Docking and Theoretical Studies of Benzoxazole Derivative with Enhanced NLO and Anti-Hyperlipidemic Activity

Introduction

Antihyperlipidemic activity refers to the ability of a compound to reduce lipid levels, particularly cholesterol and triglycerides, thereby lowering the risk of atherosclerosis, coronary artery disease, and stroke.^1,2 Key therapeutic targets include ACAT and HMG-CoA reductase, and recent efforts focus on developing novel synthetic and natural inhibitors to overcome statin intolerance.³ Notably, benzoxazole-based compounds have previously shown promising ACAT inhibitory activity, supporting their potential as antihyperlipidemic agents.^4-6
The benzoxazole nucleus, composed of a fused benzene and oxazole ring, is a key heterocyclic framework widely explored in medicinal and materials chemistry.^7-10 Its strong π-electron delocalization and planarity confer unique physicochemical and biological properties.¹¹ Benzoxazole derivatives display diverse pharmacological activities i.e. antimicrobial, anticancer, anti-inflammatory, antiviral, antioxidant, antitubercular, and antihyperlipidemic attributed to their ability to form hydrogen bonds, π-π stacking, and hydrophobic interactions with biological targets.^12-14

Benzoxazole derivatives continue to represent a privileged scaffold in medicinal chemistry due to their diverse pharmacological activities and structural versatility. Figure 1 illustrates a series of benzoxazole-based compounds (1-5) exhibiting significant biological potential across various therapeutic areas. Compound 1 acts as an anti-HIV agent.¹⁵, while compound 2 is identified as an anti-inflammatory agent.¹⁶ Compound 3 displays promising anticancer activity through possible apoptotic pathways.¹⁷ while compound 4 functions as a selective COX-2 inhibitor.¹⁸ Moreover, compound 5 exhibits antibacterial properties.¹⁹ The highlighted structure in the dashed box represents a novel benzoxazole analog designed in this work, aimed at enhancing biological potency through rational modification of the core scaffold. Beyond medicinal applications, benzoxazole derivatives hold great significance in materials science due to their superior optoelectronic properties, such as high thermal stability, strong fluorescence, and efficient intramolecular charge transfer.^20-22 These features make them attractive candidates for nonlinear optical (NLO) materials, OLEDs, and photovoltaic devices.

Figure 1: Some examples of bioactive benzoxazole derivatives. Click here to View Figure

However, despite extensive synthetic and biological studies, derivatives like N-ethyl-N-(2-(2-(5-methylbenzo[d]oxazol-2-yl)hydrazineyl)ethyl)aniline (NMBA) remain theoretically underexplored. A lack of computational investigation limits insight into their electronic structure, reactivity, and stability. Modern quantum chemical tools, especially Density Functional Theory (DFT) and Time-Dependent DFT (TD-DFT), provide powerful means to elucidate these molecular characteristics and rationalize their structure-property relationships.^23,24

Density Functional Theory (DFT) calculations at the B3LYP/6-311++G(d,p) level were performed to optimize the molecular structure of NMBA and evaluate its electronic and optical properties through FMO, DOS, MEP, and NLO analyses. Solvent effects were modelled using the PCM approach, while TD-DFT calculations provided insights into excited-state transitions and absorption spectra. Molecular docking using PyRx–AutoDock Vina against receptor 1DQ9, validated via Ramachandran analysis, revealed the compound’s strong binding affinity and stability. This integrated DFT–TDDFT–docking study elucidates NMBA’s electronic behaviour and bio interaction potential, emphasizing its dual applicability in optoelectronic and pharmaceutical fields.

Computational Details

Density functional theory (DFT) calculations

All quantum chemical calculations were carried out using the Gaussian 09W software package.²⁵ The molecular geometry of (NMBA) was fully optimized in the gas phase without any symmetry constraints using the B3LYP hybrid functional in conjunction with the 6-311++G(d,p) basis set.^26,27 Frequency calculations confirmed that the optimized geometry corresponds to a true minimum on the potential energy surface, as no imaginary frequencies were observed. All visualizations of optimized structures, FMOs, and MEP surfaces were generated using GaussView 6.0 ²⁸ and ChemCraft 1.8 ²⁹  software.

Molecular docking studies

Molecular docking is a robust computational technique used to predict the most favourable orientation of ligands within protein active sites, providing insight into interaction strength and binding specificity.³⁰ In this study, docking analyses were carried out to explore the antihyperlipidemic potential of the benzoxazole derivative (NMBA) against the ACAT enzyme (PDB ID: 1DQ9.³¹ a pivotal target in cholesterol metabolism. Inhibition of ACAT and HMG-CoA reductase (HMGR) is known to lower cholesterol esterification and enhance LDL clearance, thereby maintaining lipid homeostasis. Considering the therapeutic limitations of conventional statins, AutoDock Vina (PyRx) was employed to simulate NMBA-ACAT interactions and predict its potential mechanism of action. Protein preparation involved the removal of crystallographic water molecules and the addition of hydrogen atoms to optimize binding site geometry. The obtained docking results provided binding affinities and optimized ligand conformations, which were further analysed using BIOVIA Discovery Studio Visualizer 2025.³² This analysis enabled visualization of key hydrogen bonding, hydrophobic, and π–π stacking interactions, offering detailed insights into the binding stability and interaction mechanism of the NMBA–ACAT complex.

Results and Discussion

Optimized geometry

The optimized molecular geometry of NMBA was obtained at the B3LYP/6-311++G(d,p) level of theory in both gas and aqueous phases. The equilibrium geometrical parameters, including selected bond lengths and bond angles, are summarized in Tables 1 and 2, respectively. The optimized structure (Figure 2) reveals that NMBA maintains a nearly planar conformation around the benzoxazole and hydrazine linkage, whereas the ethyl aniline fragment exhibits slight torsional flexibility due to steric and electronic interactions.

Figure 2: Optimized molecular structure of title compound in gas and water phase. Click here to View Figure

The optimized geometrical parameters reveal minimal differences between the gas and solvent phases, indicating the structural rigidity of the NMBA framework. The C-C bond lengths within the benzoxazole ring (1.378-1.416 Å) are characteristic of aromatic conjugation, while slight elongation of bonds such as R(3-4), R(4-5), R(5-6), and R(6-7) in the aqueous phase is attributed to solvent-induced polarization and partial π-electron delocalization. The C-N bonds linking the benzoxazole and hydrazine moieties (e.g., R(3-10) = 1.4543 Å in gas, 1.4572 Å in water) are marginally longer than typical C-N single bonds, suggesting partial double-bond character due to conjugation between the benzoxazole nitrogen and the hydrazine lone pair. The N-N linkage within the hydrazine bridge further supports resonance delocalization across the donor-acceptor framework, promoting efficient π-electron flow. Meanwhile, C-H and N-H bonds (e.g., R(1-26), R(1-27), R(2-28)) exhibit negligible changes (<0.01 Å) upon solvation, reflecting minimal solvent influence on peripheral hydrogens. Overall, solvation produces only minor geometric adjustments while enhancing dipolar stabilization through dielectric screening, with slight C-N and C-O bond contraction in water suggesting additional stabilization via hydrogen bonding and dipole–dipole interactions with the solvent continuum.

The calculated bond angles of NMBA exhibit remarkable consistency between gas and solvent phases, confirming its structural stability. Angles within the benzoxazole core (e.g., A(3-4-5) ≈ 121°) align with typical sp² hybridization, supporting its aromatic nature. The N-C-N and C-N-C angles in the hydrazine linkage show slight pyramidalization due to lone-pair interactions and partial conjugation. Minimal deviations in the ethyl aniline unit upon solvation indicate negligible solvent influence on local geometry. Minor angle expansions at donor sites reflect subtle structural relaxation in polar media from enhanced charge delocalization.

Table 1: Bond lengths of title compound.

Table 2: Bond angles of title compound.

Frontier molecular orbital (FMO) and global reactivity analysis

The frontier molecular orbitals (HOMO and LUMO) are key indicators of a molecule’s electronic behaviour, stability, and reactivity.³³ The HOMO-LUMO energy gap reflects charge-transfer efficiency and chemical responsiveness. Along with, global descriptors such as ionization potential, hardness, and electrophilicity provide quantitative insight into electron-donating and accepting tendencies, collectively revealing the molecule’s reactivity and potential in optoelectronic and biological applications.^34,35  The computed E_HOMO values are -5.4139 eV (gas) and -5.4447 eV (water), while E_LUMO values are -0.6955 eV (gas) and -0.7804 eV (water), showing slight stabilization in the aqueous phase due to solvent polarity (table 3). The energy gap (ΔE) of 4.7185 eV (gas) and 4.6643 eV (water) indicate marginal narrowing upon solvation, suggesting enhanced polarizability, chemical softness, and improved charge-transfer potential features beneficial for NLO and bio-interaction properties (figure 3).

The ionization potential (5.4139 eV in gas, 5.4447 eV in water) indicates moderate electronic stability and a fair electron-donating tendency of NMBA. The electron affinity slightly increases from 0.6955 eV to 0.7804 eV in water, reflecting improved electron-accepting ability in a polar medium. A minor decrease in chemical hardness (2.3592 to 2.3322 eV) and an increase in softness (0.2119 to 0.2144 eV⁻¹) suggest enhanced polarizability and electronic flexibility, favourable for strong NLO and bioactive responses. The rise in electronegativity (3.0547 to 3.1126 eV) and the more negative chemical potential (-3.0547 to -3.1126 eV) further indicate increased electron-attracting capacity. Additionally, the electrophilicity index (1.9777 to 2.0771 eV) and maximum charge transfer index (ΔNmax: 1.2948 to 1.3346) confirm stronger electrophilic and charge-transfer tendencies in aqueous phase, consistent with enhanced reactivity and improved protein-binding potential.

Table 3: Global reactivity descriptors in gas and water phase.

Density of states (DOS) analysis

The Density of States (DOS) analysis (Figure 4), computed at the B3LYP/6-311++G(d,p) level, provides deeper insight into the electronic structure of NMBA in both gas and aqueous phases. The occupied orbitals (green) lie below the Fermi level, while the unoccupied orbitals (red) appear above it. The HOMO is primarily localized on the benzo[d]oxazole and hydrazine regions, indicating strong electron-donating capability, whereas the LUMO is mainly distributed over the aniline moiety, signifying electron-accepting characteristics. The calculated energy gaps of 4.7185 eV (gas) and 4.6643 eV (water) confirm a moderate donor-acceptor interaction and efficient charge transfer, highlighting NMBA’s potential for optoelectronic and bioactive applications.

Figure 3: FMO’s of title compound in gas and water phase. Click here to View Figure

Figure 4: Density of states (DOS) spectrum in gas and water phase. Click here to View Figure

Molecular electrostatic potential (MEP) analysis

The Molecular Electrostatic Potential (MEP) map (Figure 5) of title compound, computed at the B3LYP/6-311++G(d,p) level, illustrates the charge distribution across the molecular surface in gas and aqueous medium. The red regions indicate electron-rich sites associated with negative potential, mainly localized around oxygen and nitrogen atoms, suggesting preferred sites for electrophilic attack. Conversely, the blue regions represent electron-deficient zones, favourable for nucleophilic interactions. The distinct variation in electrostatic potential confirms the molecule’s strong intramolecular charge transfer and supports its potential reactivity in biological recognition and interaction processes.

Figure 5: MEP of title compound in gas and water phase. Click here to View Figure

Table 4: The maximum wavelength (λ_max), excitation energy, oscillator strength (f), and major contributions in gas and water phase.

TD-DFT (UV-Vis) analysis

Time-dependent DFT (TD-DFT) analysis at the B3LYP/6-311++G(d,p) level was performed to examine the electronic excitation behaviour of NMBA in both gas and aqueous phases (Figure 6). Three major π→π* transitions were observed at 262, 260, and 248 nm in the gas phase, with the most intense at 248 nm (f = 0.2024). In the aqueous phase, these bands showed a slight red shift (267, 255, and 249 nm) and increased oscillator strengths, indicating enhanced charge-transfer character and solvent stabilization of the excited states (table 4). These results confirm strong intramolecular charge transfer (ICT) and improved optical responsiveness of NMBA in polar environments, supporting its potential for NLO and bioactive applications.

Figure 6: Theoretical UV spectra of title compound in gas and water phase. Click here to View Figure

Non-linear optical (NLO) analysis

Nonlinear optical (NLO) studies are fundamental in assessing molecular systems for their potential in photonic and optoelectronic technologies, with dipole moment, polarizability, and first-order hyperpolarizability serving as key descriptors.

The following expression is employed in NLO analysis:

Other equations used in this study are:

Where μ = the total static dipole moment, α = mean polarizability, and β_tot = mean first-order hyperpolarizability.

Table 5: NLO properties for title compound in gas phase.

The nonlinear optical (NLO) properties of NMBA, calculated at the B3LYP/6-311++G(d,p) level (Table 5), were compared with those of urea, a standard NLO reference material [36]. The dipole moment (μ) of NMBA increased from 1.4117 D (gas) to 2.2498 D (water), whereas urea exhibits only 1.373 D, indicating that NMBA possesses greater molecular polarity and charge separation, particularly in polar media. The average polarizability (⟨α⟩) of NMBA was found to be 37.7110×10^-24 e.s.u. (gas) and 50.9651×10^-24 e.s.u. (water), approximately 8.3 and 11.3 times higher than that of urea (4.52×10^-24 e.s.u.), signifying enhanced electronic cloud deformation under an applied electric field. Furthermore, the total first-order hyperpolarizability (β_tot) of NMBA exhibited a remarkable increase from 5856.0579×10^-33 e.s.u. (gas) to 20447.4735×10^-33 e.s.u. (water), which is about 17.6 and 61.4 times greater than that of urea (333×10^-33 e.s.u.), respectively. This substantial enhancement demonstrates the strong intramolecular charge transfer (ICT) between the aniline donor and benzoxazole acceptor units. Collectively, the higher μ, ⟨α⟩, and βtot values confirm that NMBA possesses far superior NLO characteristics than urea, underscoring its promise for advanced optoelectronic and photonic applications.

Figure 7: Ramachandran plot of 1DQ9. Click here to View Figure

Table 6: Molecular docking of the title compounds with anti-cholesterol target proteins.

Ramachandran plot

The Ramachandran plot of the 1DQ9 protein confirms excellent stereochemical quality, with most residues located within the energetically favoured regions (figure 7). The φ–ψ torsion angles are densely clustered in the α-helical (φ ≈ -60°, ψ ≈ –45°) and β-sheet (φ ≈ -135°, ψ ≈ 135°) regions, indicating well-defined secondary structures. Nearly all residues fall within the allowed and generously allowed regions, signifying minimal steric hindrance and optimal backbone geometry. Only a few residues appear in disallowed regions, likely representing flexible loops or functionally relevant conformations. Overall, the plot validates the structural reliability and stability of the 1DQ9 protein model for subsequent computational and docking analyses.

Figure 8: (A) 3D visualization of ligand binding within the 1DQ9 active site; (B) 3D interaction; (C) 2D interaction; (D) aromatic surface; Click here to View Figure

Molecular docking

Molecular docking was employed to explore the binding interactions of NMBA with the anti-cholesterol target protein ACAT (PDB ID: 1DQ9). The compound exhibited a strong binding affinity with an energy of -7.50 kcal/mol, indicating a stable and favourable interaction within the active site (Table 6). A key hydrogen bond with ASN658 (2.02428 Å) anchored the ligand, while π-π stacking with PHE628 and multiple hydrophobic contacts with MET655, ALA654, VAL805, and ALA826 (4.22481-5.19079 Å) further stabilized the complex. These interactions reflect effective accommodation of NMBA within the receptor pocket through electrostatic and van der Waals forces. Overall, the docking results highlight NMBA’s promising inhibitory potential against ACAT, supporting its candidature as a potential antihyperlipidemic agent and emphasizing the utility of molecular docking in rational drug design.

Figure 8 presents the molecular docking visualization of the NMBA-1DQ9 complex. The overall 3D structure and binding pocket are shown in Figure 8A, with an enlarged view in figure 8B highlighting key ligand-residue interactions. The 2D interaction diagram (Figure 8C) confirms a conventional hydrogen bond with ASN658 and multiple π-π and π-alkyl interactions involving PHE628, MET655, ALA654, VAL805, and ALA826, which collectively stabilize the complex. Surface analyses in Figures 8D-I depict aromatic, hydrogen-bonding, electrostatic, ionizability, solvent-accessible, and hydrophobic features of the binding site. These visualizations demonstrate that NMBA fits snugly within the active site, forming a stable and energetically favourable complex through strong hydrogen bonding and hydrophobic interactions, underscoring its potential as a promising anti-cholesterol agent.

Conclusion

In summary, the combined DFT and molecular docking analysis of NMBA reveals its promising structural, electronic, and biological features. Solvent polarity enhances its stability and charge delocalization, while FMO and DOS analyses indicate a moderate energy gap favourable for charge transfer. TD-DFT results show solvent-induced red shifts, confirming excited-state stabilization. Notably, NMBA exhibits a hyperpolarizability over sixty times that of urea, highlighting its strong NLO potential. Docking studies with 1DQ9 further demonstrate a stable binding energy (-7.50 kcal/mol) through hydrogen bonding, π-π stacking, and hydrophobic interactions, supporting its role as an anti-cholesterol agent. Overall, NMBA emerges as a multifunctional molecule with both optoelectronic and pharmacological potential.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

The author(s) do not have any conflict of interest.

Data Availability Statement

This statement does not apply to this article.

Ethics Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval.

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