*2.1. Preface*

The micro analytical technique confirmed that the molar ratio between HPL donor and PA and TCNQ (π–acceptors) was 1:1. The conductivities of HPL-PA and HPL-TCNQ CT complexes were 45 and 53 Ω−<sup>1</sup> cm−<sup>1</sup> mol−<sup>1</sup> , respectively. The low conductance values of the synthesized CT complexes deduced the formation of D<sup>+</sup> and A<sup>−</sup> datives anions based on the association of donor–acceptor chelation. The electronic spectra of synthesized CT complexes of HPL-PA and HPL-TCNQ refer to the association of new electronic absorption bands (447 nm, 738, and 837 nm), which did not exist in the spectra of free reactants. The infrared spectrum of HPL-PA complex was assigned upon intermolecular hydrogen bonding between the –OH group of the PA acceptor and basic oxygen atom center of HPL donor (Figure 1). In the case of the infrared spectrum of HPL-TCNQ solid CT complex

(Figure 2), the –OH stretching band of HPL shifted to higher frequencies. This was assigned to the increase in polarity status, –−O-C≡NH<sup>+</sup> , during the complexation process.

**Figure 1.** Charge-transfer (CT) complex of [(HPL)(PA)].

**Figure 2.** CT complex of [(HPL)(TCNQ)].

The bonding of the –OH group of HPL and the –OH group of PA to the –CN of TCNQ acceptors via intermolecular hydrogen bonding was confirmed by proton NMR spectra of the free HPL donor and its HPL-PA and HPL-TCNQ complexes. The activation energy (E) was used to calculate the thermal stability of both HPL-PA and HPL-TCNQ complexes using Coats–Redfern and Horowitz–Metzger techniques [8–10].

The average activation energies for the [(HPL)(PA)] complex and the [(HPL)(TCNQ)] complex were 132 kJ mol−<sup>1</sup> and 98 kJ mol−<sup>1</sup> , respectively, and the variant data might be influenced by the acceptor type. The activated complexes had a more ordered structure than the reactants, and the activation of entropy (∆S ∗ ) had negative values, indicating that the reaction rates were slower than normal.

The optical band gap (Eg), which refers to the minimum transition energy, was determined based on the electronic absorption spectra. Optical absorption near the edge of the absorption band can be used to estimate E<sup>g</sup> and confirm the formation of CT complexes. The absorption coefficient (α) can be estimated from the transmittance (T) of the complex according to the following equation:

$$\alpha = 1/\text{d} \,\text{ln}\,\text{(1/T)}\tag{1}$$

where d is the sample thickness. The bandgap of CT complexes can be calculated from the relationship between α and E<sup>g</sup> based on the following equation [11]:

$$\alpha \mathbf{h} \mathbf{v} = \mathbf{A} (\mathbf{h} \mathbf{v} - \mathbf{E}\_{\mathbf{g}})^{\mathbf{m}} \tag{2}$$

where (m) equals to 1/2 and 2 for direct and indirect transitions, respectively, whereas (A) is an energy-independent constant. The values of (αhν)2 were plotted against hν. The direct optical bandgap Eg was determined from the linear relationship of the plots at the absorption edge where (αhν)2 = 0 [12]. Eg values for HPL-PA and HPL-TCNQ CT

complexes were 2.483 and 2.895, respectively (Figure 3), and the values were dependent on the nature of the acceptor. These data indicate the conducting behavior of HPL-PA and HPL-TCNQ complexes [13,14]. the nature of the acceptor. These data indicate the conducting behavior of HPL-PA and HPL-TCNQ complexes [13,14].

absorption edge where (αhν)2 = 0 [12]. Eg values for HPL-PA and HPL-TCNQ CT complexes were 2.483 and 2.895, respectively (Figure 3), and the values were dependent on

*Molecules* **2022**, *27*, x FOR PEER REVIEW 4 of 14

**Figure 3.** Plots of optical energy (hν) against (αhν)½ for (**a**) haloperidol–picric acid (HPL-PA) and (**b**) HPL-7,7,8,8-tetracyanoquinodimethane CT complexes. **Figure 3.** Plots of optical energy (hν) against (αhν) 1 <sup>2</sup> for (**a**) haloperidol–picric acid (HPL-PA) and(**b**) HPL-7,7,8,8-tetracyanoquinodimethane CT complexes.

### *2.2. Molecular Docking Studies 2.2. Molecular Docking Studies*

in Table 2.

The docking positions of the synthesized CT complexes [(HPL)(PA)] and [(HPL)(TCNQ)] against serotonin (PDB ID: 6A94) and dopamine (PDB ID: 6CM4) were determined. For comparison, HPL was employed as the control. CT complexes have a larger potential binding energy than HPL in both receptors (Tables 1 and 2). Among them, [(HPL)(TCNQ)] had the greatest docking energy. The theoretical binding energies of [(HPL)(TCNQ)] with serotonin and dopamine were −10.2, and −11.8 kcal/mol, respectively. Additionally, the higher binding energy value of [(HPL)(TCNQ)]–dopamine (CTtD) signifies a stronger interaction with dopamine compared to that with serotonin. The best docking position of CTtD is shown in Figure 4, and the docking data are given The docking positions of the synthesized CT complexes [(HPL)(PA)] and [(HPL)(TCNQ)] against serotonin (PDB ID: 6A94) and dopamine (PDB ID: 6CM4) were determined. For comparison, HPL was employed as the control. CT complexes have a larger potential binding energy than HPL in both receptors (Tables 1 and 2). Among them, [(HPL)(TCNQ)] had the greatest docking energy. The theoretical binding energies of [(HPL)(TCNQ)] with serotonin and dopamine were −10.2, and −11.8 kcal/mol, respectively. Additionally, the higher binding energy value of [(HPL)(TCNQ)]–dopamine (CTtD) signifies a stronger interaction with dopamine compared to that with serotonin. The best docking position of CTtD is shown in Figure 4, and the docking data are given in Table 2.

**Target: PDB: 6A94** 

**Table 1.** Docking score of the ligands and their interactions with serotonin (6A94).


**Table 1.** Docking score of the ligands and their interactions with serotonin (6A94).

**Table 2.** Docking score of the ligands and their interactions with dopamine (6CM4).


**Figure 4.** The best-docked position showing a helical model of dopamine docked with (**a**) CT complex and (**b**) HPL drug only.

The illustration of molecular docking for ligand–receptor interactions depicted in Figure 5a,b. As shown in Figure 5a, CT complex [(HPL)(TCNQ)] with dopamine (CTtD) revealed that the amino acid residues, including His393, Ser193, and Tyr416, formed hydrogen bond interactions. Additionally, Val91 and Trp413 (π-Alkyl); Tyr408 (π-π T-Shaped); Cys118 (π-Alkyl); Thr412 and Leu94 (π-Sigma); and Asp114 (Attractive charge) interactions were present [15,16].

**Figure 5.** 3D representation of the interactions for dopamine docked with (**a**) CT complex and (**b**) HPL drug only.

Molecular docking of HPL drug with serotonin and dopamine revealed the potential binding energies as −10.0 and −10.9 kcal/mol, respectively. The higher binding energy value of HPL–dopamine (HPLD) signifies stronger interaction with dopamine compared to that with serotonin. The best docking position with dopamine (HPLD) is shown in Figure 4, and the docking data are shown in Table 2. Figure 5b shows the interaction between HPL and dopamine, which reveals that the amino acid residue Asp114 formed hydrogen bond interactions. Additionally, Phe198, Phe382, Cys118, and Val91 (π-Alkyl); Trp100, Trp386, and Phe390 (π-π T-shaped); and Lue94 and Thr412 (π-Sigma) interactions were present. This shows that the CT complex [(HPL)(TCNQ)] binds to both receptors more efficiently as compared toHPL alone, and among them, CTtD had the highest binding energy value. 2D representations of ligand–receptor interactions are shown in Figure 6. Hydrophobic, ionizability, aromatic, and hydrogen bond surfaces at the interaction site of [(HPL)(TCNQ)] and dopamine are represented in Figure 7, and those for HPL and dopamine are shown in Figure 8.

**Figure 6.** 2D representation of the interactions for dopamine docked with (**a**) CT complex and (**b**) HPL drug only.

**Figure 7.** Representation of (**a**) hydrogen binding, (**b**) hydrophobic, (**c**) aromatic, and (**d**) ionizability surfaces between dopamine and CT complex.

**Figure 8.** Representation of (**a**) hydrogen binding, (**b**) hydrophobic, (**c**) aromatic, and (**d**) ionizability surfaces between dopamine and HPL drug only.
