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. 2023 Sep 7;8(37):33928–33942. doi: 10.1021/acsomega.3c04710

Ternary Mixture of Pentanamide in Solvent Analogy with Halogenated Phenol: Experimental, Theoretical, and In Silico Biological Studies

A Aathif Basha †,*, F Liakath Ali Khan †, Attar Kubaib ‡,*, Predhanekar Mohamed Imran ‡, Nadia Nebbache §
PMCID: PMC10515181  PMID: 37744853

Abstract

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This research describes the preparation of mixtures of new halogen-substituted phenol derivatives and their effects due to linkages with a fatty amide (pentanamide). The molecules were optimized using DFT, and the vibrational and electronic analysis was done subsequently. The energies of frontier molecular orbitals (FMOs) were used to estimate the global chemical reactivity parameters as we suggest that hydrogen-bonded networks may have contributed to the stability and reactivity of the compound. In addition to the experimental investigation, dielectric parameters were calculated. Fukui functions were analyzed to study the chemical reactivity. To get insight into interactions of σ → π* orbitals, natural bond orbital calculations were done. Additionally, surface analysis of the MEP and Hirshfeld charges were performed at the equivalent DFT levels. The research also indicated that both (interaction region indicator) IRI and (electron delocalize range) EDR would proficiently identify chemical-bonding and weak interaction regions, providing a significant advantage in exploring diverse chemical systems and reactions. This indicated that compounds could diffuse through noncovalent interactions, including intramolecular hydrogen bonding. Dielectric relaxation studies taken at five distinct molar ratios identified significant dielectric properties such as ε′, ε″, ε0, and ε∞. The PA with FP, CP, BP, and IP molecules has potential antiviral and antioxidant benefits for carbonic anhydrase, with favorable drug-like features and diverse biological benefits. Pharmacological effects were forecasted using the PASS server, and these molecules exhibited favorable pharmacokinetic properties.

1. Introduction

Novel halogen-substituted phenol derivatives (interaction between the hydrogen atom of the hydroxyl group (donor)) and pentanamide (oxygen atom of the carbonyl group (acceptor)) linkage are essential for novel drug development. The high interest in halogen-substituted phenols and pentanamides stems from their distinctive physical, chemical, and medicinal characteristics.1,2 Pentanamide, with the structure RCONH2, has applications in biologically active fields as an antiviral and antioxidant.

4-Fluorophenol is a water-soluble, colorless solid, and a polar solvent.3 4-Chlorophenol is manufactured as a predecessor to hydroquinone. It is a well-known precursor of quinizarin when reacting with phthalic anhydride.4 Quinizarin, a commercial dye, reacts with phthalic anhydride and then hydrolyzes the chloride. 4-Bromophenol is any organobromide of phenol that contains one or more covalently bonded bromine atoms. It plays various roles, including those of a mouse metabolite, a natural pollutant that persists over time, a human xenobiotic metabolite, a rat metabolite, a human urine metabolite, and a marine metabolite. The natural substance 4-bromophenol is found in Euglena gracilis and Ulva lactuca.(5) 4-Iodophenol is a mono-iodophenol and a colorless solid. Numerous coupling processes take place on 4-iodophenol.6 Additionally, it is used to enhance chemiluminescence for the detection of cancer cells and in the Eclox assay.7 The diazonium salt can be used to make 4-iodophenol from 4-aminophenol. A different production method includes decarboxylation after the salicylic acid and iodine reactions.

In investigations of biological systems, density functional theory (DFT) is a suitable and often employed method. Using DFT to predict a molecule’s geometry, electrical structure, and spectroscopic characteristics helps determine organic polar molecules’ structural behavior in a nonpolar solvent. The features of the PA with FP, CP, BP, and IP compounds were theoretically estimated and characterized using several local and global reactivity descriptors and thermodynamical parameters. The geometry obtained from DFT optimization and the molecular docking studies corresponds well with the NBO findings that support the existence of a hydrogen-bonding network.8 Using the TD-DFT method and IEFPCM (integral equation formalism polarizable continuum model), a comprehensive spectral analysis was done, which provided excited-state information.9 According to NBO calculations, the compound’s stability is due to the hyperconjugative interactions and hydrogen-bonding structure. To calculate the local reactivity of inhibitor compounds, condensed Fukui functions were utilized.10 The molecular electrostatic potential surface and Hirshfeld surface contour map were created to understand the PA with FP, CP, BP, and IP compound properties better. The interaction region indicator (IRI), a minor change of the RDG, is a unique real-space function that we propose. We observed that IRI could efficiently depict chemical bonding and weak interaction zones, which is particularly valuable in studying various chemical systems and events. IRI differs from previous algorithms because it has a simpler definition, a lower computing cost, and a higher graphical effect. Furthermore, chemical reactivity and biological activity were compared using global and local reactivity parameters.

The investigation of inter- and intramolecular interactions of molecules and the fluctuation of these parameters with temperature provided information on the physical behavior of molecules. Various studies11−13 investigated the connection of two polar molecules caused by hydrogen bonding using dielectric relaxation studies at microwave frequencies. These approaches have grown considerably more dependable in predicting the characteristics of molecules with high accuracy in recent times.

The goal of the study is to extensively use the DFT method to investigate the structure and electrical characteristics of a newly prepared ternary mixture halogen-substituted phenol derivative linkage with pentanamide. Further, analyses using natural bonding orbitals (NBOs), molecular electrostatic potential (MEP), Fukui index, Hirshfeld surface, interaction region indicator (IRI), and electron delocalize range (EDR) were carried out to anticipate any intramolecular charge transfer and redistributing electron energies in different orbitals. Due to its extreme sensitivity to structural changes, vibrational spectroscopy might provide essential details about the molecular potential for biological activity. Molecular docking analysis was done on the molecule and two control medicines, ampicillin and against protein receptors. Docking was used to keep ligand complexes rigid by changing all rotatable bonds to nonrotatable bonds. Lipophilicity, druggability, target identification, and pharmacokinetics are among the analyses performed, and they are based on previously recognized ADMET characteristics.14 The biological activity of the PA with FP, CP, BP, and IP compounds was predicted for the effect of the combination against different biological assays, which was employed using PASS.15 To present the experimental results, a microwave region (9.34 GHz) at 298 K was used to study the dielectric behavior of PA+FP, CP, BP, and IP with benzene at different molar ratios.16

2. Materials and Methods

2.1. Materials

The BDH Analar variety of 4-fluorophenol (FP), 4-chlorophenol (CP), 4-bromophenol (BP), and 4-iodophenol (IP) were distilled and then purified by recrystallization from diluted ethanol. Pentanamide was produced by condensing valeric acid and ammonia. The E. Merck variety of pentanamide (PA) was utilized without additional purification.

2.2. Methods

2.2.1. (a) Quantum Chemical (QC) Calculations

The compound’s entire geometry is analyzed from Chemdraw. Gaussian 16W was used to perform all quantum chemical calculations. The input files were generated using Chemdraw, and the output data was visualized using Gauss View 6.017,18

2.2.1.
2.2.1.
2.2.1.
2.2.1.
2.2.1.

It is essential to utilize the provided equations precisely to obtain quantum chemical reactivity parameters. Density functional theory (DFT) calculations using B3LYP utilizing the LANL2DZ basis set were used to accomplish the whole compound optimization as shown in Figure 1, followed by analyses of the NBO,19 Fukui index, FMO, MEP, and vibrational frequencies.20−23 The band energy gap information was obtained from the highest occupied and lowest unoccupied molecular orbital representations (HOMO–LUMO). Global reactivity descriptors and thermodynamical parameters for different temperatures were computed and reported to expose the qualities of the PA with FP, CP, BP, and IP compounds. The methods employed here were DFT/B3LYP24 at the basis set of 6-311++G(d,p) and LANL2DZ. The complete vibrational assignments are made with the potential energy distribution (PED) calculation using VEDA425 software. Also, UV–vis spectra and electronic properties such as frontier molecular orbital analysis (HOMO–LUMO) were computed with the help of the time-dependent DFT (TD-DFT) method.

Figure 1.

Figure 1

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Optimized geometrical structure of PA with (FP, CP, BP, and IP) compounds.

2.2.2. (b) Noncovalent Interaction (NCI) Analysis

A multidimensional wave function analysis tool, called Multiwfn,26,27 was used to perform IRI and EDR, while the VMD program was used to generate all isosurface maps. The Hirshfeld surface analysis of the experimental structure was performed using the Crystal Explorer 3.1 tool.28

2.2.3. (c) Docking Simulation

The optimized molecule was utilized to compare chemical reactivity and biological activity, and Autodock suite 4.2.1 was used to conduct molecular docking investigations. A detailed examination of the residues implicated in noncovalent interactions between the ligands and protein was carried out using Accelyrs Discovery Studio 4.129

2.2.4. (d) Dielectric Measurements

By combining PA with various molar ratios of FP, CP, BP, and IP in benzene (1:3, 1:2, 1:1, 2:1, and 3:1), a ternary mixture was proposed in a 10 mL solution (benzene). At a microwave frequency in the X-band of 9.34 GHz, the dielectric constant at an angular frequency (ε′) and the dielectric loss (ε″) were measured. With a dipole meter operating at 220 V and a WTW dipole meter DM 01 type, the static dielectric constant (ε0) was determined at 298 K.30 The derived values of ε′ and ε″ are accurate to within ±1 and ±5%, respectively. With Abbe’s refractometer, the refractive index was calculated.31 The measurement error for the refractive index is +0.003. Using a water-circulating thermostat, the temperature of all of these measurements was kept at 30°C. Thermostatically, the temperature was maintained within ±0.5°C. The density was determined using a 20 cm3 specific gravity container.

3. Results and Discussion

3.1. Structure Optimization

The centrosymmetric triclinic system with a P-1 space group was the crystallized structure of the chemical described in the PA with FP, CP, BP, and IP compounds;32 the unit cell parameters are a, b, c = 15.94Å and α, β, γ = 90°. This unit formula consisted of two halogen-substituted phenol derivative linkages with pentanamide (C11H17XN), where X is F, Cl, Br, I, and one benzene molecule. A relation of N–H/O–H···O hydrogen bonds connected these aspects. The parameters of molecular bonds are summarized here. According to the data presented in Table 1, using the DFT technique leads to the prediction of the NH (PA) - OC (FP) bond lengths to be around 1.40 Å. This finding implies a strong interaction within the PA with FP, CP, BP, and IP compounds.

Table 1. Optimized Geometrical Parameters for PA with FP, CP, BP, and IP Compound B3LYP/LANL2DZ Basis Set.

symbol bond (Å) [FP] angle (°) bond (Å) [CP] angle(°) bond (Å) [BP] angle (°) bond (Å) [IP] angle (°)
C1                
C2 2.565   2.565   2.565   2.564  
C3 1.544 34.015 1.544 34.017 1.544 34.017 1.544 34.018
N4 2.471 127.452 2.471 127.356 2.471 127.782 2.471 128.027
O5 2.298 61.409 2.298 61.403 2.298 61.409 2.298 61.414
C6 1.543 146.472 1.543 146.471 1.543 146.481 1.543 146.487
C7 1.278 30.564 1.278 30.565 1.278 30.567 1.278 30.567
H8 1.097 109.945 1.097 109.944 1.097 109.943 1.097 109.945
H9 1.100 109.515 1.100 109.512 1.100 109.522 1.100 109.528
H10 1.101 89.761 1.101 89.791 1.101 89.797 1.101 89.792
H11 1.101 89.800 1.101 89.767 1.101 89.761 1.101 89.766
H12 1.098 110.352 1.098 110.356 1.098 110.343 1.098 110.333
H13 1.099 107.351 1.099 107.355 1.099 107.319 1.099 107.300
H14 1.099 111.020 1.099 111.026 1.099 111.034 1.099 111.034
H15 1.098 110.955 1.098 110.952 1.098 110.950 1.098 110.949
H16 1.098 111.243 1.098 111.240 1.098 111.239 1.098 111.239
H17 1.011 88.484 1.011 88.496 1.011 88.492 1.011 88.486
H18 1.019 152.299 1.019 152.332 1.019 152.334 1.019 152.324
H19 1.615 82.660 1.608 82.829 1.609 82.846 1.611 82.824
H20 7.006 86.730 6.999 87.117 6.997 87.133 6.993 86.841
H21 5.671 121.250 5.672 122.586 5.663 122.377 5.655 121.723
H22 4.986 143.089 4.987 142.962 4.996 142.873 4.997 142.937
H23 3.166 123.881 3.186 125.149 3.184 124.830 3.181 124.178
C24 6.099 102.516 6.120 103.395 6.127 103.348 6.135 102.929
C25 1.399 80.181 1.403 79.429 1.405 79.156 1.408 78.802
C26 1.397 42.678 1.401 42.434 1.404 42.093 1.407 41.707
C27 1.406 118.455 1.406 119.008 1.406 119.336 1.406 119.755
C28 1.407 118.510 1.407 119.063 1.407 119.388 1.407 119.802
C29 1.412 120.170 1.411 120.194 1.411 120.198 1.411 120.188
O30 1.386 117.877 1.384 117.971 1.384 118.016 1.384 118.053
X31 1.413 161.043 1.832 161.316 1.978 161.311 2.148 161.291
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3.2. Quantum Chemical Analysis

The impact of the solvent environment on the electronic structure and energetics of the molecule is duly considered in the IEPCM. The IEPCM accurately accounts for the interaction between the solute and solvent molecules in the presence of a solvent. Calculations were performed in the presence of the solvent to analyze the energetic behavior.33 The calculated energy values for PA+FP, HOMO, and LUMO in the solvent were −6.065 and −0.511 eV. The energies and the pictorial illustration of HOMO, LUMO, and NBO are shown in Figures 2 and 3. The presence of red regions in the molecular orbitals indicates nucleophilic sites, which attract electrons. Green regions indicate electrophilic sites, which donate electrons. This color scheme helps identify the molecule’s reactivity and potential for chemical interactions, clearly representing its electronic properties.

Figure 2.

Figure 2

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HOMO and LUMO surface maps of PA with FP, CP, BP, and IP compounds.

Figure 3.

Figure 3

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Charge-transfer interactions by NBO studies of the PA with FP, CP, BP, and IP compounds.

Accordingly, the energy gap of HOMO–LUMO explains the eventual charge-transfer interaction within the mixture.34 Furthermore, in going from the FP to the BP, the increasing value of the energy gap suggests that the molecule is becoming more stable. Furthermore, a molecule with a small frontier orbital gap is easily polarizable and has strong chemical reactivity but low kinetic stability.35−37 Additionally, global chemical reactivity descriptors (GCRDs) are an important tool for understanding the chemical characteristics of a compound such as η, μ, S, χ, and ω. The GCRDs are obtained from HOMO–LUMO energies, under Koopman′s approximation HOMO as ionization potential (I) and LUMO as electron affinity (A), and the data are tabulated in Table 2. These characteristics are connected in the following equations:38 using the preceding equations, the chemical potential, hardness, and electrophilicity index have been determined, and their results were compared with two different basis sets, as displayed in Table 2 (Table S1). The ionization potential value indicates that an energy of 6.065 eV in the solvent phase is required to remove an electron from the HOMO. The lower value of electron affinity shows higher molecular reactivity with the nucleophiles. Higher hardness and lower softness values confirm the higher molecular hardness associated with the PA with FP, CP, BP, and IP compounds. The electrophilicity index helps in describing the biological activity of the mixture. Figure 4 shows the Mulliken charge distribution on 4N, 6C, and 30O atoms of PA with FP, CP, BP, and IP compounds and O atoms of the proton–acceptor molecule. Because of the existence of the N•••H-bond and O•••H-bond, the title chemical is a typical model of the class of molecules that form intermolecular H-bonds (Table 3).

Table 2. Calculated Energy Values of PA with FP, CP, BP, and IP Compounds in Benzene Solvent at 298 K in Its Ground States with Singlet Symmetry, First-Order Hyperpolarizability (β), Polarizability (α), and Dipole Moment at the DFT/LANL2DZ Method.

LANL2DZ IEFPCM, solvent: benzene parameters PA + FP PA + CP PA + BP PA + IP
EHOMO –6.051 –6.065 –6.008 –5.930
ELUMO –0.546 –0.541 –0.511 –0.830
ionization potential 6.051 6.065 6.008 5.930
electron affinity 0.546 0.541 0.511 0.830
EHOMO – ELUMO 5.505 5.523 5.497 5.100
electron negativity (χ) 3.298 3.303 3.260 3.380
chemical potential (Inline graphic) –3.298 –3.303 –3.260 –3.380
absolute hardness (Inline graphic) 2.752 2.762 2.749 2.550
softness (S) 0.182 0.181 0.182 0.196
electrophilicity index (ω) 1.976 1.975 1.933 2.240
electronic charges (ΔNmax) –0.600 –0.598 –0.593 –0.663
E(RB3LYP) (a.u) –733.813 –648.906 –647.124 –645.344
dipole moment (Debye) 8.082 8.390 8.146 7.781
polarizability 141.494 152.201 159.243 166.726
hyperpolarizability 290.374 183.069 224.850 325.979
entropy (S) (cal/mol/K) 139.218 144.317 152.384 146.783
heat capacity (Cv) (cal/mol/K) 58.746 59.600 65.892 60.089
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Figure 4.

Figure 4

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Mulliken charges of PA with FP, CP, BP, and IP compounds.

Table 3. Mullikan’s Atomic Charges of PA with FP, CP, BP, and IP Compounds.

    Mullikan’s atomic charges
s. no. atoms (X = F, Cl, Br, I) V + FP V + CP V + BP V + IP
1 C –0.452 –0.452 –0.452 –0.442
2 C –0.300 –0.300 –0.300 –0.300
3 C –0.307 –0.307 –0.307 –0.307
4 N –0.634 –0.632 –0.633 –0.641
5 O –0.367 –0.368 –0.368 –0.404
6 C –0.657 –0.657 –0.657 –0.653
7 C 0.299 0.300 0.301 0.322
8 H 0.210 0.210 0.210 0.211
9 H 0.182 0.182 0.182 0.183
10 H 0.177 0.177 0.177 0.176
11 H 0.180 0.181 0.181 0.180
12 H 0.197 0.198 0.198 0.199
13 H 0.223 0.223 0.223 0.225
14 H 0.198 0.198 0.198 0.197
15 H 0.201 0.201 0.201 0.201
16 H 0.205 0.205 0.205 0.204
17 H 0.339 0.339 0.339 0.339
18 H 0.370 0.369 0.369 0.385
19 H 0.401 0.401 0.402 0.406
20 H 0.255 0.253 0.250 0.249
21 H 0.254 0.252 0.249 0.249
22 H 0.251 0.252 0.252 0.249
23 H 0.254 0.255 0.255 0.250
24 C 0.312 –0.119 –0.242 –0.356
25 C –0.335 –0.179 –0.124 –0.136
26 C –0.331 –0.173 –0.117 –0.128
27 C –0.319 –0.343 –0.344 –0.340
28 C –0.341 –0.369 –0.372 –0.363
29 C 0.294 0.299 0.298 0.324
30 O –0.517 –0.513 –0.513 –0.555
31 X –0.242 –0.082 –0.060 0.074
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3.3. TD-DFT Calculations

The molecule’s absorption spectrum exhibited one broad band, a long wavelength maximum across the 220–300 nm range, as shown in Table 4. These measured absorption wavelength maxima values 257.13, 257.86, 259.43, and 299.53 nm correspond to the calculated values.39,40 To investigate the system’s interactions, the IEFPCM model41 was employed. The electronic transition from the highest occupied molecular orbital, HOMO, to the lowest unoccupied molecular orbital, LUMO, accounts for 89, 87.8, 87.9, and 98.9% of the maximum absorption wavelength. The UV spectrum of PA with halogenated phenols is presented in Figure 5.

Table 4. Theoretical Electronic Absorption Spectral Values of PA with FP, CP, BP, and IP Compounds Using the TD-B3LYP/LANL2DZ Basis Set.

compounds energy (cm–1) excitation energy (eV) wavelength (nm) oscillator strength (f) coefficient %
F 38891.22 4.8219 (state 1: 56 → 60, 57 → 58) 257.13 0.0683 11.0, 89
40945.52 5.0766 (state 2: 57 → 59) 244.23 0.0084 98.7
45443.67 5.6343 (state 3: 55 → 59) 220.05 0.0014 95.3
Cl 38780.73 4.8082 (state 1: 55 → 59, 56 → 57) 257.86 0.0522 11.8, 87.8
41076.18 5.0928 (state 2: 56 → 58) 243.45 0.0113 98.2
45472.71 5.6379 (state 3: 54 → 58, 56 → 60) 219.91 0.0022 2.1, 96.3
Br 38545.22 4.7790 (state 1:55 → 60, 56 → 57) 259.43 0.0469 11.5, 87.9
39354.19 4.8793 (state 2: 56 → 59) 254.10 0.0003 98.0
40793.89 5.0578 (state 3: 56 → 58) 245.14 0.0127 97.0
I 33385.69 4.1393 (state 1:56 → 57) 299.53 0.0003 98.9
38225.82 4.7394 (state 2: 55 → 60, 56 → 58) 261.60 0.0408 11.0, 88.0
40407.55 5.0099 (state 3: 56 → 59) 247.48 0.0146 97.0
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Figure 5.

Figure 5

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TD-DFT of PA with FP, CP, BP, and IP compounds.

3.4. Analysis of Natural Bond Orbitals (NBOs)

NBO can be used to explain filled orbitals, unoccupied orbitals, and second-order stabilization energy. One of the most well-known methods for investigating inter- and intramolecular bonding interactions, along with interpreting conjugative interactions and charge transformation processes in the system under study, is the natural bond orbital (NBO) technique. In an NBO investigation, the second-order Fock matrix helps evaluate the reciprocal interaction between the donor and acceptor. The analysis of the Fock matrix using second-order perturbation theory reveals many hyperconjugative interactions, as shown in Table 5, and E(2) exhibits a simple association with the size of interactions between the donor and acceptor.

Table 5. Donor–Acceptor Interactions of PA with FP, CP, BP, and IP Compounds.

type donor NBO (i) type acceptor NBO (j) E(2) kcal/mol E(j) – E(i) a.u. F(i,j) a.u.
PA + FP
σ H19–O30 σ* C1–C7 0.12 1.12 0.01
σ H19–O30 σ* N4–H18 0.15 1.22 0.01
σ H19–O30 σ* O5–C7 0.11 0.80 0.01
σ H19–O30 π* O5–C7 0.47 1.19 0.02
LP(1) O30 σ* N4–H18 0.56 1.00 0.02
PA + CP
σ H19–O30 σ* C1–C7 0.11 1.12 0.01
σ H19–O30 σ* N4–H18 0.14 1.22 0.01
σ H19–O30 σ* O5–C7 0.10 0.80 0.01
σ H19–O30 π* O5–C7 0.48 1.19 0.02
LP(1) O30 σ* N4–H18 0.50 0.99 0.02
PA + BP
σ H19–O30 σ* C1–C7 0.11 1.12 0.01
σ H19–O30 σ* N4–H18 0.14 1.22 0.01
σ H19–O30 σ* O5–C7 0.10 0.80 0.01
σ H19–O30 π* O5–C7 0.49 1.20 0.02
LP(1) O30 σ* N4–H18 0.52 0.99 0.02
PA + IP
σ H19–O30 σ* C1–C7 0.17 1.10 0.01
σ H19–O30 σ* N4–H18 0.23 1.20 0.02
σ H19–O30 σ* O5–C7 0.07 0.73 0.01
σ H19–O30 π* O5–C7 0.66 1.14 0.03
LP(1) O30 σ* C1–C7 0.05 0.89 0.01
LP(1) O30 σ* N4–H18 1.96 0.98 0.04
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3.5. Vibrational Investigations

Figure 6 shows the IR spectra, and Table 6 (Tables S2 and S3) provides summaries of theoretically estimated frequencies, relative intensities, likely assignments, and potential energy distribution (PED) of two different basis sets for PA+(FP, CP, BP, IP). The compound consists of 31 atoms and has 87 fundamental vibrational modes. The possible energy distributions (PEDs) provide ≥10% of the assignments. Regarding the structure, benzene is similar to heterocyclic aromatic compounds and its derivatives. With a PED contribution of 69%, the IR band was found at 3241.15, 3238.59, 3235.43, and 3232.13 cm–1 and its assigned to CH. With a PED contribution of 30%, the IR band was detected at 1519.73, 1519.72, 1519.74, and 1519.70 cm–1 assigned to CN. The NH stretching modes generally contain vibrational bands in analyzing the level above 3000–3500 cm–1. Observed at 3432 cm–1, this band is in the IR spectra. They have a theoretically determined harmonic wavenumber at 3723.59 and 3535.94 cm–1 with an 82% PED contribution. The C=O peak in the current study should theoretically arise at wavelengths of 1651.64 cm–1. Although the C=C stretching modes in the compound’s benzene rings are seen at around 1642.93 cm–1 in IR spectra, the C=C structural stretching vibrations in the aromatic rings typically emerge at 1430–1625 cm–142,43 It may also be noted in the IR spectra that it is at 1665.64 cm–1. Stretching modes identified at 1444.57 cm–1 in IR spectra are assigned to C–N vibrations with a 30% PED contribution. The FP (O–H) stretching vibration mode with a PED contribution of 93% is given to the absorption band in IR spectra centered at 2997.75 cm–1 at high wavenumbers.

Figure 6.

Figure 6

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Theoretical IR spectra of the PA with FP, CP, BP, and IP compounds.

Table 6. FT-IR Spectra of PA with FP Compounds with Two Different Basis Setsa.

PA + FP (B3LYP/LANL2DZ)
 PA + FP (B3LYP/6-311G++(d,p))
assignments and freq. scaled IR (cm–1) assignments and freq. scaled IR (cm–1)
γNH 3723.59 107.66 γNH 3702.07 113.94
γNH 3535.94 202.57 γNH 3551.09 146.98
γOH 3246.48 2.35 γOH 3335.42 1697.09
γCH 3241.15 7.64 γCH 3084.39 91.67
γOC 1665.64 3.13 γOC 1693.86 510.23
γCC 1642.93 14.75 γCC 1639.10 62.93
βHOC 1328.3 7.06 βHOC 1263.62 216.76
βCCC 844.68 1.93 βCCC 1263.62 216.76
τHNHO 749.27 12.09 τHNHO 1477.56 33.38
τHCCC 676.52 50.06 τHCCC 1395.15 113.39
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a

Scaling factor: 0.961; γ, stretching; β, in-plane-bending; α, out-of-plane bending; ρ, scissoring; ω, wagging; r, rocking; t, twisting; τ, torsion.

3.6. Molecular Electrostatic Potential (MEP)

In this part, the surface of molecular electrostatic potential (MEP) is created to predict and analyze the molecular reactive behavior of a studied molecule. The mapping was done using a DFT/B3LYP method. It is related to the electronic density and is very useful for studying hydrogen-bonding interactions and for determining electrophilic and nucleophilic attack sites. In terms of color grading, electrostatic potential is used to depict the molecular and electrostatic potentials.44Figure 7 displays the potential as a multicolored MEP map. These mappings’ color codes vary from −8.060 a.u to 8.060 a.u. Donor atoms are shown in blue regions with positive potential; localized hydrogen atoms represent these strongest positive electrostatic potential (nucleophilic site). Acceptor atoms with a negative potential in red areas have the strongest electronegative potential (electrophilic sites), mainly located over anionic groups. The green or yellow color indicates the neutral zone. Electrophilic sites are near hydrogen atoms, whereas nucleophilic sites are near oxygen atoms. The MEP surface is a donor–acceptor interaction that confirms the formation of hydrogen bonds.45 The negative region mainly forms a hydrogen bond interaction with the protein. This is highly corroborated by molecular docking and molecular dynamics studies.

Figure 7.

Figure 7

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Surface distance projection map by MEP of PA and FP compounds.

3.7. Hirshfeld Surface Evaluation

The molecular Hirshfeld surface,46−48 curvedness, de, di, fragment, dnorm, shape index, and hydrogen-bonding interaction (as dashed lines) for the PA+(FP, CP, BP, IP) compounds are depicted in Figure 8a–g and are mapped on dnorm—ranges (0.7568–9.7750), shape index ranges (1.000–1.000), curvedness (4.000–0.400), and de ranges (1.6541–12). The dnorm values were mapped on the Hirshfeld surface by the use of red, blue, and white color plots; the red region appear for the region of close contacts and blue longer contacts. These contacts have been observed on the de map where the large orange spots are attributed to the N–H...O hydrogen bonds, while the small blue spots correspond to the H...H, F...H, and H...F contacts. The absence of red circles on the shape index map and the small flat segments delimited by red circles on the curvedness map include the presence of π–π and C–H···π interactions in our crystal structure.49 Two-dimensional (2D) map fingerprint plots examine the whole range of intermolecular interactions (Figure 9). The compound’s characteristic is stimulated by hydrogen-bonding and intermolecular interactions inside the crystal. The intermolecular H•••F, H•••H, and F•••H interactions, with total Hirshfeld areas of around 30.7, 57.1, and 7.5%, respectively, are shown to be the primary contacts in the 2D fingerprints shown in Figure 9.

Figure 8.

Figure 8

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Hirshfeld surfaces of individual compounds of PA with FP showing (a) curvedness, (b) de, (c) di, (d) fragment, (e) dnorm, (f) shape index, and (g) hydrogen-bonding interactions (as dashed lines).

Figure 9.

Figure 9

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Fingerprint plots of pentanamide with fluorophenol.

3.8. Interaction Region Indicator (IRI)

The vdW interaction marked by sync between the PA and FP may also be located using the IRI map. The six-membered carbon rings’ IRI isosurface maps in Figure 10a show the steric effect as red dots within the rings. IRI is beneficial for understanding chemical interactions because it may reveal a change in the strength of chemical bonds and weak connections. Figure 10 presents two chemical systems, which not only contain chemical bonds but also involve intramolecular or intermolecular interactions. In the case of PA and FP, it can be seen that IRI nicely exhibits the interaction between hydroxyl and carbonyl groups. At suitable locations, the IRI isosurfaces’ color is gradually blue. IRI isosurfaces demonstrate the presence of the noncovalent C=O···H interaction during the reaction. Green to yellow isosurfaces indicate the electron delocalize range (EDR) in Figure 10b, which shows the EDR with an intermolecular contact between the PA of the carbonyl group and the FP of the hydroxyl group. Belonging to H-bond interactions, one spike is found in the region at −1.70. In addition, two spikes are found in the region between −1.70 and −4.80, which belong to vdW interactions and spikes belonging to steric effects that are located in 7.0. Figure 10a,b depicts title structures that include chemical-bonding and intramolecular or intermolecular interactions.

Figure 10.

Figure 10

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(a) Interaction region indicator and (b) electron delocalized range of PA and FP compounds.

3.9. Selectivity of Active Sites

Current descriptors, such as dual descriptor Δf(r), an abbreviated version of Δf(r) ΔSk, were computed for better comprehension.50 If Δf(r) > 0, the dual descriptor Δf(r) is provided by

3.9.

This formula is Δf(r) times the molecular softness (ΔSk)51 in a more condensed form

3.9.

The explanation is related to Δf(r). Table 7 (Tables S4–S6) provides each atom’s Fukui functions and local softness values for the studied PA and FP molecules.

Table 7. Calculated Fukui Functions for the Studied PA and FP Molecules.

atoms f– f+ f0 dual descriptor hardness (au) W– (eV) W+ (eV)
C1 0 0.0142 0.0071 0.0142 –0.0001 0 0.0135
C2 0 0.0075 0.0037 0.0075 –0.0001 0 0.0071
C3 0 0.0187 0.0094 0.0187 –0.0001 0 0.0178
N4 0 0.0084 0.0042 0.0084 –0.0001 0 0.008
O5 0 0.3212 0.1606 0.3212 –0.0025 0 0.3049
C6 0 0.0003 0.0001 0.0003 0 0 0.0002
C7 0 0.6243 0.3122 0.6243 –0.0048 0 0.5926
H8 0 0.0022 0.0011 0.0022 0 0 0.0021
H9 0 0.0002 0.0001 0.0002 0 0 0.0002
H10 0 0 0 0 0 0 0
H11 0 0.0001 0 0.0001 0 0 0.0001
H12 0 0.0001 0.0001 0.0001 0 0 0.0001
H13 0 0.0007 0.0003 0.0007 0 0 0.0006
H14 0 0 0 0 0 0 0
H15 0 0 0 0 0 0 0
H16 0 0.0001 0 0.0001 0 0 0.0001
H17 0 0 0 0 0 0 0
H18 0 0.0001 0.0001 0.0001 0 0 0.0001
H19 0 0.0012 0.0006 0.0012 0 0 0.0011
H20 0 0 0 0 0 0 0
H21 0 0 0 0 0 0 0
H22 0 0 0 0 0 0 0
H23 0 0 0 0 0 0 0
C24 0.0122 0 0.0061 –0.0122 0.0031 0.0116 0
C25 0.4806 0 0.2403 –0.4806 0.1226 0.4562 0
C26 0.0001 0 0.0001 –0.0001 0 0.0001 0
C27 0.4943 0 0.2472 –0.4943 0.1261 0.4692 0
C28 0.0002 0.0001 0.0002 –0.0001 0 0.0002 0.0001
C29 0.0124 0.0002 0.0063 –0.0122 0.0032 0.0118 0.0002
O30 0.0001 0.0003 0.0002 0.0003 0 0.0001 0.0003
F31 0 0 0 0 0 0 0
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The maximum threshold mainly determines the nucleophilic and electrophilic behaviors of different sites of the compounds fk+ and fk values. When a molecule accepts electrons, the changes in electron density are measured by the fk+ values, while the fk values give the measures of the changes in electron density when the molecules lose the electrons. The high fk+ and fk values imply the molecules’ high electron acceptance and donation capabilities, respectively. From the calculated Fukui indices (Table 6), it can be observed that the most susceptible sites for electron acceptance or donation are the O5 heteroatoms, followed by C7 and C27 atoms of the aliphatic compound. The favorable centers for electron acceptance, i.e., O5 and C7 atoms having fk+ 0.3212 and 0.6243, respectively, are nucleophilic attacks. On the other hand, the susceptible sites for electrophilic attacks, i.e., electron donation, are C27 atoms having fk 0.4943. In addition, it is also observed that the calculated Fukui indices are in good accord with the electron density distribution in the HOMO and LUMO of the studied molecules. Hence, these analyses signify the same reactive sites for the corresponding D–A-type interaction on the metallic surfaces.

3.10. Dielectric Relaxation Analysis

The current investigation is being done to identify noncovalent interactions between PA and halophenol in benzene. This work uses the Higashi technique52 to validate Debye’s single-frequency equation. The average relaxation time (τ1), total relaxation time (τ2), and geometric meantime (τ0) are determined by the Debye equation, which defines slopes a’ and a″. The relaxation time (τ0) values for the title molecule were measured at room temperature for five distinct mole ratios: 1:3, 1:2, 1:1, 3:1, and 2:1. The relaxation time was determined to be the maximum at a 1:1 molar ratio. Due to the H bonding between the halogenated phenols hydroxyl hydrogen and the N atom in the PA, NH group, the formation is like (PA) HNδ−.... δ+HO. An increase in the effective size of the molecular spinning unit might explain the increased relaxation time.53 The relaxation time appears to decrease for various mole ratios. The value of relaxation time is a 1:1 ratio; the resulting value agrees with Higashi’s method. Using the Higashi approach for an equal mole ratio, the title compounds’ value was determined and is shown in Table 8.

Table 8. Dielectric Parameter Values of PA with (FP, CP, BP, and IP) in Benzene (X-Band) at 298 K for Various Weight Fractions.

  weight fraction         relaxation time (ps)
ratio w2 ε0 ε’ ε″ ε∞ τ1 τ2 τ0
PA + FP
1:3 0.03745 6.1342 2.9875 0.9717 2.6399 21.34 21.91 21.62
1:2 0.03714 6.1423 2.9887 0.9704 2.6341 20.87 21.09 20.98
1:1 0.03652 6.1678 3.0130 0.9779 2.6410 21.67 22.42 22.04
2:1 0.03589 6.1479 2.9856 0.9701 2.6378 20.79 20.83 20.81
3:1 0.03558 6.1371 2.9864 0.9712 2.6387 21.42 21.47 21.45
PA + CP
1:3 0.04168 6.1401 2.9928 0.9753 2.6411 21.16 21.20 21.18
1:2 0.04092 6.1502 2.9969 0.9762 2.6392 20.78 20.96 20.87
1:1 0.03933 6.1790 3.1013 0.9792 2.6480 21.35 22.09 21.72
2:1 0.03777 6.1599 2.9926 0.9788 2.6396 20.34 20.69 20.51
3:1 0.03699 6.1407 2.9943 0.9723 2.6409 21.14 21.11 21.12
PA + BP
1:3 0.05310 6.1463 3.0993 0.9771 2.6439 21.05 21.04 21.04
1:2 0.05105 6.1545 3.0600 0.9794 2.6409 20.63 20.78 20.71
1:1 0.04695 6.1824 3.1641 0.9812 2.6508 21.21 21.72 21.46
2:1 0.04284 6.1620 3.0893 0.9802 2.6440 20.23 20.39 20.31
3:1 0.04079 6.1508 3.0499 0.9785 2.6428 20.98 20.96 20.97
PA + IP
1:3 0.06517 6.1509 3.1410 0.9897 2.6473 20.75 20.84 20.79
1:2 0.06178 6.1647 3.1036 0.9841 2.6445 20.32 20.45 20.38
1:1 0.05499 6.1862 3.2024 0.9862 2.6563 21.19 21.34 21.26
2:1 0.04821 6.1670 3.1075 0.9819 2.6460 19.87 20.12 19.99
3:1 0.04482 6.1542 3.0994 0.9875 2.6487 20.79 20.49 20.64
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3.11. Molecular Docking

The crystalline structure of Staphylococcusaureustyrosyl-tRNA synthetase ligase (Uniprot = Q15631 for Translin), which has antibacterial and antifungal properties, was obtained from PDB.54 Chemsketch was used to generate ligand molecules. The molecules were rendered in 3D using the Babel software. The Protein Preparation Wizard Module55 was used to produce the receptor structures, and the ligand models were created using Schrodinger’s ligprep module to ensure that they were chemically precise. Molecular docking was performed using the Glide ligand docking module.56 The glide receptor grid generation module was used to build receptor grids. For the prepared proteins, grids were built. Ciprofloxacin-centered grids were formed for the S. aureusgyrase complex and SB-239629 ligand-centered grids for the S. aureusTyrRS complex. The boundary box was set to its default size, 14 Å × 14 Å × 14 Å, which was large enough to include the binding area by the ligand.57 The COACH-D server,58 which uses the Autodock Vina method,59,60 was also used to conduct docking between the ligands and the S. aureustyrosyl-tRNA synthetase protein structure (PDB id: 1JIJ). The protein–ligand interactions were classified into four types such as hydrophobic interactions, ionic bonding, hydrogen bonding, and disulfide linkages. The latter is commonly grouped, such as acceptor, donor, backbone donor, and backbone acceptor categories. They play a crucial role in ligand–protein binding and are essential to consider when designing new drugs. The interactions identified Arg-12 and Leu-274 as the H-bond interacting amino acid residues for the 1J1J complex. As discovered, pi-interactions involving the ligand PA with FP, CP, BP, and IP compounds in all of the examined systems, as shown in Table 9 and Figure 11(Figures S1 and S3), and many biologically relevant factors were evaluated. Table 10 and Figures 12 and 13 mentioned in the analyses include lipophilicity, druggability, solubility, and pharmacokinetics based on ADMET (absorption, distribution, metabolism, excretion, and toxicity).61,62 All components were computationally screened for possible biological effects; PASS63 was employed to calculate quantitative structure–activity connections by analyzing chemical structures into 2D and 3D descriptors and then generating models from bioactive ligands.64 Results of predictions were reported as a proportion of probable activity (Pa) and probable inactivity (Pi) (Pi). Pa and Pi values for four of the top moves with Pa > Pi and Pa > 0.700 were considered in this assessment.

Table 9. Affinity and Hydrogen Bond Interaction of PA with FP, CP, BP, and IP Compounds.

residue type interaction distance binding energy/coordinates donor type interactions
1JIJ-F
ARG12 2.44 Å –6.30 kcal/mol −13.23, 21.25, 110.35 oxygen H-Bond
ARG12 2.93 Å oxygen H-Bond
LEU274 2.48 Å oxygen H-Bond
1JIJ-Cl
ARG12 2.45 Å –6.30 kcal/mol −13.25, 21.21, 110.36 oxygen H-Bond
ARG12 2.81 Å oxygen H-Bond
LEU274 2.38 Å oxygen H-Bond
1JIJ-Br
ARG12 2.52 Å –6.40 kcal/mol −13.31, 21.21, 110.42 oxygen H-Bond
ARG12 2.86 Å oxygen H-Bond
LEU274 2.43 Å oxygen H-Bond
1JIJ-I
ARG12 3.14 Å –6.40 kcal/mol −13.27, 21.22, 110.38 oxygen H-Bond
ARG12 3.87 Å oxygen H-Bond
LEU274 3.12 Å oxygen H-Bond
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Figure 11.

Figure 11

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(a) Aromaticity, (b) charges, (c) H-bond, and panels (d, e) show the best pose, which corresponds to the lowest energies of the ligands-FP in the 1J1J protein and 2D interactions.

Table 10. ADMET of PA with FP, CP, BP, and IP Compounds.

molecule molecule 1 molecule 2 molecule 3 molecule 4
formula C11H17FNO2 C11H17ClNO2 C11H17BrNO2 C11H17INO2
MW 213.25 229.7 274.15 321.15
#heavy atoms 15 15 15 15
#aromatic heavy atoms 6 6 6 6
#rotatable bonds 3 3 3 3
#H-bond acceptors 3 2 2 2
#H-bond donors 3 3 3 3
MR 58.59 63.64 66.33 71.35
TPSA 66.48 66.48 66.48 66.48
iLOGP 0 0 0 0
XLOGP3 2.5 3.03 3.09 3.74
MLOGP 2.37 2.51 2.65 2.79
silicos-IT log P 0.95 1.17 1.21 1.5
consensus log P 1.66 1.86 1.93 2.11
ESOL log S –2.84 –3.27 –3.58 –4.29
ESOL solubility (mg/mL) 3.12 × 10–1 1.23 × 10–1 7.14 × 10–2 1.66 × 10–2
ESOL solubility (mol/L) 1.46 × 10–3 5.36 × 10–4 2.60 × 10–4 5.18 × 10–5
silicos-IT class soluble soluble moderately soluble moderately soluble
GI absorption high high high high
BBB permeant yes yes yes yes
Pgp substrate no yes yes yes
CYP1A2 inhibitor no no no no
CYP2C19 inhibitor no no no no
CYP2C9 inhibitor no no no no
CYP2D6 inhibitor no no no no
CYP3A4 inhibitor no no no no
bioavailability score 0.55 0.55 0.55 0.55
synthetic accessibility 1.2 1.21 1.33 1.84
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Figure 12.

Figure 12

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BOILED-egg predictive model for PA with FP, CP, BP, and IP compounds.

Figure 13.

Figure 13

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Bioavailability radar of PA with FP, CP, BP, and IP compounds that correspond to an optimum range for each property is shown by the pink area.

4. Conclusions

The study mainly focused on noncovalent interactions of PA with FP, CP, BP, and IP compounds. IR spectra were utilized to assign frequencies and validate the computational approach through excellent agreement with data from the literature. The HOMO and LUMO energy changes within the molecule were found to facilitate charge-transfer interactions. Through the solvation effect using TD-DFT/B3LYP with the IEFPCM model, the reactive sites were predicted with the aid of MEP and Hirshfeld charges. Additionally, the compound was subjected to the DFT method to test its chemical and thermal stability. The effectiveness of IRI analysis for characterizing changes in covalent and noncovalent interactions in ab initio molecular dynamics simulations is highly promising. The relaxation time of the PA with FP, CP, BP, and IP compounds was determined using the Higashi technique, and it revealed that the complex formation is maximal at a 1:1 ratio due to hydrogen bonding between PA and halogen-substituted phenol derivatives. The drug-likeness of the molecule and ligand–protein interactions, as with molecular docking simulations, and pharmacokinetics were evaluated to investigate the potentiality of these therapeutics. The in silico docking simulations showed several interactions between ligand and protein clusters with high binding energy scores, supporting the biological efficacy of the four novel ternary mixture compounds against various bacterial infections. Further, in silico pharmacokinetics analyses indicated that the pharmacological compounds (PA•••FP, PA•••CP, PA•••BP, and PA•••IP) have significant inhibitory effects, implying that these promiscuous molecules may further be studied for cancer therapy.

Acknowledgments

The authors thank the Management of Islamiah College (Autonomous) for the facilities provided to carry out the research work in the Department of Physics & Chemistry, Islamiah College (Autonomous), Vaniyambadi.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c04710.

  • Evaluated quantum chemical properties of the PA+FP, CP, BP, and IP compounds by the DFT/B3LYP/6-311++G(d,p) method; assignments of theoretical wavenumbers of PA+FP, CP, BP, and IP compounds with the 6-311++G(d,p) basis set; and reactivity and selectivity of the Fukui functions and the figures of molecular docking stimulation of the PA+FP, CP, BP, and IP compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao3c04710_si_001.pdf (1.1MB, pdf)

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