Solvent role in molecular structure level (TD-DFT), topology, and molecular docking studies on liquid 2′, 4′-dichloroacetophenone

4.1 Structural properties

The optimization of geometrical parameters are notably indispensable step in quantum chemical calculations. The structure after optimizing 2′, 4′-dichloroacetophenone in addition to the atom numbering is portrayed in Fig. S1. The HF/B3LYP/CAM-B3LYP /6–311++G (d, p) methods were deployed to optimize the system. The optimized geometric parameters for the named chemical are shown in Table S1, along with their correlation to the experimental XRD data (Demircioğlu et al., 2015). The studied compound includes two ‘Cl’ and one ‘C = O’ group with a benzene ring, along with the theoretical value we can figure out that the measured value of the bond length is marginally lower than the optimized value. The reason for the inclusion of isolated molecule theoretical computations in the gaseous phase is noteworthy. Simultaneously, the experimental outcome is a constituent of the solid-state molecule. The vibrational frequencies were measured primarily based on calculated geometrical parameters and it’ll be a good approximation for the calculation of the above parameters. As an effect of the electronegative substituent on the benzene ring little distortion seems within the benzene ring and the angle is barely out of perfect hexagonal structures. Evaluating bond angles and bond length reckoned leveraging the B3LYP is better than HF and well correlates with the experimental value (Elkaeed et al., 2022). As a result of the hydrogen atoms being substituted with chlorine, oxygen, and CH3 groups, the phenyl rings are marginally deformed and deviate slightly from their hexagonal shape. For the benzene ring, the reckoned CC bond spacing ranges from 1.405 Å to 1.379. The HF approach yielded the smallest CC bond length of 1.379 Å, whereas the prolonged CC bond length measured 1.514 Å by DFT. In the most extreme cases, they differ by 0.1 Å within the same method of calculation. The C-Cl bond lengths vary between 1.760 Å to 1.739 Å, and when the observed values exhibit a strong concurrence with the values measured 1.736 Å & 1.732 Å (Abozeed et al., 2022). The estimation of this bond length is observed to be overestimated in the DFT approaches, while it is diminished in the HF method.

The C–H bond lengths of aromatic benzene rings and methyl groups were reckoned in the present work ranging from 1.072 Å to 1.093 Å. However, the experimental values had been stated as 1.082, 0.930, 1.090 Å, and 1.000, 0.860, and 0.910 Å respectively. The C = O bonds have respective lengths of 1.189, 1.215, and 1.209 Å. The arrangement of bond angles makes it evident that the phenyl ring is asymmetrical. C2-C1-C12 < C1-C6-C5 < C1-C12-C14 < C3-C4-C5 < C1-C2-C3 < C2-C3-C4. As a result of the substitution of Cl and CH₃ At 117.5,121.6,121.1° for HF 117.0,121.7, 121.1° for B3LYP, and 117.3,121.5,121.0° for CAM- B3LYP. The calculated bond angles that differ from experimental values are 116.7, 122.3, and 120.5°.

4.2 Vibrational spectral analysis

In organic chemistry, vibrational spectroscopy is frequently used to analyze to identify functional groups in organic compounds, as well as to investigate molecular confirmations, kinetics, and reaction mechanisms. The 2′, 4′-dichloroacetophenone is composed of 17 atoms and has the molecular formula C₈H₆Cl₂O. It has 45 normal vibrational modes, including stretching, bending, torsion, and a few mixed vibrations, and it is symmetrical in the C_s point group, classified into 29A′ and 16A″ species (Jeyavijayan, 2015a). The in-plane and out-of-plane vibrations are denoted by the A′ and A′′ species, respectively. The reckoned frequencies, PED, and complete vibration assignments of 24DCA are documented in Table 2. The present research effort primarily aims to figure out the correct experimental wave number by comparing it to theoretically scaled wave numbers with PED adopting the aforementioned methodologies, along with the aid of normal mode studies (N. Elangovan et al., 2021b). According to the findings, the DFT values tend to exhibit less variation than HF values. Figs. 1 & 2 exhibit the correlation graph of the reported and predicted FT-IR and FT-Raman vibrational frequencies providing visual comparison.

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Fig. 1

Observed and Calculated FTIR spectrum of 24DCA.

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Fig. 2

Observed and Calculated FT-Raman spectrum of 24DCA.

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4.3 Frontier molecular orbital analysis

The energy of the atomic orbital and atomic contribution coefficients constitute significant in articulating the reactivity of molecular properties. The orbitals have an enormous effect on the overall molecular behavior. Molecular orbital offers essential perspectives into the bonding and other chemical properties of molecules. HOMO serves as the orbital responsible for supplying electrons, whereas LUMO, which occupies a lower energy level, operates as the orbital responsible for receiving electrons termed as Frontier molecular orbital. It has the potential to function as a as a straightforward indicator of kinetic stability. Both possess the ability to absorb and release electrons. These specific orbitals allow the molecule to have its strongest interactions with itself (Diya et al., 2023). The ligand s' optimized structure was employed to figure out the electron cloud shapes and electronic transition energies of the substance, the graphical representation of the FMOs depicts the outcomes of the calculation done in this work on gas, Dimethyl sulfoxide, ethanol, and methanol solvents respectively, also depicted in Fig. 3. The green and red regions respectively represent negative and positive charges. The primary focus of the current investigation on the 24DCA compound is on the HOMO charge distribution, with particular emphasis on the chlorine & hydrogen atoms throughout the whole ring system. By contrast the dislocation of the LUMO-π nature, specifically the benzene ring, across all C–C bonds, is symbolized by the HOMO → LUMO transition. This transition proposes an electron distribution movement from the chlorine atom to the C–C bond of the benzene ring and the CO-CH₃ group. The determination of the compound's transition energy from HOMO → LUMO with the shortest to the highest energy gap: 4.458 eV (ethanol), 4.461 (methanol), 4.464 (DMSO), 4.467 (water), 4.546 (Gas). As the header compound's gas phase had a wide energy gap, we may infer that the molecule was more stable than compared to other solvents with chemical harness 2.273. Water was discovered to have the greatest chemical hardness (2.233) among all solvents. The header molecule has a softness index of 0.439 (Gas), 0.447 (methanol), 0.430 (DMSO), 0.447 (water), and 0.449 (ethanol) which means that the molecule under exploration possessed non-toxic traits. The 24DCA complex exhibits higher Electronegativity (χ) values across all phases 5.212 for gas, 5.182 for water, 5.179 for DMSO, 5.174 for ethanol, and 5.177 for methanol, indicating that the screened molecules function as Lewis’s acids (Elangovan and Sowrirajan, 2021). Having higher electron-accepting indices (ω⁺) in the water phase seems to be linked to a better ability to handle electron density. Moreover, the ability to donate electrons (ω⁻) in the water phase was higher (8.882) compared to other solvent phases. The reckoned global reactivity parameters are documented in Table S2.

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Fig. 3

FMO surface map of 24DCA.

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4.4 UV spectral analysis

U-V visible spectra were examined in different solvents to study solvent effects on electronic transitions. The most precise theoretical approach to evaluating the dynamic and static properties of excited-state molecules is the Time-dependent density-functional theory (TD-DFT) method. For the compounds under study, the TD-DFT method was used to determine the peak absorption wavelength (λ_max), excitation energies (E), oscillator strength (f), energy gap (eV), and molecular orbital contribution. The spectral data of the selected solvents are being studied by UV–visible spectra, to assess the impact of solvents in transitions (N Elangovan et al., 2024c). The correlated spectrum and data are explored in Fig 4 and Table 2. The fact that the projected maximum values for different solvents are practically equal suggests that the solvent influences the compound's optical activity. The maximum absorption peak of the experimental UV–visible absorption in ethanol was measured at 282 nm. Theoretical spectra have been performed in the gas phase and several polar solvents, such as DMSO (aprotic), C₂H₆O, and CH₃OH (protic). The highest possible absorption values are 288.17 nm and 4.3019 eV with an oscillator strength of 0.052 in the gas phase, 302.50 nm and 4.0981 eV in ethanol, 308.28 nm and 4.0213 eV in methanol & DMSO, all with the same oscillator strength of 0.076. Moreover, the highest transition efficiency observed for HOMO-3 > LUMO was 78 % across all solvents (Rajimon et al., 2023). These outcomes and predictions lend evidence for selecting the molecule as a highly energetic and stable chemical for biological purposes.

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Fig. 4

Experimental and Theoretical UV– Vis spectral analysis of 24DCA.

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4.5 Molecular electrostatic potential

MEP investigation is an efficacious descriptor to forecast the nucleophilic and electrophilic attack for 2′, 4′-dichloroacetophenone by the aforementioned approaches to scrutinize the chemical reactivity of the molecules, to explore the correlations among a chemical configuration along with its physiochemical characteristics, MEP projection is extremely helpful (Elangovan et al., 2022). The role of molecular electrostatic potential surfaces in computer-aided drug design is noteworthy, by aiding in the optimization of the ligand–protein electrostatic interactions. Fig. 5 illustrates, a graphical depiction of the compound under investigation. With the use of color coding, this surface provides reaction point knowledge. Distinct color tones have denoted the surface electrostatic potential values of the MEP map. The strongest attraction is betrayed by blue color and red bespeaks strongest repulsion. Conventionally, negative potential sites are linked to the lone pair of electronegative atoms. The color scheme of the map in our compound is in the vicinity of 4.541e^-2 (deepest red) to 4.541e^-2 (deepest blue). The majority of the negative potential sites are centered on the electronegative oxygen atoms of the CO-CH3 group, according to the MEP sketch of the compound in issue (Priya et al., 2023b). Electrophilic attack sites are possible in the darkest red zone exposed around the O atom. In contrast, the H atoms inside the benzene rings are covered by positive potential. The blue color examines the available sites for nucleophilic attack on the benzene ring. The leftover spices are embraced by zero potential, which is highlighted in green color.

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Fig. 5

Calculated 3D Molecular electrostatic potential contour map of 24DCA.

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4.6 Mulliken atomic charges

The charge distribution of the chemical in question is depicted in Table S3. Mulliken atomic charge distribution of 24DCA, computed by the above-mentioned methodologies is portrayed in Fig. S2. The Mulliken population provides information regarding Mulliken charges and makes it possible to assess partial atomic charges from the calculation accomplished by the computational chemistry method. The title compound under investigation has a total of 17 atoms in its chemical structure. Eight carbon atoms are present together with six hydrogen atoms, two chlorine atoms, and one oxygen atom. Carbon atoms together with negative values are dominant in C2, C3, C5, C12, and C14 owing to hydrogen and oxygen coupling. The residual carbon atoms C1, C4, and C6 are positive as a result of the re-distribution prompted by the attachment of CO-CH₃ and chlorine groups (N. Elangovan et al., 2021c). The utmost negative charge values of about −1.682e in the C2 atom and approximately 0.802e is the greatest positive charge of C1 in the molecule at the HF level. According to Mulliken’s atomic charges, all of the hydrogen atoms connected with benzene rings have net positive charges, At the contrary, due to their proximity to the chlorine atom, H10 atoms possess a higher positive charge than the remaining hydrogen atoms. With an atomic charge value of 0.287e (HF). All electronegative (oxygen atoms maintain a negative charge), all electropositive (hydrogen atoms maintain a positive charge), and depending on position, carbon atoms can maintain either a negative (or positive) charge.

4.7 Donor-Acceptor interaction

Understanding inter- and intramolecular bonding interactions is critical to exploring charge transfer or hyperconjugation interactions inside a molecular system. The investigation of the Natural Bond Orbital (NBO) indicates strong charge-transfer interactions in the isolated gas-phase molecule of 24DCA. In this work, the investigation focused on a variety of donor–acceptor bond interactions, outlined in Table 3. Higher E (2) values propose stronger interactions between electron providers and electron recipients, implying a greater degree of electron coupling delocalization across the system. The table lists the stabilization interaction energies of 2′, 4′-dichloroacetophenone above 5 kcal/mol. The natural bond orbital computations were carried out at the B3LYP6-311++G (d, p) level (Geethapriya et al., 2023). Regarding the head molecule, The BD*(2) electron's delocalization from distributed anti-bonding to anti-bonding demonstrates high stabilization Energy of 157.48 kcal/mol for BD*(2) C1-C2 $\to$ BD*(2) C5-C6 which could be a cause of the title molecule's biologically active behavior (Elangovan and Arumugam, 2024). A higher stabilization energy value is also achieved for the interaction between BD*(2) C3-C4 $\to$ BD*(2) C5-C6 = 106.72 kcal/mol, BD*(2) C12-O13 $\to$ BD*(2) C1-C2 = 48.27 kcal/mol, BD (2) C5-C6 $\to$ BD*(2) C3-C4 = 23.27 kcal/mol and BD (2) C5-C6 $\to$ BD*(2) C1-C2 = 21.11 kcal/mol. Besides that, the stabilization interaction occurs between lone pair LP (2) of O13 $\to$ BD*(1) C12-C14 and LP (2) of O13 $\to$ BD*(1) C1-C12, it is the order of 8.65 and 9.87 kcal/mol respectively. Meanwhile, the stabilization interaction energy value of the corresponding interaction between the lone pair of chlorine, LP (3) Cl9, and the BD*(2) C3-C4 orbital was calculated to be 13.36 kcal/mol, and between LP (3) Cl (11) and the BD*(1) C14-H16 orbital to produce a stabilization interaction amounting to 18.06 kcal/mol and these values are spotted in Table 3. These interactions cause the lone pair orbital occupancy to significantly decrease compared to occupancy, and there is a chance of hyperconjugation between chlorine, oxygen atoms, and the aromatic ring.

4.8 Non-covalent interaction (NCI)

Investigated reduced density gradient (RDG), a method that provides an approachable graphical representation of different forms of non-covalent interactions in three dimensions. Weak interactions known as non-covalent interactions are key, arising from the quantum electron density and its first derivatives in real space (Mallika et al., 2024). A basic dimensionless variable, the electron density value in a decreased density gradient may be used to ascertain the intensity of an interaction; and it is transcribed by $$\mathit{RDG}(r)=\frac{1}{2{(3{\pi }^2)}^{1/3}}\frac{\left|\mathrm{\nabla }\rho (r)\right|}{\rho {(r)}^{4/3}}$$ where the electron density has been betokened by the symbol ρ (r), and the norm of the electron density vector is bespeak by $\left|\mathrm{\nabla }\rho (r)\right|$ . The highest value of the lessian matrix of electron density, sign (λ ₂), aids in determining the type of interaction by color coding. The λ sign was deployed to differentiate between bonded (λ < 0) and non-bonded (λ > o) interactions. Fig. 6 displays the predicted RDG plot for the aforementioned molecule, Through the use of multiwfn and the visual molecular dynamics (VMD) program (Sowrirajan et al., 2022a). Areas of weak attractiveness are rendered in green on this graph, (λ $\approx$ 0) like Van der Waals interactions, while the blue regions correspond to strongly attractive interactions like H bonds and C-Cl bonds. The steric effect is depicted by the color red. The left side of the figure's negative sign λp values (green in color) shows attractive interactions with the other molecule. While the right side of the figure's (red) positive sign λ p-value indicates a strong repulsive interaction. Fig. 6 clearly demonstrate that the isosurface of RDG for the header compound is more affected by strong Van der Wall interactions when it is close to the methyl group, which is indicated by a greenish-brown isosurface, which denotes a low electron density in the area. A pronounced steric effect is manifested in red fusiform areas that existed in the middle zones of the phenyl ring, encircling the C = O bond, and within a ring-like configuration connecting Cl9 and Cl11.

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Fig. 6

NCI analysis of 24DCA.

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4.9 Prediction of the ligand’s (ADMET) profile and drug scans approach

The most recent technique to pinpoint the compounds that are suggested to confirm the nature of a potentially active drug is called “drug-likeness.” Drug similarity analysis is carried out based on several pharmacophoric characteristics of the sample, including those of bioavailability, reactivity, and metabolic stability. The Swiss ADME web server generated bioavailability radar shown in Fig. 7 was used to confirm the “drug-likeness” requirements which use Lipinski's (Ro5) filter method descriptors, a chemical or drug compound is more likely to be a potential drug for human use if it meets specific requirements including MW < 500 Dalton, HBA < 10, HBD < 5, and lipophilicity laid out as log p < 5 TPSA < 140, and rotatable bonds < 10) (Elangovan et al., 2023). Within that study, the title compound 24DCA shows a molecular weight of 189.09 g/mol within the acceptable range, and the number of hydrogen bond donors and acceptors is 0 and 5 for each. Besides that, the number of rotatable bonds for the current drug is 2, and Lipinski's rule count is less than 10. The molar refractivity of the drug currently being used, 24DCA, is 46.66, which is between the threshold ranges of 40 and 130. The capabilities of drug transportation, including blood–brain barrier crossing, intestinal absorption, and penetration, can be inferred from the topological polar surface area, In the current scenario, 17.072 Å.² is the predicted value, which is below the permissible range of 140 Å.². The lipophilicity values of header composition are as follows: log P = 2.09, XLOGP3 = 2.72 and an MLOG P (octanol partition co-efficient) value of 2.94 less than 5 pointing to the compound's balanced hydrophobic/lipophilic nature. Further examination of the Ghose filter elements, such as molar refractivity and atom count (17), reveals that the title compound also complies with the Goose rule. The aforementioned requirements are often not violated by more than one orally bioactive medication. With a bioavailability score of 0.55, the substances included in the current scenario demonstrate strong oral bioavailability since they adhere closely to Lipinski's criteria.

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Fig. 7

Ligand 24DCA embedded in active sites of Insuliin inhibitor (a) 1B1U, Antifungal (b) 1PCV, Antioxidant (c) 2 V32 Antiseptic (d) 5ZEC, Antiviral (e) 6UEI targeted proteins.

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The qualities evaluated using the Swiss ADME server exhibited beneficial attributes, such as fantastic solubility (log s = -3.06) and a high likelihood of gastrointestinal absorption, leading to a promising potential for oral bioavailability. Pharmacokinetic studies examine the effects of drug-to-drug interactions on the activity of P-gp substrates and the suppression of CYP (Cytochrome enzymes) activities (Priya et al., 2023a). The protease-activated protein gp enables the movement of active substances across the membrane of living organisms. Furthermore, it plays a crucial function in the process of repelling objects. This compound is devoid of any p-gp substrates. This medicine exerts an influence on the enzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4, which are impacted by the substance. Pan-assay interference chemicals (PAINS) are toxicological compounds that frequently induce spurious positive outcomes in high-throughput screening assays in medicinal chemistry. As an alternative, 24DCA has exhibited a 0-alert characteristic, signifying that it generates the intended analeptic effect exclusively through interaction with a particular receptor protein. PAINS interacting with multiple biological targets is more common than with a single target. Lead likeness aids chemical optimization performance by choosing the ideal starting locations. This chemical has no “lead-like” prospects despite therapeutic research. We further assessed the compound's hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, and toxicity (LD50 880 mg/kg) using the Protox II web server. Endpoint and toxicity model results are in Table S4. The chemical has two AMES mutagenicity and carcinogenicity alerts.

Moreover, SwissADME encompasses a “BOILED-egg evaluation” feature delivering information on the human gastrointestinal absorption and blood–brain barrier permeability based on lipophilicity (WLOGP) and polarity (topological polar surface area, TPSA) as exemplified in Fig. S4 (top right). At certain points in the egg, the yolk and white align with the molecules that were expected to pass through the BBB and be absorbed by the gastrointestinal tract. Blue and red spots indicate compounds expected to be effluxed and not effluxed from the central nervous system by p-glycoprotein, respectively. The 24DCA molecule was positioned just inside the yolk region of the boiled egg model, as evidenced by the red dot position in Fig. 7. This indicates that the chemical portrays a rapid absorption rate in the gastrointestinal tract and readily traverses the blood–brain barrier. In addition to reflecting that the molecule cannot traverse the blood–brain barrier, the red dot's presence in the white area signifies a rapid rate of absorption in the gastrointestinal system. The chemical compound exhibits medicinal properties due to its high gastrointestinal absorption and skin permeability values (Log kp = -5.52 cm/s), together with its capacity to pass through the blood–brain barrier, emphasizing the potential for therapeutic use of the tested compound 24DCA.

4.10 Molecular docking

In the design and discovery of new drugs, molecular docking has demonstrated itself to be an effective sequential asset. Molecular docking allows for a comprehensive understanding of the interactions between potential therapeutic compounds and the binding site of the targeted protein, providing new perspectives on underlying biological systems. Furthermore, molecular docking is an economical drug-designing approach that might offer a compact molecule, with more accurate and reliable binding positions when compared to experimental results (N. Elangovan et al., 2021a). It determines the types of interactions and binding conformations seen between the ligand and the active site protein, as well as their bonding distances and residue group proximity target protein to be used for docking with the ligand, is chosen based on the binding energy value; spices with a lower binding energy value are more likely to be able to dock with the target protein. This research looked at the DFT/B3LYP theory, applied to the 6–311++G (d, p) method, yielded the optimal ligand structure. Gaussian 09 W was used to dock into the active sites of receptors 1B1U, 1PCV, 2 V32, 5ZEC and 6UEI of the insulin inhibitor, antifungal, antioxidant, antiseptic and antiviral proteins downloaded from the protein data bank PASS (prediction of atomic spectra) which is a web-based tool that makes predictions about various types of activities. Concerning binding affinity with all of the targeted proteins, the ligand molecule was docked appropriately for its position and orientation (Elangovan et al., 2024b) Fig. 7 highlights optimized ligand-target protein orientations by the least energy of binding. All computations were done exploiting Auto dock to predict the ligand–protein active binding site interaction. Leveraging the Kollaman and Gasteiger phase process, the co-factors and polar hydrogen were appended to the suitable intended protein in pdb style, while the co-crystalline ligand water was eliminated. For the first two ranks (1 and 2), the ranking capacity of the ligand with the targeted protein is pictured by Lamarckian docking binding energies (Kcal/mol), estimated inhibition constants (M), and reference RMSD values. The best pose was ascertained by having a higher binding energy value and the existence of a significant number of conventional hydrogen bonds. Considering the minimum energy of binding of interactions among ligands and proteins, the optimized ligand-target protein orientations are shown in Fig. 7. As illustrated in Fig. 7 the titled molecule contains a carbonyl group (C = O) that has hydrogen bond interaction with residues LEU A: 17(2.6 Å), ARG A: 44 (2.23 Å), ASN A: 200 (2.08 Å), VAL A: 198(1.80 Å) LEU A: 87, and CYS A: 73 (1.99 Å) (3.05 Å). The binding energies of proteins1B1U,1PCV, 2 V32, 5ZEC and 6UEI are −4.55 kcal/mol, −4.72 kcal/mol, −5.69 kcal/mol, −5.95 kcal/mol −6.18 kcal/mol, respectively, with estimated inhibition constant values of 213.10 µM, 214, 50 µM, 67.58 µM,43.15 µM and 29.67 µM reported in Table S5. Amongst these four proteins, the header molecule reacted favorably with antifungal protein (6UEI) which has the good binding energy-6.18 kcal/mol, inhibition constant 29.67 µM, total intermolecular energy of −6.48 kcal/mol and RMSD value 69.88 Å with the higher number of hydrogen bonds to the amino acid residues LEU A: 87, and CYS A: 73. It is noteworthy that this molecule interacts with active sites containing oxygen atoms through hydrogen bonding. The preceding arguments promote the possibility of using 24DCA as potent antiviral medications.