Crystal structure and molecular docking study of (E)-2-{[(E)-2-hydroxy-5-methylbenzylidene]hydrazinylidene}-1,2-diphenylethan-1-one

The title compound, C22H18N2O2, is a Schiff base that exists in the phenol–imine tautomeric form and adopts an E configuration. The molecular structure is stabilized by an O—H⋯N hydrogen bond, forming an S(6) ring motif.


Chemical context
Schiff bases have wide applications interests as corrosion inhibitors (Antonijevic & Petrovic, 2008), biologically active materials (Al Zoubi, 2013) and thermostable systems (Destri et al., 1998). The optical and semiconducting phenomena of the azomethine linkage group have been also widely investigated as a result of their photo-efficiency, with wavelengths depending on the chemical architecture of the Schiff-base molecules (Iwan & Sek, 2008). Schiff bases have significant importance in the development of metal complexes, because Schiff base ligands are potentially capable of forming stable complexes by coordination of metal ions via their oxygen and nitrogen donors (Ebrahimipour et al., 2012). Hydrazine, hydrazone and hydrazide derivatives are relatively scarce in nature and have been isolated from plants, marine organisms and microorganisms. These compounds exhibit remarkable structural diversity and relevant biological activities (Le Goff & Ouazzani, 2014). Salicylaldehyde complexes with transition metals have worked as antimalarial and antileukemic agents (Scovill et al., 1982). In this study, a new Schiff base with potential biological character, (E)-2-{[(E)-2-hydroxy-5-methylbenzylidene]hydrazineylidene}-1,2-diphenylethan-1-one, was obtained in crystalline form from the reaction of 2-hydroxy-5-methylbenzaldehyde with (E)-2-hydrazineylidene-1,2-diphenylethan-1-one. We report here the synthesis, crystal and molecular structure of the title compound. We have also performed a molecular docking study to determine possible intermolecular interactions between the COVID-19 main protease (PDB ID: 6LU7) and the title compound.

Structural commentary
The asymmetric unit of the title structure contains one molecule ( Fig. 1), which crystallizes in the phenol-imine tautomeric form with an E configuration for the imine functionality. The hydroxy H atom is involved in a strong intramolecular O-HÁ Á ÁN hydrogen bond, forming an S(6) ring motif, which stabilizes the molecular structure. The dibenzylidene hydrazine unit is approximately planar with the dihedral angle formed by the two terminal phenyl rings of 7.62 (15) . On the other hand, the molecule is non-planar, because the C1-C6 ring is nearly perpendicular to the C9-C14 and C16-C21 rings with dihedral angles of 88.78 (13) and 82.26 (14) , respectively. The C17-O2, C15-N2 and C15-C16 bond lengths in the molecule are 1.359 (5), 1.287 (5), and 1.452 (5) Å , respectively. These results suggest single-bond character for C17-O2 and C15-C16 and double-bond character for the C15-N2 bond as expected for a phenol-imine structure (Kaştaş et al., 2020). The bond lengths and angles in the title molecule agree reasonably well with those found in closely related structures (Bouchama et al., 2015;Wieland et al., 2011). Based on the refinement parameters, the tautomeric form of the compound is the phenol-imine form in which the tautomeric proton (H2) is located on the phenolic oxygen atom (O2). The distance of 2.650 (5) Å between the nitrogen and the oxygen atoms show that the molecule has a strong O-HÁ Á ÁN intramolecular hydrogen bond, forming an S(6) ring motif.

Figure 2
A view of the crystal packing of the title compound. Blue dashed lines denote the intermolecular C3-H3Á Á ÁO2 hydrogen bonds forming an inversion dimer (Table 1).

Figure 1
The molecular structure of the title compound with the atom-labelling scheme. Displacement ellipsoids are drawn at the 40% probability level. Dashed lines denote the intramolecular O-HÁ Á ÁN hydrogen bonds forming an S(6) ring motif.

Molecular docking study
Molecular docking is a crucial method for investigating the interaction between small molecules and macromolecules. Intermolecular contacts that occur between a ligand and a protein are evaluated by molecular docking. In summary, this method is one of the major approaches to estimate the binding area where the ligand connects with the protein. In this study, AutoDockVina (Trott & Olson, 2010) was utilized for predicting binding sites between the title molecule and 6LU7. 6LU7 is a main protease of COVID-19, and can be efficient for drug design to treat ailments (Jin et al., 2020). The threedimensional structure of 6LU7 was received from the Protein Data Bank (PDB). Before the computation, the protein must be prepared for efficient insertion. Therefore, all water molecules and ligands were removed from protein active sites. LYS102, VAL104, GLN110, THR111, ASN151, ASP153 and SER158 were defined as active areas. According to these active sites, grid box dimensions were determined to be 100 Â 100 Â 95 Å . In addition, 'x, y, z' centers were adjusted to be À20.378, 27.848, 69.124, respectively, and then the 6LU7 protein was saved in PDBQT format for calculations. In the next step of the experiment, rotatable angles for coupling structures were identified and recorded in PDBQT format. Discovery Studio Visualizer (Biovia, 2017)  Three-dimensional visualization of the intermolecular interactions for the best binding pose of the title compound docking with 6LU7.

Figure 4
Two-dimensional visuals of the intermolecular interactions for the best binding pose of the title compound docking with 6LU7.
bonding type of interaction is demonstrated in Fig. 3. The 2D and 3D visuals of the intermolecular interactions for the best binding pose of the title compound docked into macromolecule 6LU7 can be seen in Fig. 4. In addition, the docking conformation is shown in Fig. 5. As a consequence, the title compound could be a potential molecule for drug design to treat severe acute respiratory syndrome resulting from the novel corona virus SARS CoV2 because of its affinity and ability suitable to adhere to active sites of the protein.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The O-bound H atom was located in a difference-Fourier map and refined with O-H = 0.82 Å and U iso (H) = 1.5U eq (O). The C-bound H atoms were positioned geometrically and refined using a riding model with C-H = 0.93 and U iso (H) = 1.2U eq (C) for aromatic H atoms, and with C-H = 0.96 Å and U iso (H) = 1.5U eq (C) for methyl H atoms.   SHELXL2018/3 (Sheldrick, 2015b); molecular graphics: PLATON (Spek, 2020); software used to prepare material for publication: WinGX (Farrugia, 2012).

(E)-2-{[(E)-2-Hydroxy-5-methylbenzylidene]hydrazinylidene}-1,2-diphenylethan-1-one
Crystal data Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.