*3.2. Crystal Structure of C-2 [Cu(C11H7O2) (C12H8N2) Cl]*·*H2O*

This complex crystallizes in the triclinic system, space group *P*-1, with Z = 2. The asymmetric unit in this structure is composed of a copper (II) cation that is coordinated with the nitrogen atoms of the 1,10-phenanthroline, two oxygen atoms of the 2-hydroxy-1 naphtaldehyde in the equatorial plane, and a chlorine anion in the axial position. We also note the presence of a water molecule.

The Cu(II) atom adopts a square-pyramidal geometry, with a tau value of 0.02 (τ<sup>5</sup> = (β − α)/60, where β = N1-Cu1-O2 = 164.59◦ and α = N2-Cu1-O1 = 163.34◦). In the CuN2O2Cl coordination sphere, the bond lengths of Cu1-N1 and Cu2-N2 are 2.012 (10)Å and 2.007(10)Å, respectively. The bond lengths of Cu1-O1, Cu1-O2, and Cu1-Cl1 are 1.917 Å, 1.931 Å, and 2.537 Å, respectively (Table S2). The apical bond is longer than those of the basal plane, which is in accordance with the literature [30]. These experimental parameters were compared with those calculated in the gas phase; the calculated bond lengths in the copper coordination sphere agree with the corresponding experimental values within a maximum deviation of 3.4%, whereas the bond angles exhibit a maximum deviation of 7.4% (Figure S1a). The dihedral angle between the two planes containing the ligands is 7.33◦ (Figure S1b).

The structure of C-2 is stabilized as a result of the occurrence of an extensive network of C-H···O, C-H···Cl and O-H···Cl hydrogen bonding interactions. One intramolecular hydrogen bond is observed between H5 of C5 with O2, between 1,10-phenanthroline and 2-hydroxy-1-naphthaldehyde; this generated S(5) ring motifs and seven intermolecular hydrogen bonds, as shown in Table 2 and Figure 4a. Moreover, it is worth noting that the cohesion in the crystal is also ensured by the three weak interactions between the π···π stacking type. The first interaction is observed between the centroid of the 1,10-phenanthroline ring (Cu1/N1/C1/C9/N2) (Cg1) and the centroid of the 2-hydroxy-1-naphthaldehyde ring (C13-C18) (Cg2), with a Cg1 ... Cg2 distance of 3.915 Å. The second interaction occurs at a distance of 3.594 Å, between Cg1 and the centroid Cg3 (C15/C16/C19/C20/C21/C22). The third interaction is between Cg4 (C1/C2/C6/C7/C8/C9) and Cg3, with the ring centroids separated by 3.653 Å (Figure 4b).

#### *3.3. FT–IR and UV-Visible Absorption Spectra*

Figure 5a shows the FT-IR spectra of the two complexes. Overall, both complexes show similar IR bands. The strong absorptions at 1604 cm−<sup>1</sup> and 1119 cm<sup>−</sup>1, correspond to the C=O and C-O bonds of the aldehyde, respectively. The C-1 complex exhibits a broad band in the region of 3100–2800 cm−1, which is attributed to the υ(C-H) of the aromatic ring. The bands appearing at 1562 cm−<sup>1</sup> and 1014 cm−<sup>1</sup> are due to the υ (C=N) and υ(C-N) of the 2-2 -bipyridine, respectively. The υ (C=N) band of the thieno ligand is observed at 2063 cm<sup>−</sup>1. In the FT-IR spectrum of C-2, the bands appearing at 3100 cm−<sup>1</sup> and 2855 cm−<sup>1</sup> correspond to the aromatic υ(C-H). The spectrum also shows bands at 1434, 1274, and 730 cm<sup>−</sup>1, which are assigned to the coordinated phenanthroline molecule [31,32].

The two complexes exhibit a d–d transition band at 624–640 cm−1, and a band at 821–833 cm<sup>−</sup>1, which is typical for square pyramidal geometry [30].

Figure 5b shows the UV-visible spectra in the range of 280–440 nm for C-1 and C-2. The absorption peaks of these two complexes are very similar. Nevertheless, those of C-2 are very weak. In the UV region, the two complexes show peaks near 290–300 nm due to the π → π\* aromatic ring. Moreover, we noticed two intense peaks, or a shoulder, in

the (305 → 315 nm) (I)—(310 → 325 nm) (II) region, which can be assigned to the charge transfer between the ligand and the metal.

**Figure 4.** (**a**) Diagram packing of hydrogen bonding, parallel to (**b**,**c**). Dashed lines (green, black) indicate intra- and intermolecular H-bonds, respectively. (**b**) A view of the aromatic ring organization, with centroid–centroid distances (Å) for C-2.

**Figure 5.** The FT–IR Spectrum (**a**) and the overlapping UV-visible spectrum in the DMSO (**b**) of complexes C-1 and C-2.

No d–d bands were observed in the spectra of the two complexes. These bands should be observed in the region of 500–600 nm. Their absence is due to the low concentration (10−<sup>5</sup> mol·L<sup>−</sup>1) of the solutions of the complexes.

#### *3.4. Hirshfeld Surface Analysis*

The intermolecular interactions and the packing modes that occur in crystalline structures can be studied quantitatively using Hirshfeld surface analysis [33]. Hirshfeld surfaces (HS) and fingerprint plots [34] were carried out using Crystal Explorer software [35].

The HS of the C-1 complex was mapped over dnorm in the range of −0.1832 to +1.3833 a.u., as shown in Figure 6a. Color coding is used for each specific region to identify the nature of the occurring intermolecular interactions, wherein contacts that are shorter, equal to, and longer than the sum of the van der Waals radii, correspond to the red, white and blue areas, respectively. The major interactions are caused by H···H, H···S/S···H, H···C/C···H, C···C and H···N/N···H contact. (Figure 6a).

The shape–index surface (Figure 6b) indicates the presence of blue and red triangles that are characteristic of π···π interactions between neighboring molecules, whereas the flat surface patches in the curvedness plots (Figure 6c) reveal planar stacking.

The 2-D fingerprint plots for the C-1 complex show the relative contributions of H···H, H···S/S···H, H···C/C···H, C···C and H···N/N···H contacts to the Hirshfeld surface; these are illustrated in Figure 6d. Contact between H···H comprise the predominant form of interactions (33.7%).

The HS of the C-2 complex is depicted in Figure 7a. The dominant interactions between (water) O-H, C-H, and Cl atoms are represented by the bright-red areas, which are marked as 1, 2, and 3. The light-red spots denoted as 4, 5, 6 and 7 are due to C-H···O and C-H···Cl interactions.

The π···π interactions in the C-2 complex are revealed by the characteristic blue and red triangles on the shape–index surface (Figure 7b), whereas planar stacking is identified by the curvedness plots (Figure 7c) that exhibit characteristic flat surface patches.

The relative contributions of the H···H, H···C/C···H, H···O/O···H, H···Cl/Cl···H and H···N/N···H contacts to the Hirshfeld surface in the C-2 complex are determined using the 2-D fingerprint plots, as illustrated in Figure 7d. As in the C-1complex, the fingerprint plots of the C-2 complex show that the H···H contacts provide the most significant contribution to the Hirshfeld surface (45.1%).

#### *3.5. Inhibitory Activity of the C-1 and C-2 Complexes against the HIV-1 Protease Enzyme*

To provide insight into the binding mode of C-1 and C-2, a molecular docking investigation was carried out. As shown in Figure 8 (upper panel), the tested complexes occupied a common cavity in the receptor, suggesting that C-1 and C-2 block access to the active site of the HIV-1 protease. They are located in the hydrophobic pocket of HIV-1 protease, and they are surrounded by the Val32, Pro81, and Pro79 residues of the active site, and Gly48, Gly49, Ile50, Ile84, Ile47, and Leu84 of the subsites S1/S1 , S2/S2 , and S3/S3 , wherein a strong hydrophobic interaction was observed, as illustrated in Figure 8 (lower panel). The ligand–receptor complex indicates that most of the ligand is positioned in the flap region of the enzyme, as represented by the Ile50, Gly51, Gly52, and Gly49 residues. No hydrogen bonds were found in the docked structures.

The estimated binding energies were −7.6 kcal/mol for C-1 and −7.1 kcal/mol for complex-ref, respectively. This result suggests that the tested compounds that were produced with HIV-1 protease formed stable complexes. The best ligand/receptor complex was formed by using C-2 with a binding energy equal to −8.3 kcal/mol.

**Figure 6.** A view of the Hirshfeld surface for (I), which is mapped over (**a**) dnorm in the range of −0.1832 to +1.3833 arbitrary units. (**b**) Shape–index, (**c**) curvedness, and (**d**) 2-D fingerprint plots for the C-1 complex, which reveal the contributions of all contacts.

**Figure 7.** A view of the Hirshfeld surface for (II), which is mapped over (**a**) dnorm in the range of −0.4175 to +1.3253 arbitrary units. (**b**) Shape–index, (**c**) curvedness, and (**d**) 2-D fingerprint plots for the C-2 complex, which reveal the contributions of all contacts.

**Figure 8.** The upper panel shows the molecular docked model of C-1 (blue color) and C-2 (green color) in the HIV-1 protease active pocket. The enzyme is shown as a surface; the lower panel shows the best-docked conformation of C-1 (**a**) and C-2 (**b**) in the binding site of HIV-1.

#### **4. Conclusions**

Two new copper (II) complexes, based on 2,2 -bipyridine and 1,10-phenanthroline ligands, were synthesized and characterized using X-ray crystal diffraction, FT–IR, and UV-visible spectroscopies, as well as DFT calculations.

The crystalline structure of synthesized complexes consists of five coordinated Cu (II) ions in a square-pyramidal geometric structure, wherein the packing arrangement is mainly stabilized using hydrogen bonding networks and π–π stacking interactions. Hirshfeld surface analysis indicates that H··· H interactions account for 33.7% and 45.1% of the total Hirshfeld surface of the C-1 and C-2 complexes, respectively.

Based on computational results, the docking analysis revealed that both C-1 and C-2 Cu (II) complexes were more potent than the inhibitor reference when binding to the HIV-1 protease; the interactions that occurred were hydrophobic, resulting in their stabilization in the enzyme cavity.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cryst12081066/s1, Figure S1: The copper square-pyramidal environment (a), and the dihedral angle between the two ligands (b) of C-2; Table S1: Selected experimental and calculated bond lengths (Å) and angles (◦) for C-1; Table S2: Selected experimental and calculated bond lengths (Å) and angles (◦) for C-2.

**Author Contributions:** Conceptualization, M.H. and H.M.; Data curation, M.H., I.H., M.D. and S.R.; Formal analysis, M.H., I.H., M.D. and S.R.; Funding acquisition, F.A.M.A., M.A.A. and S.T.; Investigation, M.H. and I.H.; Methodology, M.D., Y.B. and S.R.; Project administration, H.M.; Resources, I.H., M.D. and H.M.; Software, M.H. and M.D.; Supervision, H.M.; Validation, F.A.M.A., M.A.A., S.T. and H.M.; Writing—original draft, M.H., I.H., M.D. and Y.B.; Writing—review & editing, Y.B., N.S., F.A.M.A., M.A.A. and S.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

