving insights into the possible antiviral mechanisms of C1–C3. The obtained in silico antiviral trend was supported by the prediction of the electronic and physical–chemical properties of C1–C3 via the density functional theory (DFT) theoretical approach.

2. Results and Discussion

2.1. X-Ray Crystallography and Solid-State Structures

The synthesis of the ligands L2 and L4 and the complexes C1–C3 is shown in Scheme 1. The ORTEP-3 crystallographic structural projections of the dinuclear complexes C1–C3 in the solid state are shown in Figure 1, Figure 2 and Figure 3, respectively, while L2 and L4 are shown in Figures S1 and S2, respectively, in the Supplementary Material.
The formation of helical complexes systematically depends on the characteristics of the ligands and metal centers used and, in some cases, on the use of templates or more specific synthesis conditions [37]. In addition to helical complexes, another possibility in coordination-driven self-assembly processes is the formation of meso-helicate structures, also called “mesocates” or “side-by-side complexes” [63,64].
For the formation of helical complexes, the ligands must have several coordination units along the strand (multidentate ligands) that allow for the recognition and coordination of metallic centers. In addition, they must have organic spacers with a certain flexibility that allows for wrapping around the metal centers to form the final helical structure but prevents the coordination of several units of the same strand to only one metal atom [17]. In this work, in ligands L2 and L4, the two cavities of the same ligand unit are separated by aliphatic organic (sp3 hybridization) spacers of two (L2) [46] or four methylenes (L4) [51], which confers a certain flexibility, enabling three molecules of the ligand to wrap with each other and three cavities of three distinct molecules to coordinate with a metallic center. At the same time, the presence of only two or four carbon atoms prevents the coordination of the two cavities of the same molecule to only one metallic center, which occurs with a similar dihydrazide-derived ligand with eight methylenes as organic spacer and an iron(III) metallic center [44].
In complexes C1–C3, L2 and L4 act as bis-tridentate ligands, presenting two O,N,O tridentate chelating cavities; that is, they coordinate to the metallic centers via anionic phenolate oxygen (after deprotonation), neutral imine nitrogen, and neutral carbonyl oxygen. This behavior of the carbonyl oxygen and the absence of deprotonation of the hydrazide nitrogen atoms are confirmed by the bond length values of N–N(H), C=O, and (O)C–N(H) and the bond angle values of N–N(H)–C(O) [44] shown in Table 1. In C1–C3, each metallic center is coordinated to three distinct chelating cavities, each one being a component of a bis-tridentate ligand unit. In the same complex, each ligand molecule coordinates to both metallic centers. Thus, each metal center is coordinated to three nitrogen atoms and six oxygen atoms, resulting in nine-coordinated M-N3O6 coordination spheres; the three monoanionic phenolate oxygens neutralize the cationic charge of the metal ions with trivalent oxidation states. Table 1 contains the bond length values of the coordination spheres of C1–C3. Crystal data and more details of the data collection and refinements of complexes C1–C3 are presented in Table S1 in the Supplementary Material, while the bond length and angle values of the coordination spheres of the complexes C1–C3 are fully listed in Tables S2 and S3, respectively, in the Supplementary Material. For reference purposes, the bond length values of rare earth complexes with similar coordination profiles [46,65,66] are summarized in Table S4 in the Supplementary Material.
Furthermore, in the three dinuclear complexes, the two metal centers have distances between them equal to 7.1637(4) Å (C1), 7.1609(6) Å (C2), and 9.3770/9.4962 Å (C3). These similar distances between C1 and C2 are explained by the same organic spacer between the L2 cavities and the similar ionic radii between YIII and DyIII [67,68], while the larger distances for C3 relative to C1 and C2 are caused by the larger organic spacer in L4 [69] (four versus two methylenes). In C1 and C2, there are two and four protonated pyridine nitrogens, respectively, which are neutralized in the form of salts by two chloride ions (C1) and three nitrate and a chloride ions (C2). Thus, these two complexes are considered complex ions, and C3, in turn, is a neutral complex. In C2, there is a molecule of dimethyl sulfoxide (DMSO) as a crystallization solvate. The crystallographic structural projections emphasizing the coordination polyhedra of the complexes C1–C3 in the solid state are shown in Figure 4, Figure 5 and Figure 6.
One difference between helicates and mesocates is the way the ligands are organized in space. In helical complexes, the ligand adopts a “Pseudo-S” or “S-type” conformation [63,70], with a higher degree of ligand twisting [71], while in mesocate complexes, the ligand adopts a “Pseudo-C” or “C-type” conformation [63,70]. The spontaneous preference for one of the types of structures is associated with some variables, and therefore, the prediction of which one is uncertain. In this sense, Albrecht and coworkers created an empirical rule, the “even versus odd” rule, based on a study with bis(catecholate) ligands and titanium(IV) metal centers [72,73]. In ligands containing linear, flexible alkyl spacers, their preferred conformation is zigzag (antiperiplanar in the σ bond). Thus, spacers with even numbers of carbons lead to a preferred “Pseudo-S” structure of the ligand, and the complex tends to be a helicate, while spacers with odd numbers of carbons lead the ligand to a preference for a “Pseudo-C” structure and the complex, a meso-helicate [37,63]. However, due to the presence of coordinating donor atoms outside the aromatic unit of pyridoxal, including carbonylic oxygens from a hydrazide linkage (rotational σ bond from the amide), this rule may not apply to the ligands L2 and L4 and the formation of the respective triple-stranded complexes. Certainly, the organic spacer directly influences the structure formed, with a tendency for helicate structures to exist with a high degree of flexibility of the central C–C bond, and with ligands with less flexible central C–C bond, there is a tendency for meso-helicate structures to exist [74].
In C1–C3, the torsion angle values of each alkyl spacer C(O)–(CH2)–(CH2)–C(O) of ligand L2 units are equal to 88.9 (6), 89.2 (5), and 98.7 (5) for C1 and 90.6 (5), 93.7 (4), and 95.2 (4) for C2, while the values of the alkyl spacers of ligand L4 units (disregarding the two central methylenes from (CH2)4 moieties) are equal to 80 (1) and −93.9 (7) (C3). Considering the five- and six-membered metallacycles formed between the O,N,O cavities and the metallic center (9 atoms) as a plane, as shown in Figure 7, the angle values between the two planes of the same ligand L2 or L4 units are equal to 73.96, 80.96, and 87.92 (C1); 75.43, 77.91, and 79.50 (C2); and 84.33 and 87.70 (C3).
Another difference between helicates and mesocates relies on the presence or not of chirality. Dinuclear helical complexes containing achiral ligand molecules lead to the formation of a complex with both metal centers with the same chirality (Δ or Λ). Thus, there is the formation of a complex with stereospatial conformation ΔΔ or ΛΛ and the presence of chirality. In meso-helicate complexes, the coordinated ligands lead to metal centers with different steric configurations between them (Δ and Λ), forming a compound with no chirality (ΔΛ) [75]. According to the direction of the helicity formed, the helical complex can be named P (plus) if it is clockwise (right-handed) or M (minus) if it is counterclockwise (left-handed) [76,77].
In C1–C3, due to the crystallization in achiral space groups (C1 and C2: triclinic P 1 ¯ , C3: trigonal R 3 ¯ ), it is understood that there is crystallization of the complexes in the form of racemate, that is, equal amounts of the species P and M. Such behavior is expected considering works already published report dinuclear double/triple-stranded helicates with similar achiral ligands [19,45,47].

2.2. DFT Analysis

To analyze the electronic properties of the C1–C3 complexes, quantum chemical calculations were carried out with the experimental X-ray data using Gaussian 09W software and the visualization software Gaussview 05. There are reports highlighting key insights into the molecule charge distribution by the Electrostatic Surface Potential (ESP) approach [78,79,80]. Thus, Figure 8A–C depict the ESP, focusing on the electronic allocation for the C1–C3 structures, respectively. Regions in red represent negatively charged areas and indicate nucleophilic reactivity, while blue regions correspond to positively charged areas and indicate electrophilic reactivity [81,82]. It was observed that the structure of the inorganic complexes becomes distorted to enhance stability, with the negative charge shifting to one side and the positive charge to the opposite side of the complex.
The Electron Localization Function (ELF) is a quantum technique to explore the interactions between atoms in molecules and solids and is very effective in terms of the ability to differentiate between covalent and ionic interactions. The ELF for C1–C3 is represented in Figure 8D–F, respectively. Considering that lanthanides form two complexes, the prevalence of the ionic character is expected in the cores, and it can be observed by a more spherical electron distribution around the DyIII (Figure 8D) and EuIII (Figure 8F) compared to YIII (Figure 8E); the same behavior was reported previously by Savin and coworkers [83]. In terms of the electron density distribution, the ELF also demonstrates an unbalanced electron distribution, as evidenced in the ESP results, and this is the flagship that will lead to the amplification of biological electronic reactivity.
The frontier molecular orbital energies can be considered indicators of reactivity between molecules and biological sites. The energy difference between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) may provide important information about the biological activity of a specific molecule’s interaction with a protein or DNA structure. Molecules with a smaller HOMO-LUMO energy gap may exhibit enhanced chemical reactivity. On the other hand, molecules with a more stable LUMO can receive electron density from a biological target with appropriately balanced higher HOMO energy; similarly, molecules with a more energetic HOMO can donate electrons to biological targets with appropriately balanced lower LUMO energy [84,85,86,87].
DFT calculations provide the frontier molecular orbitals isosurfaces and the energetic profile for the C1–C3, as demonstrated in Figure 9; the HOMO, LUMO, and HOMO-LUMO gap energies are given in eV. The C1 has an intermediate value of HOMO-LUMO gap of 0.37 eV and an intermediate value for HOMO (−2.94 eV) and LUMO (−2.57 eV). Interestingly, the C2 has the smallest HOMO-LUMO gap (0.15 eV) and the highest energy for HOMO (−2.37 eV) and LUMO (−2.04 eV). Alternatively, the C3 indicates having a higher HOMO-LUMO gap (0.53 eV) and the smallest energy for HOMO (−4.58 eV) and LUMO (−4.05) frontier orbitals.
Table 2 summarizes the frontier orbitals HOMO and LUMO, energy gap (Eg), and DFT chemical reactivity descriptors (in eV) for complexes C1–C3. Also, the frontier orbitals HOMO and LUMO for C1–C3 are shown in Figure 9. Among the three complexes, C2 shows the uppermost HOMO energy (−2.37 eV) compared to C1 (−2.94 eV) and C3 (−4.58 eV). Assuming electron transfer from the HOMO of C2 to the biological target, a higher HOMO energy corresponds to enhanced electron-donating ability due to its greater urgency for stabilizing higher energy electrons, transferring them to the LUMO from protein targets. As can be observed, C2 also presented the smallest Eg (0.15 eV), more than 100% lower in comparison with C1 (0.37 eV) and C3 (0.53 eV). In general, the literature reports that molecules with a smaller energy gap (Eg) between the HOMO and LUMOs and lower hardness (η) tend to exhibit greater biological activity.
Additionally, a lower electrophilicity index (ω) indicates higher nucleophilicity, resulting in a greater electron-donation ability [88,89,90,91]. Given these circumstances, the fact that the complex C3 exhibits the highest ω value (35.13 eV) suggests less ability to act as a nucleophile. In contrast, C2 has the smallest ω value (14.73 eV), indicating that this complex is more likely to donate electron density from its HOMO to the biological target. Furthermore, a high hardness value (η) reflects significant resistance to exchanging electrons with the environment, and C2 has the lowest η (0.16 eV), indicating minimal resistance to electron donation. This leads us to conclude that, in terms of electronic availability for transfer to a biological site, C2 is the most promising candidate based on key factors: (1) lowest electrophilicity index (ω), (2) the lowest energy gap (Eg), (3) the highest HOMO energy level, and (4) the lowest chemical hardness (η).

2.3. Molecular Docking Calculations

In a post-pandemic scenario caused by the respiratory virus SARS-CoV-2, new strategies and drugs should be developed to counter the chance of further infections [92,93]. In this sense, the search for new drugs should be initially screened via in silico calculations and then validated for their antiviral behavior using in vitro and in vivo assays. Thus, as a preliminary approach, the new C1–C3 complexes, of which C1 and C3 are derived from lanthanide salts, were not only synthesized but also in silico-screened against the structural SARS-CoV-2 spike glycoprotein. Structural, instead of non-structural, viral proteins were chosen mainly due to the high steric volume of C1–C3 that might negatively impact the cellular uptake, and there are reports highlighting the importance of spike glycoprotein as a feasible druggable target to metallodrugs [34,36,94,95]. More specifically, molecular docking calculations were carried out on the viral-receptor-binding domain (RBD) of the spike glycoprotein, considering its dynamics in the down-state (non-active to interact with the cellular receptor, PDB code: 6VXX), up-state (active to interact with the cellular receptor, PDB code 6VYB), and in complex with human ACE2 (the cellular receptor, PDB code: 7KJ2) to better in silico reproduce the in vitro and in vivo possibilities [96]. As the first approach, the wild-type spike glycoprotein was considered.
The molecular docking results of complexes C1–C3 with the RBD in the down- and up-states and ACE2-bound conformations are displayed in Table 3. The best docking pose for each case is shown in Figure 10. For a better illustration, the viral RBD and the cellular receptor ACE2 are represented in red and golden color, respectively. Initially, analyzing the outcomes for the down-state, C2 was the most promising inorganic complex with higher predicted potential affinity, showing the lowest calculated energy of −9.191 kcal/mol, compared to −8.963 and −9.129 kcal/mol for C1 and C3, respectively. This trend was previously predicted using DFT calculations (Table 2), as C2 exhibited the lowest energy gap (Eg) and hardness (η). These two DFT factors are reported as important predictors to achieve biological activity [89,90,91]. Regarding the up-state and the ACE2-bound complex, C1 showed the highest predicted potential activity. This may be related to two main factors: (a) lower Eg energy barrier and (b) lower Mulliken charges (Figures S3–S5 for C1–C3 in the Supplementary Material) on the external fragments, such HO–CH2– present in the pyridoxal ring (Figure S3, atoms O6 and O9 in the Supplementary Material), which was observed to interact directly, forming two hydrogen bonds with the RBD residues (ARG-466) in the ACE2-bound conformation (Figure 11). The same characteristic was observed for C3 (Figure S5, external atoms O61 and O121 in the Supplementary Material), but taking into consideration the high Eg value (Table 2), explaining its lower potential prediction of biological activity due to the higher energetic barrier between frontier orbitals HOMO and LUMO.
Furthermore, ELF in Figure 8A,C showed the ability of DyIII and EuIII to disperse electronic density out from the central core of the molecule, contributing to enhancing the negative Mulliken charge of external fragments. Differently, the spiral of Mulliken charges for C2 showed that the lowest Mulliken charge is located in the internal core of the molecule, close to the metal (Figure S4, atoms O153 and O142 in the Supplementary Material). This could be associated with the highest ELF at the YIII (Figure 8B), leading to a better potential prediction of biological activity in the full down-state of the spike glycoprotein, where the drug is encapsulated, interacting in all directions. In this case, the internal Mulliken electron density may be beneficial, following our previous report about the cobalt(III) complexes that showed more stable energy in a possible in silico competitive mechanism, i.e., the docking scores values for the three down-state models were more effective [97].
Finally, considering all three glycoprotein conformations, the highest predicted potential binding affinity was obtained for the ACE2-bound complex with C1. Based on the highest predicted potential affinity energy (Table 3), the three inorganic complexes C1–C3 might preferentially act via an in silico non-competitive mechanism. In the down-state of the glycoprotein, the docking occurred with RBD internally for all the complexes, whereas in the up-state and ACE2-bound, the docking occurred externally. Furthermore, the complexes C1 and C2 exhibited similar hardness (η) values, whereas C3 showed a considerably higher value. The similar η values of C1 and C2 may be associated with greater coordination stability, which aligns with the docking results observed in the up-state and in complex with ACE2, where both compounds are bound at the same binding site (Figure 10B,C). In contrast, C3, with a higher η value, docked at a distinct site. However, in the case of the down-state, both C1, C2, and C3 were anchored in the same internal region of the protein (Figure 10A).
The amino acid residues from the SARS-CoV-2 spike glycoprotein complexed with ACE2 that were predicted to interact with C1 are depicted in Figure 11. Interestingly, it can be observed that the complex C1 was able to interact with the amino acid residues ASN-165, ARG-357, ARG-355, ARG-466 (RBD), GLU-169, LYS-129, LYS-356, and SER-359, performing ten hydrogen bonds and three hydrophobic interactions. Two hydrogen bonds were predicted between C1 and RBD’s ARG-466 at a distance of 2.94 and 3.18 Å, respectively. Compared to previously reported results, this represents a favorable outcome, as derivatives of acetyl 11-keto-β-boswellic acid (AKBA) are capable of forming three hydrogen bonds across the RBD region, precisely with residues TYR-505, TYR-473, and GLN-409 [98]. The highest number of hydrogen bonds with RBD indicates C1 as the most promising lanthanide metallodrug candidate to be experimentally evaluated in terms of inhibiting SARS-CoV-2 proliferation by in vitro or in vivo assays.

3. Materials and Methods

3.1. General Characterization and Instrumentation

On a Bruker DPX-400 spectrometer (Bruker Corporation, Billerica, MA, USA), 1H (400 MHz) and 13C{1H} (100 MHz) nuclear magnetic resonance (NMR) spectra were recorded. Deuterated water (D2O) was used as the solvent and tetramethylsilane (TMS, SiMe4) as the internal reference. Chemical shifts are reported in parts per million (ppm, δ) and were referenced to residual solvent peaks with the multiplicities expressed as follows: s, simplet; and m, multiplet. The Fourier-transform infrared (FT-IR) spectra in transmission mode were recorded on a Bruker Vertex 70 spectrometer equipped with a diamond attenuated total reflectance (ATR) accessory in the 4000–30 cm–1 region with 64 scans and 4 cm−1 resolution. The UV-Vis absorption spectra of N,N-dimethylformamide (DMF), 5% DMF/Tris-HCl (pH 7.4) buffer, and dimethyl sulfoxide (DMSO) solutions of the complexes were recorded in a UV-2600 Shimadzu spectrometer (Shimadzu Scientific Instruments, Inc., Columbia, MD, USA) in a cuvette with 1.0 cm of optical path. All the characterization spectra of the compounds are presented in Figures S6–S26 in the Supplementary Material.

3.2. X-Ray Crystallography

Data were collected on a Bruker D8 Venture Photon 100 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. Measurements were made at low temperature using a Cryostream 800 unit from Oxford Cryosystems (Hanborough Business Park, Long Hanborough, UK). The structures were initially solved by the intrinsic phasing method using the XT/SHELXT program and refined with XL/SHELXL version 2018/3 with anisotropic displacement factors for non-hydrogen atoms [99]. Full-matrix least-squares made all refinements on F2 with anisotropic displacement parameters for all non–hydrogen atoms. Hydrogen atoms were included in the refinement in calculated positions, but the atoms (of hydrogens) that are contributing to the special bond were located in the Fourier map. Structural projections were performed using ORTEP-3 2020.1 [100,101] and Diamond 3 [102] for Windows, and the analysis of crystallographic structures was performed using Mercury 4.1.0 for Windows [103]. Crystal data and more details of the data collection and refinements of complexes C1–C3 are presented in Table S1 of the Supplementary Material. The ORTEP-3 structural projections of L2 and L4 in the solid state are in Figures S1 and S2 of the Supplementary Materials.

3.3. Synthetic Procedures

3.3.1. Synthesis of Ligands L2 and L4

The synthesis of these two imine derivatives has already been published in previous works [22,23]. In a 50 mL round-bottom flask, 1.00 mmol of succinic dihydrazide (L2, 0.146 g) or adipic acid dihydrazide (L4, 0.174 g) was suspended in 10 mL of methanol via an ultrasound bath for 15 min. To the suspension, 2.20 mmol of pyridoxal hydrochloride (0.448 g) solubilized in methanol (15 mL) was added under constant magnetic stirring. The mixture was kept under constant magnetic stirring and heating in an oil bath at 70 °C for 6 h. The resulting mixture was filtered by simple filtration to give light yellow (L2) or light beige (L4) solids. The solid was purified by four additions of methanol (10 mL each).
•
Ligand L2 (chloride salt): Yield: 0.466 g, 90%. M.P.: 220 °C (decomposition). Elem. Anal. for C20H26N6O6Cl2 (M.W. = 517.36 g mol−1), Calc. (%): C, 46.43; H, 5.07; N, 16.24. Found (%): C, 46.45; H, 5.09; N, 16.21. FT-IR (ATR, cm−1): 3048 [w, ν(C–H)aromatic], 2962 [w, ν(C–H)aliphatic], 1698 [m, ν(C=O)], and 1658 [w, ν(C=N)]. 1H NMR (D2O, 400 MHz): 3.27 (s, 6H, CH3), 3.53 (s, 4H, CH2), 5.49 (s, 4H, CH2), 8.75 (s, 2H, ArH), 9.21 (s, 2H, CHimine). 13C{1H} NMR (D2O, 100 MHz): 19.52, 36.06, 61.77, 127.70, 131.93, 132.00, 132.53, 148.69, 152.83, 163.13, 177.67.
•
Ligand L4 (chloride salt): Yield: 0.485 g, 89%. M.P.: 180 °C (decomposition). Elem. Anal. for C22H30N6O6Cl2 (M.W. = 545.42 g mol−1), Calc. (%): C, 48.45; H, 5.54; N, 15.41. Found (%): C, 48.44; H, 5.59; N, 15.40. FT-IR (ATR, cm−1): 3119 [w, ν(C–H)aromatic], 2940 [w, ν(C–H)aliphatic], 1686 [s, ν(C=O)], and 1624 [w, ν(C=N)]. 1H NMR (D2O, 400 MHz): 2.13 (s, 4H, CH2), 2.85 (m, 4H, CH2), 2.98 (s, 6H, CH3), 5.20 (s, 4H, CH2), 8.46 (s, 2H, ArH), 8.93 (s, 2H, CHimine). 13C{1H} NMR (D2O, 100 MHz): 19.54, 26.52, 36.09, 61.72, 127.70, 131.93, 132.00, 132.53, 148.69, 152.83, 163.16, 177.67.

3.3.2. Synthesis of Complexes C1–C3

In a 50 mL round-bottom flask, 0.20 mmol of the ligand (C1 and C2: L2, 0.103 g; C3: L4, 0.109 g) was suspended in 10 mL of methanol via an ultrasound bath for 15 min. To the suspension, 0.40 mmol of a deprotonating agent (C1 and C2: lithium hydroxide, LiOH, 0.010 g or C3: 1,8-diazabicyclo[5,4,0]undec-7-ene, DBU, 0.061 g, 60 µL) was added under constant magnetic stirring. After 10 min, 0.20 mmol of metal salt (C1: DyCl3∙6H2O, 0.076 g; C2: Y(NO3)3∙6H2O, 0.077 g; C3: Eu(NO3)3·5H2O, 0.086 g) was added. The mixture remained yellow in color and was kept under constant magnetic stirring and heating in an oil bath at 70 °C for more than 3 h. After this period, in C1, 2 mL of deionized water was added to the suspension. The resulting mixture of C1–C3 was filtered to remove the residual precipitate, and the supernatant was added to small vials.
Single crystals suitable for X-ray diffraction of C1 and C3 were obtained after slow evaporation of methanol at room temperature, while single crystals of C2 were obtained from a dimethyl sulfoxide solution. The crystalline material of C1–C3 was separated and washed with ethanol (10 mL), and the material was dried in open atmosphere. The yields were calculated relative to the ligand.
•
Complex [Dy2(L2)3]2Cl∙15H2O (C1): Yield: 0.072 g, 54.1%. M.P.: 350 °C (decomposition). FT-IR (ATR, cm−1): 2974 [w, ν(C–H)aliphatic], 1629 [m, ν(C=O)], and 1610 [m, ν(C=N)]. UV-Vis λmax: 303 nm; ε: 40,135 M−1 cm−1 in DMF(5%)/Tris-HCl pH 7.4 buffer mixture. λmax: 290 nm; ε: 14,336 M−1 cm−1 in DMSO solution.
•
Complex [Y2(L2)3]3(NO3)Cl∙14H2O (without crystallization from DMSO) (C2): Yield: 0.033 g, 02.7%. M.P.: 338 °C (decomposition). FT-IR (ATR, cm−1): 3045 [w, ν(C–H)aromatic], 1646 [s, ν(C=O)], and 1609 [m, ν(C=N)]. UV-Vis λmax: 291 nm; ε: 33,549 M−1 cm−1 in DMF(5%)/Tris-HCl pH 7.4 buffer mixture. λmax: 292 nm; ε: 44,618 M−1 cm−1 in DMSO solution.
•
Complex [Eu2(L4)3]∙12H2O (C3): Yield: 0.032 g, 24.9%. M.P.: 350 °C (decomposition). FT-IR (ATR, cm−1): 3047 [w, ν(C–H)aromatic], 1641 [s, ν(C=O)], and 1603 [m, ν(C=N)]. UV-Vis λmax: 300 nm; ε: 106,879 M−1 cm−1 in DMF (5%)/Tris-HCl pH 7.4 buffer mixture. λmax: 291 nm; ε: 55,496 M−1 cm−1 in DMSO solution.

3.4. DFT Calculations

The DFT simulations were conducted using a Gaussian 09W [104] theoretical level method with a hybrid basis set 6-31G(d) [105] for the O, H, C, and N atoms and the Stuttgart/Dresden (SDD) [106] pseudo-potential for Dy, Y, and Eu atoms. Solvent effects were modeled with the PCM implicit solvation model using toluene as the solvent. The X-ray coordinates for C1–C3 were used to calculate the single-point energy to obtain the energies of the HOMO and LUMOs and to calculate the quantum descriptors: Eg, η, and ω. The X-ray coordinates for C1–C3 were used to calculate the single-point energy and to obtain data on the energies of the HOMO and LUMOs. The software GaussView 5.0 was employed to generate the molecular orbital density distribution, ESP, and ELF.

3.5. In Silico Evaluations

The spike glycoprotein structures of the wild-type SARS-CoV-2 were obtained from the Protein Data Bank (PDB). For the three conformational states, one displayed all three receptor-binding domains (RBDs) in the “down” position (PDB code: 6VXX), another had one RBD in the “up” position and the remaining two “down” (PDB code: 6VYB), and a third represented the spike glycoprotein bound to the human ACE2 receptor (PDB code: 7KJ2). The structural data for the complexes C1–C3 were obtained from experimental X-ray crystallography measurements. Molecular docking simulations were conducted using AutoDock Vina software in version v1.2.7 [107,108]. Hydrogen atoms were added to the polar atoms, and then Kollman charges were applied to the biomacromolecules. For the RBD of SARS-CoV-2, the center of the grid box was positioned at the geometric center of RBD residues and adjusted to fully cover the investigation zone. Docking was performed with exhaustiveness set to 128 for an extensive search. The figures containing the complex conformations and proteins were constructed using the PyMOL Delano Scientific LLC software (DeLano Scientific LLC: San Carlos, CA, USA). The complexes and protein interactions were obtained using the Protein-Ligand Interaction Profiler (PLIP, https://plip-tool.biotec.tu-dresden.de/plip-web/plip/index, accessed on May 2025) tools [109] and opened in PyMOL (DeLano Scientific LLC: San Carlos, CA, USA).

4. Conclusions

Three helical lanthanide complexes (C1–C3) containing pyridoxal and dihydrazides were synthesized and characterized. Crystallographic and spectroscopic analyses confirmed the formation of helical architectures, in which the ligands act as tridentates, favoring appropriate conditions for cation coordination. For the first time, this class of complexes was in silico-predicted in terms of antiviral candidates, focusing on the interaction with the SARS-CoV-2 spike glycoprotein in different conformations, including the spike-ACE2 complex. Molecular docking studies revealed promising predicted affinity energy values, highlighting complex C1 as the most promising candidate, with potential for future in vitro and in vivo assays. The predictions obtained in the docking calculations were corroborated by density functional theory (DFT) calculations, which provided an overview of the electronic and physicochemical properties of the complexes. These results open a new research perspective for the development of antiviral agents based on cation complexes with helical structures.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/inorganics13080252/s1: Figures S1–S26. Supplementary data: CCDC 2465735, 2465736, and 2465743 contain the supplementary crystallographic data for complexes C1–C3, respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (accessed on 20 May 2025) 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.

Author Contributions

Conceptualization, F.M.M., Y.C.A.S., M.M.O., C.S., O.A.C., and D.F.B.; methodology, F.M.M., Y.C.A.S., M.M.O., O.A.C., and D.F.B.; software, Y.C.A.S. and O.A.C.; validation, F.M.M., Y.C.A.S., O.A.C., and D.F.B.; formal analysis, F.M.M., M.M.O., and D.F.B.; investigation, F.M.M., Y.C.A.S., M.M.O., C.S., O.A.C., and D.F.B.; resources, O.A.C. and D.F.B.; data curation, Y.C.A.S., O.A.C., and D.F.B.; writing—original draft preparation, F.M.M., Y.C.A.S., M.M.O., C.S., O.A.C., and D.F.B.; writing—review and editing, F.M.M., Y.C.A.S., M.M.O., C.S., O.A.C., and D.F.B.; visualization, F.M.M., Y.C.A.S., O.A.C., and D.F.B.; supervision, O.A.C. and D.F.B.; project administration, F.M.M. and D.F.B.; funding acquisition, O.A.C. and 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-2022; 308411/2022-6 and N° 32/2023 Pós-Doutorado Júnior—PDJ 2023-174545/2023-1) 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/00313/2025 and UIDP/00313/2025.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article or Supplementary Material.

Acknowledgments

OAC acknowledges Programa de Pós-Graduação em Biologia Celular e Molecular from Oswaldo Cruz Foundation (Rio de Janeiro, Brazil) and CAPES for the grant PIPD (process SCBA 88887.082745/2024-00 with subproject 31010016).

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. ORTEP-3 crystallographic structural projection of complex [Dy2(L2)3]2Cl∙15H2O (C1) in solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms, counterions, and water of crystallization were omitted for better visualization.
Figure 1. ORTEP-3 crystallographic structural projection of complex [Dy2(L2)3]2Cl∙15H2O (C1) in solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms, counterions, and water of crystallization were omitted for better visualization.
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Figure 2. ORTEP-3 crystallographic structural projection of complex [Y2(L2)3]3(NO3)Cl∙14H2O∙DMSO (C2) in solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms, counterions, dimethyl sulfoxide solvate, and water of crystallization were omitted for better visualization.
Figure 2. ORTEP-3 crystallographic structural projection of complex [Y2(L2)3]3(NO3)Cl∙14H2O∙DMSO (C2) in solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms, counterions, dimethyl sulfoxide solvate, and water of crystallization were omitted for better visualization.
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Figure 3. ORTEP-3 crystallographic structural projection of complex [Eu2(L4)3]∙12H2O (C3) in solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms and water of crystallization were omitted for better visualization.
Figure 3. ORTEP-3 crystallographic structural projection of complex [Eu2(L4)3]∙12H2O (C3) in solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms and water of crystallization were omitted for better visualization.
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Figure 4. Crystallographic structural projection emphasizing the coordination polyhedra of the complex [Dy2(L2)3]2Cl∙15H2O (C1) in the solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms, counterions, and water of crystallization were omitted for better visualization.
Figure 4. Crystallographic structural projection emphasizing the coordination polyhedra of the complex [Dy2(L2)3]2Cl∙15H2O (C1) in the solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms, counterions, and water of crystallization were omitted for better visualization.
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Figure 5. Crystallographic structural projection emphasizing the coordination polyhedra of the complex [Y2(L2)3]3(NO3)Cl∙14H2O∙DMSO (C2) in the solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms, counterions, dimethyl sulfoxide solvate, and water of crystallization were omitted for better visualization.
Figure 5. Crystallographic structural projection emphasizing the coordination polyhedra of the complex [Y2(L2)3]3(NO3)Cl∙14H2O∙DMSO (C2) in the solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms, counterions, dimethyl sulfoxide solvate, and water of crystallization were omitted for better visualization.
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Figure 6. Crystallographic structural projection emphasizing the coordination polyhedra of the complex [Eu2(L4)3]∙12H2O (C3) in the solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms and water of crystallization were omitted for better visualization.
Figure 6. Crystallographic structural projection emphasizing the coordination polyhedra of the complex [Eu2(L4)3]∙12H2O (C3) in the solid state. Thermal ellipsoids were calculated with a 50% probability level. Hydrogen atoms and water of crystallization were omitted for better visualization.
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Figure 7. Planes formed by the five- and six-membered metallacycles involving the O,N,O donor atoms and the metallic center of each chelating cavity from one ligand unit. The other two ligand units of the triple-stranded helicate are omitted.
Figure 7. Planes formed by the five- and six-membered metallacycles involving the O,N,O donor atoms and the metallic center of each chelating cavity from one ligand unit. The other two ligand units of the triple-stranded helicate are omitted.
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Figure 8. Electrostatic Surface Potential (ESP) for C1 (A), C2 (B), and C3 (C). Electron Localization Function (ELF) for C1 (D), C2 (E), and C3 (F).
Figure 8. Electrostatic Surface Potential (ESP) for C1 (A), C2 (B), and C3 (C). Electron Localization Function (ELF) for C1 (D), C2 (E), and C3 (F).
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Figure 9. Frontier molecular orbital density and energy levels for configurations C1 (A), C2 (B), and C3 (C), calculated with B3LYP using SDD for Dy, Y, Eu, and 6-31G(d) for light elements (O, H, C, and N), with PCM solvation in toluene.
Figure 9. Frontier molecular orbital density and energy levels for configurations C1 (A), C2 (B), and C3 (C), calculated with B3LYP using SDD for Dy, Y, Eu, and 6-31G(d) for light elements (O, H, C, and N), with PCM solvation in toluene.
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Figure 10. Superposition of the more stable docking conformations for complexes C1–C3 in the viral-receptor-binding domain (RBD) all in down-state (A—internal cavity—image with 50% transparency), two in down- and one up-state (B—external cavity), and one in up-state interacting with ACE2 (C—external cavity) of the spike glycoprotein from SARS-CoV-2. Color legends: C1 (green), C2 (cyan), C3 (orange), RBD: red, Chain A: black, Chain B: gray, Chain C: ruby, and ACE2: golden.
Figure 10. Superposition of the more stable docking conformations for complexes C1–C3 in the viral-receptor-binding domain (RBD) all in down-state (A—internal cavity—image with 50% transparency), two in down- and one up-state (B—external cavity), and one in up-state interacting with ACE2 (C—external cavity) of the spike glycoprotein from SARS-CoV-2. Color legends: C1 (green), C2 (cyan), C3 (orange), RBD: red, Chain A: black, Chain B: gray, Chain C: ruby, and ACE2: golden.
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Figure 11. Intermolecular hydrogen bonds and hydrophobic interactions between C1 and the amino acid residues from the SARS-CoV-2 spike glycoprotein complexed with ACE2 (RBD—Receptor Binding Domain).
Figure 11. Intermolecular hydrogen bonds and hydrophobic interactions between C1 and the amino acid residues from the SARS-CoV-2 spike glycoprotein complexed with ACE2 (RBD—Receptor Binding Domain).
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Scheme 1. General synthesis of the ligands L2 and L4 and the complexes C1–C3.
Scheme 1. General synthesis of the ligands L2 and L4 and the complexes C1–C3.
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Table 1. Selected bond length and angle values of the complexes C1–C3.
Table 1. Selected bond length and angle values of the complexes C1–C3.
Bond Length Values (Å)
BondC1C2C3 *
MIII–N(imine)2.595(4), 2.604(4), 2.627(4), 2.579(5), 2.580(5), 2.593(5)2.575(4), 2.585(4), 2.592(4), 2.593(4), 2.567(4), 2.584(4) 2.668(4), 2.621(4),
2.679(5), 2.631(7)
MIII–O(phenolate)2.246(4), 2.259(4), 2.274(4), 2.246(4), 2.260(4), 2.291(4)2.266(3), 2.234(3), 2.269(3),
2.239(3), 2.269(3), 2.260(3)		2.290(4), 2.310(3),
2.279(4), 2.297(5)
MIII–O(carbonyl)2.410(4), 2.412(4), 2.443(4), 2.424(4), 2.429(4), 2.434(4)2.395(3), 2.403(3), 2.416(3), 2.422(3), 2.408(3), 2.390(3)2.433(4), 2.483(3),
2.465(4), 2.461(6)
N(imine)–N(amide)(H)1.380(7), 1.386(6), 1.386(6), 1.384(6), 1.378(6), 1.390(8) 1.382(5), 1.388(5), 1.377(5),
1.383(5), 1.378(5), 1.391(5)		1.382(6), 1.390(5),
1.389(6), 1.384(8)
C–N(amide)1.342(6), 1.343(8), 1.347(6), 1.340(7), 1.344(7), 1.348(8)1.349(6), 1.352(6), 1.341(5), 1.341(6), 1.343(6), 1.347(5)1.348(7), 1.338(6),
1.321(8), 1.346(14)
C=O(carbonyl)1.224(7), 1.233(6), 1.234(6), 1.229(6), 1.232(7), 1.238(6)1.235(5), 1.230(5), 1.233(5), 1.236(5), 1.236(5), 1.245(5)1.230(7), 1.234(6),
1.232(8), 1.237(12)
Bonds Angle Values (°)
AngleC1C2C3 *
N(imine)–N(amido)(H)–C(O)115.9(4), 118.4(4), 118.4(5), 117.1(4), 117.4(4), 117.9(5)116.9(4), 117.3(4), 117.8(4),
116.9(4), 117.4(4), 117.7(4)		117.6(5), 116.8(4), 117.7(6), 117.5(9)
* Two independent units of C3.
Table 2. Frontier orbitals LUMO and HOMO, the energy gap (Eg), electrophilicity index (ω), and hardness (η) in eV for C1–C3 complexes.
Table 2. Frontier orbitals LUMO and HOMO, the energy gap (Eg), electrophilicity index (ω), and hardness (η) in eV for C1–C3 complexes.
CompoundEgHOMOLUMOωη
C10.37−2.94−2.5720.510.18
C20.15−2.37−2.0414.730.16
C30.53−4.58−4.0535.130.26
Table 3. The calculated affinity energies (Kcal/mol) for the interactions between the inorganic complexes C1–C3 and spike glycoprotein.
Table 3. The calculated affinity energies (Kcal/mol) for the interactions between the inorganic complexes C1–C3 and spike glycoprotein.
ComplexDown Conformation
(Kcal/mol)		Up Conformation
(Kcal/mol)		Complex ACE2
(Kcal/mol)
C1−8.963−8.392−9.506
C2−9.191−7.403−9.348
C3−9.129−7.664−9.170
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Martins, F.M.; Sokolovicz, Y.C.A.; Oliveira, M.M.; Serpa, C.; Chaves, O.A.; Back, D.F. Synthesis, Structural Characterization, and In Silico Antiviral Prediction of Novel DyIII-, YIII-, and EuIII-Pyridoxal Helicates. Inorganics 2025, 13, 252. https://doi.org/10.3390/inorganics13080252

AMA Style

Martins FM, Sokolovicz YCA, Oliveira MM, Serpa C, Chaves OA, Back DF. Synthesis, Structural Characterization, and In Silico Antiviral Prediction of Novel DyIII-, YIII-, and EuIII-Pyridoxal Helicates. Inorganics. 2025; 13(8):252. https://doi.org/10.3390/inorganics13080252

Chicago/Turabian Style

Martins, Francisco Mainardi, Yuri Clemente Andrade Sokolovicz, Morgana Maciél Oliveira, Carlos Serpa, Otávio Augusto Chaves, and Davi Fernando Back. 2025. "Synthesis, Structural Characterization, and In Silico Antiviral Prediction of Novel DyIII-, YIII-, and EuIII-Pyridoxal Helicates" Inorganics 13, no. 8: 252. https://doi.org/10.3390/inorganics13080252

APA Style

Martins, F. M., Sokolovicz, Y. C. A., Oliveira, M. M., Serpa, C., Chaves, O. A., & Back, D. F. (2025). Synthesis, Structural Characterization, and In Silico Antiviral Prediction of Novel DyIII-, YIII-, and EuIII-Pyridoxal Helicates. Inorganics, 13(8), 252. https://doi.org/10.3390/inorganics13080252

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