key: cord-1030940-ataghgfx authors: Ghasemi, Liana; Hasanzadeh Esfahani, Maryam; Abbasi, Alireza; Behzad, Mahdi title: Synthesis and crystal structures of new mixed-ligand Schiff base complexes containing N-donor heterocyclic co-ligands: molecular docking and pharmacophore modeling studies on the main proteases of SARS-CoV-2 virus (COVID-19 disease) date: 2022-04-04 journal: Polyhedron DOI: 10.1016/j.poly.2022.115825 sha: 690d434261405be11ab113564e11163f596daabc doc_id: 1030940 cord_uid: ataghgfx Three new mixed-ligand copper(II) complexes (1-3) with NN'O type unsymmetrical tridentate Schiff base ligands (SB) and N-donor heterocyclic co-ligands, with general formula [Cu(SB)(L)]ClO(4), were synthesized and characterized using single crystal x-ray diffraction (SCXRD), FT-IR and UV-Vis spectroscopy and elemental analyses. The SB ligand is the half-unit form of the condensation of 1,3-propanediamine with 5-methoxysalicylaldehyde and the co-ligands (L) are pyridine (py in (1)), 2,2'-bipyridine (bpy in (2)) and 1,10-phenanthroline (phen in (3)). Crystal structures of (2) and (3) were obtained by SCXRD. Molecular docking and pharmacophore studies were performed to study the interactions between the synthesized complexes and SARS-CoV-2 virus main proteases (PDB IDs: 6LU7, 6WQF and 6W9C). Results revealed that complex (3) with phen co-ligand showed better docking scores with the three receptors, i.e. 6LU7 (-8.05 kcal.mol(-1)), 6W9C (-7.70 kcal.mol(-1)) and 6WQF (-7.75 kcal.mol(-1)). The order of the binding best energies for (3) was also as follows: 6LU7>6WQF>6W9C. All of the studied complexes showed considerable performance, comparable to the standard drug, Favipiravir. Schiff bases (SBs) have a specific role as chelating ligands and SB complexes with transition metal ions have been studied in different fields such as catalyst, photocatalyst, corrosion inhibition, magnetism and biochemistry due to having various physical and chemical properties [1] [2] [3] [4] . From the pharmacological point of view, they have shown antibacterial, antifungal, anti-inflammatory, antioxidant, anti-proliferative, etc. activity and numerous studies have been performed to develop efficient medicines with SB backbone [5] [6] [7] [8] . According to the World Health Organization (WHO), the novel coronavirus COVID-19 was informed pandemic at 2019 and over 270 million people were infected by the end of 2021. Various studies have been directed to find efficient medicines for this disease [9] . Molecular docking is an efficient tool that is used to study the interactions between two or more molecular structures, e.g. drugs and proteins or enzymes [10] . This method is aimed to study the interactions of small molecules in the binding pockets of the target proteins to identify the correct poses of the ligands in such binding pockets [11] . Considering the above mentioned, in this study, we report the synthesis and characterization of new Cu(II) mixed-ligand Schiff base complexes by various spectroscopic techniques including SCXRD. The SB complex (1) with NN'O type unsymmetrical main ligand and pyridine co-ligand was synthesized following a template method using 1,3-propanediamine, 5methoxysalicylaldehyde, pyridine, and copper(II)perchlorate hexahydrate. The other target complexes were synthesized from (1) with ligand exchange of the monodentate pyridine by bidentate ligands. The molecular docking was employed to study the interactions between these complexes and the main proteases (MPros) of the SARS-CoV-2 virus (PDB IDs: 6LU7, 6WQF, and 6W9C) [12, 13] . The studied MPros are shown to be the key for SARS-CoV-2 virus replication which makes it the potent target for inhibitor drugs [14] [15] [16] . Our results show that the synthesized complexes showed great interaction with the studied three main proteases of COVID-19. These data could be used for rational drug design against this disease. The starting materials and solvents were purchased from commercial vendors and were consumed without re-purification. Fourier transform infrared spectra were obtained using KBr pellets by a Shimadzu 8400S device in the area from 400-4000 cm -1 . The ultraviolet-visible absorption spectra were obtained on a Shimadzu UV-1650 PC apparatus using a quartz cuvette and methanol as the solvent and reference. The elemental analyses were done on an Eager 300 for EA1112 analyzer. The X-ray diffraction measurements were carried out on a MAR345 dtb diffractometer equipped with an image plate detector using Mo-K α X-ray radiation. The structures were solved by direct methods using SHELXS-97 and refined using full-matrix least-squares method on F2, SHELXL [17, 18] . All non-hydrogen atoms were refined anisotropically. Molecular docking simulations were performed using the software AutoDock 4.2. The crystallographic data for complexes (2) and (3) were exported as a CIF file and converted to PDB format using Mercury software. The complex (1) was optimized via standard 6-311G** basis sets which were used for C, H, N, and O atoms while the LANL2DZ basis set along with the effective core potential (ECP) functions were employed for Cu. The crystal structures of SARS-CoV-2 primary proteases (PDB IDs: 6LU7, 6W9C, and 6WQF) were downloaded from Protein Data Bank (https://www.rcsb.org) and the standard drug was downloaded from PubChem. By eliminating all water molecules, assigning Gasteiger partial charges, and adding polar hydrogen, the 6LU7/6W9C/6WQF proteins structures were created. A grid box with 116×100×126 Å points and a grid-point spacing of 0.636 was used to create docking simulations for 6LU7. For 6W9C and 6WQF the grid box with 126×126×126 Å points and the same spacing was used. A Lamarckian genetic algorithm method was also employed in this investigation. The number of assessments and genetic algorithm runs were limited to 200. We looked at the constructions and chose the ones with the lowest energy among those that were similar. The interactions of 6LU7/6W9C/6WQF with the complexes, as well as their binding modalities, were then investigated using the AutoDock program, UCSF Chimera 1.5.1 software, Accelrys Discovery Studio 3.0, and DS Visualizer, LigPlus [12, [19] [20] [21] . Pharmit link (http://pharmit.csb.edu) was used to search for pharmacophore modeling. This study aims to investigate interaction features between Cu(II) complexes to coronavirus variation structures as a receptor. The number of H-bond acceptor (H-acc.), H-bond donor (H-don.), Hydrophobic (Hyd.) were also reported [22] . In a typical experiment, 0.76 g of 2-hydroxy-5-methoxybenzaldehyde (5.00 mmol) was dissolved in 30 mL of methanol in a round-bottom flask. While this solution was being continuously stirred at room temperature, 5 mL of an aqueous solution of Cu(ClO 4 ) 2 .6H 2 O (5.00 mmol, 1.85 g) was slowly added, followed by the addition of 0.80 g (10.00 mmol) of pyridine. The reaction mixture was stirred for 1 hour. 0.37 g of 1,3-propandiamine (5.00 mmol), dissolved in 5 mL of methanol, was then added dropwise to the reaction mixture. This reaction mixture was further stirred for 3 hours without heating. The green precipitate was collected by filtration and washed with diethyl ether and air-dried. The obtained powder was recrystallized from methanol to give needle-shaped polycrystals of the target complex. The yield was 1. 1 mmol, 0.44 g of (1) was suspended in 10 mL of methanol and then, 5 mL of methanolic solution of 2,2'-bipyridine (2 mmol, 0.31 g) was slowly added to the reaction mixture. The reaction mixture was stirred for 3 h. This complex was prepared following a similar procedure as described for (2) Salen-type tetradentate SBs are the most-widely studied SB ligands and are categorized as symmetrical and unsymmetrical SBs [7] . Such symmetrical ligands contain diamines that have a plane of symmetry (such as ethylenediamine and 1,3-propanediamine) which are doubly condensed with the same aldehyde or ketone (Scheme 1). and were also solube in other polar solvents such as methanol, ethanol and dichloromethane. The complexes were stable below about 200 ºC but decomposed above it. This is usual for the perchlorate salts which decompose, sometimes explosively at elevated temperatures. Single crystals suitable for x-ray crystallography were grown by slow evaporation of the methanolic solution of the complexes over a week or two. Figure 1 shows the molecular structure of (2) with atom numbering Scheme. Molecular structure of (3) is also shown in figure 2 . The crystallographic data and the refinement parameters are collected in table 1. Table 2 contains the selected bond lengths and angles around the central metal ion. The molecular structure of (2) is consisted of one complex cation together with a disordered perchlorate anion in the asymmetric unit. Two perchlorate oxygen atoms are disordered in three positions with refined occupancy factors of O3/0.65, O6/0.75 and O7/0.6. As could be seen from uncondensed NH 2 group, N atom from the C=N, and the O atom from the deprotonated phenolic group. This ligand is mono-anionic, and since the other ligand i.e. bpy is neutral, the complex has a (+1) charge which is compensated by the negatively charged perchlorate anion. The apical position of the SBP is also occupied by the other N atom from the bpy ligand. The geometry index (τ) which was calculated from τ = (β-α)/60 is equal to 0.435 [21] . This value is zero for the ideal SBP while it is equal to 1 for ideal trigonal bipyramidal (TBP) geometry. In this equation, β and α are the two greatest bond angels around the central metal ions, respectively. The value of (τ) is almost between the two limiting values but it is slightly closer to that of SBP and hence, the geometry could be described as distorted SBP [22] . The obtained bond lengths, bond angles, and the (τ) value is in the same range of previously reported similar complexes [23, 24] . The weak hydrogen bonds N-H…O, table 3, together with the CH-π and π -π stacking interactions stabilize the entire 3D Network structure (figure 3). Crystal structure of (3) is very much similar to (2). It consists of one complex together with one perchlorate ion in the asymmetric unit. As could be seen from figure 2, the Schiff base ligand in this complex is also deprotonated from the phenolic OH and is monoanionic. The value of τ for this complex is 0.388 and again, the geometry around the central metal ion could be considered as The IR and UV-Vis spectroscopic data could be easily explained based on the obtained crystallographic data. In the FTIR spectra of the three complexes (supplemental figures S.1-3 In the electronic spectra of the complexes (supplemental figures S.4-6), four signals were observed. The two high intensity and energy signals which were observed below 300 nm where assigned to the π→π* transitions. The medium intensity signal at around 400 nm could be assigned to the MLCT and the very low intensity signals above 600 nm, which were only observed at higher concentrations could also be easily assigned to the d→d transitions [26] . The coronavirus illness (COVID-19) epidemic has caused severe damages all around the world. A lot of researches have been conducted to find new and effective drugs for this disease. Molecular docking is a great tool to study the drug/receptor interactions and is used to discover factors affecting the effectiveness of the drugs towards a special disease [10, 12] . Metal-based drugs have also been examined both theoretically and clinically to cure some diseases such as cancer, etc. Both and GLU166 at 2.17, 2.11 and 1.88 Å. One C-H. bondings was found between the C of amine to the oxygen atoms of LEU141 at 3.28 Å. One π-σ Hyd. was found between the C of OCH 3 to HIS41 at 3.76 Å. One π-Alkyl Hyd. was also found between the aldehyde ring to MET165 at 5.38 Å. Another structure of coronavirus is papain-like protease of SARS CoV-2 (6W9C) [19] . We The other SARS CoV-2 protease structure that we studied, in this paper, was the 6WQF protein [12] . The ligand (SB) and complexes (1), (2) and ( 6 and figure 7) . Like 6WC9 and 6LU7, when relative binding energies (∆G binding ) were compared, complex (3) performed better than (SB) ,complexed (1), (2), and the standard drug Favipiravir. Using Pharmit link, the maximum interactions between the new compounds and coronavirus structures (6LU7, 6WC9 and 6WQF) was obtained [27] . The initial step towards understanding how different complexes can bind to receptor, is pharmacophore. The reason why (3) had better anti-COVID-19 efficacy than (SB), (1), (2) and Favipiravir was determined by pharmacological characterization [28] . Three new mixed-ligand complexes with an unsymmetrical Schiff base ligand and N-donor heterocyclic coligands were synthesized and characterized. Crystal structures of two of the complexes were obtained by SCXRD. Molecular docking and pharmacophore modelings were performed to investigate the interactions between these three complexes as well as the main Schiff base ligand with three main proteases of SARS-CoV-2. The following results were obtained from molecular docking and pharmacophore studies: 1. Complex (3) showed better docking scores with the studied proteases. The order of the binding best energies for (3) were as follows 6LU7>6WQF>6W9C. All of the complexes showed better results than Favipiravir. Besides, the order of the scores were (3)>(2)>(1)>(SB) which could be attributed to the presence of more aromatic rings. The higher the number of the aromatic rings, the higher the affinity of these compounds to interact with the aminoacids at the active sites. 2. The (SB) main ligand had greater effect on the drug/receptor interactions than the co-ligands. This could be rationalized based on the fact that the interactions of the (SB) moiety were observed at lower distances. 3. The pharmacophore results confirmed the docking results. 4. Our studies suggest that such complexes may merit further studies in the context of possible therapeutic agents for COVID-19. Three new mixed-ligand Schiff base complexes with N-donor co-ligands were synthesized and characterized. Molecular docking and pharmacophore modeling were performed on main proteases of SARS-CoV-2 virus. 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