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Turkish Journal of Chemistry logoLink to Turkish Journal of Chemistry
. 2022 Jun 2;46(5):1548–1564. doi: 10.55730/1300-0527.3460

Synthesis, characterization, computational analyses, in silico ADMET studies, and inhibitory action against SARS-CoV-2 main protease (Mpro) of a Schiff base

Songül ŞAHİN 1,*, Necmi DEGE 2
PMCID: PMC10390206  PMID: 37529731

Abstract

COVID-19 disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) has struck the whole world and raised severe health, economic, and social problems. Many scientists struggled to find a vaccine or an antiviral drug. Eventually, both vaccines and recommended drugs, repurposed drugs, or drug combinations were found, but new strains of SARS-CoV-2 continue to threaten human life and health. As part of the fight against COVID-19 disease, this study involves an in silico molecular docking analysis on the main protease (Mpro) of SARS-CoV-2. To this aim, a Schiff base compound was synthesized and characterized using spectroscopic techniques, including X-ray, FTIR, and UV-Vis. Surface analysis and electronic properties of this molecule were investigated using the DFT method. The drug-likeness parameters of the title compound were studied according to the rules of Lipinski, Veber, Ghose, Egan, and Muegge and were found in agreement with these rules. In silico toxicity analyses revealed that the new compound is a potentially mutagenic and carcinogenic chemical. The title compound was predicted to be an inhibitor of cytochrome P450 enzymes (5 CYPs). This inhibitory effect indicates a weak metabolism of the molecule in the liver. In addition, this compound was displayed good intestinal absorption and blood-brain barrier penetration. The druggability properties of the title compound were investigated, and SwissTargetPrediction predicted it to be a protease inhibitor. In this context, the SARS-CoV-2 main protease was selected as a biological target in molecular docking studies. Docking results were compared with the known native ligand N3 inhibitor. The value of binding energy between the Schiff base compound and the binding pocket of the main protease is higher than that of the reference ligand N3. The calculated free energies of binding of the Schiff base compound and the reference ligand N3 are −8.10 and −7.11 kcal/mol, respectively.

Keywords: Schiff base, SARS-CoV-2, ADMET, X-ray, COVID-19, main protease (Mpro)

1. Introduction

So far, seven coronaviruses, including HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2, have been detected in humans. In late December 2019, COVID-19 disease related to the latest one, SARS-CoV-2, was reported for the first time in Wuhan, China [1,2]. The novel virus of 2019 was initially named 2019-nCoV by WHO. On February 11, 2020, the International Committee on Taxonomy of Viruses renamed the virus as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on phylogenetic analysis [3]. In March 2020, the disease was declared a global pandemic because it has spread to over 100 countries [4]. As of December 4, 2021, the most recent data show that SARS-CoV-2 has caused 263,563,622 cases and 5,232,562 deaths worldwide [5] (Access date: December 04, 2021).

Clinical symptoms in pediatrics are usually absent or mild [6]. In adults, symptoms can range from moderate symptoms to severe health problems such as cough, fever, headache [7–10], dyspnea [8–10], myalgia [8, 9], tiredness, loss of taste or smell, aches, cold, discoloration of fingers or toes, breathing difficulties to dysfunction of organs [7], pneumonia [8, 9], acute respiratory distress syndrome (ARD), kidney failure, coagulation abnormalities, sepsis [9], multiple organ failure [8], cytokine storm [11]. At the beginning of the pandemic, when there was no FDA-approved vaccine, using various repurposed drugs or their combinations, including chloroquine, remdesivir [12–14], ribavirin [12, 13], galidesivir, tenofovir, sofosbuvir [12], favipiravir, lopinavir, hydroxychloroquine, oseltamivir, arbidol, interferons, ritonavir [13,14] methylprednisolone, bevacizumab, human immunoglobulin [14], darunavir, cefpiramide, tocilizumab [13] was recommended for the treatment of COVID-19. On August 23, 2021, the first COVID-19 vaccine, Pfizer-BioNTech’s vaccine, received full FDA approval [14].

The main protease (Mpro) of SARS-CoV-2, also known as 3C-like protease (3CLpro) [15], plays a pivotal role in viral replication and maturation, and has been reported as a valuable target for drug development against COVID-19 [16,17]. The monomeric structure of Mpro consists of 306 amino acids and three domains, including N-terminal domain-I (8–101 residues), N-terminal domain-II (102–184 residues), and C-terminal domain-III (201–306 residues) [16, 18]. HIS 41 and CYS 145 are catalytic dyads in the main protease [16, 19, 20], and they play an important role in protease activity [20, 21]. Therefore, inhibition of the catalytic dyad in 3CLPro may be a rational target for anti-CoV drug development [22].

Some authors have examined the inhibitory effect of Schiff base ligands on SARS-CoV-2 main protease (Mpro) using molecular docking methods [19, 23–26]. They found the binding energy of Mpro-ligand complexes between −5.88 and −9.10 kcal/mol. In this study, a new imine compound was synthesized. The molecular structure was determined by spectroscopic methods, including X-ray, FTIR, and UV-Vis. The electronic properties, surface characterization, and intermolecular interactions were calculated using the DFT and other techniques. In silico drug-like nature of the title compound was determined using the online in silico web tools. Druggability studies indicated that the title compound is most likely a protease inhibitor. In this sense, the SARS-CoV-2 main protease (Mpro) was selected as a biological target for the title compound in molecular docking experiments. Docking studies showed that the title compound had higher binding energy (−8.10 kcal/mol) against SARS-CoV-2 than the native N3 inhibitor (−7.11 kcal/mol).

2. Experimental

2.1. Materials and method

Chemicals: 5-nitro-2-(piperidin-1-yl)benzaldehyde; 2-methoxyaniline; ethanol/Sigma Aldrich.

Apparatus: Merck TLC plates/thin layer chromatography; CAMAG-UV cabinet/visualization; Stuart SMP 30/melting point; Precisa balance/weighing; Heidolph magnetic stirrer/heating.

Spectrometers: Perkin-Elmer/FT-IR; Thermo Fisher Scientific/UV-Vis; Stoe IPDS II [27]/X-ray.

X-ray and computational analysis: SHELXT [28], SHELXL [29]/solving and refinement; PublCIF [30]/CIF file; Gaussian 03 [31]/DFT [32] and B3LYP/6-31G (d, p) level of theory [33, 34]/frontier molecular orbitals, electrostatic potential map, Mulliken charges, geometrical parameters; Crystal Explorer [35]/Hirshfeld surfaces and fingerprint plots; Mercury [36]/crystal packing and intermolecular interactions.

Docking and druglike nature: AutoDock4 and AutoDockTools4 [37]/molecular docking; PDB [38]/3D structure of protein-ligand complex; PLIP [39]/secondary interactions and species; SwissADME [40]/pharmacokinetics, drug-likeness, and medicinal chemistry; PPB [41]/multitarget identification; ProTox-II [42] and pkCSM [43]/toxicity properties.

2.2. Synthesis

The synthesis reaction of the (E)-N-(2-methoxyphenyl)-1-(5-nitro-2-(piperidin-1-yl)phenyl)methanimine compound is given in Scheme 1. First, a mixture of 5-nitro-2-(piperidin-1-yl)benzaldehyde (11 mg, 0.047 mmol) and 2-methoxyaniline (5.8 mg, 0.047 mmol) was dissolved in ethanol (25 mL) and the reaction temperature of the mixture was raised to the reflux temperature. The mixture was periodically analyzed by the thin-layer chromatography (TLC) using hexane: ethyl acetate (95:5) mobile phase to understand whether the reaction was completed. After the reactant plots disappeared in TLC, 22 h later, the reaction was completed. The solution was filtered and cooled at room temperature. The solvent was vaporized by the slow evaporation method in eight days. The yellow crystals were used for the whole analysis process. Melting point: 141–143 ºC. Yield: 85% (9.35 mg). C19H21N3O3. Molecular weight: 339.39 g/mol. FTIR (attenuated total reflectance, ATR), ν/cm−1: 3099, 3079 (Ar C-H); 2986, 2968, 2941, (Al C-H); 2900 (CH=N); 1681 (C=N); 1675, 1596, 1499, 1481 (Ar C=C); 1500, 1324 (NO2); 1248, 1232, 1063 (C-N); 1126, 1074 (C-O); 1025, 943, 910, 855, 828, 817, 765, 752, 715, 639, 517 (Figure S1). UV-Vis (in EtOH, 1.57 x E-04 M), λmax nm (logɛ): 361 (3.86) (Figure S2).

Scheme 1.

Scheme 1.

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The synthesis reaction of the title compound.

3. Results and discussion

3.1. Crystallographic, structural and geometrical parameters

Single-crystal X-ray diffraction data for the synthesized compound were collected using a STOE IPDS II diffractometer. Graphite monochromated MoKα radiation (λ = 0.7073 Å) was used for the measurements. The X-RED32, SHELXT, and SHELXL programs were used for cell refinement, structure solving, and refinement, respectively. The title compound with a molecular formula C19H21N3O3 and name (E)-N-(2-methoxyphenyl)-1-(5-nitro-2-(piperidin-1-yl)phenyl)methanimine is a small molecule with azomethine structure, yellow color, and prism-shape. It has space group P21/n and is crystallized in a monoclinic crystal system. As expected from this crystal system, three axes in the unit cell have unequal lengths: a ≠ b ≠ c (Å) = 10.1685, 13.3628, 13.416. The unit cell contains four monomeric molecules (Figure 1a). The symmetry operators of the crystal show that the structure is centrosymmetric; consequently, it is a nonlinear optical (NLO) inactive material. The geometric dimensions of the crystal selected for structure determination are 0.71 × 0.48 × 0.24 mm3. More information on the X-ray analysis and structural parameters can be seen in Table S1, which also lists the other crystal parameters. When we examine the molecule for its structural composition, we can identify four different molecular groups: anisole (green ring and -OCH3), C7H7O; nitrobenzene (purple ring and -NO2), C6H3NO2; piperidinyl (orange ring), C5H10N; and azomethine (cyan circle), CH=N. The azomethine group in the structure was bonded to the benzene rings, which have electron-withdrawing (NO2) and electron-donating (OCH3) substituents (Figure 1b and 1c). These substituents have a positive effect on the synthesis reaction by facilitating the condensation between amine and aldehyde reactants (through inductive and mesomeric effects). The calculated and measured bond lengths, bond angles, and dihedral angles are listed in Tables S2–S4, respectively. We have listed some important values here. Bond lengths (measured-calculated max/min.): Ar. C=C: 1.427–1.425 (C6-C5)/1.378–1.386 (C4-C3); Al. C-C: 1.517–1.530 (C12-C11)/1.529–1.533 (C11-C10); C-N: 1.479–1.478 (C12-N2)/1.406 (C5-N2)–1.400 (C13-N3); C7=N3: 1.277/1.282; 01-N1: 1.235/1.231; N1-O2: 1.230/1.233; C-O: 1.429–1.421 (C19-O3)/1.382–1.371 (C18-O3). Bond angles (measured/calculated): O1-N1-O2: 117.6/117.9; C7-N3-C13: 123.9/123.5; C6-C7-N3: 119.7/120.3; C1-C2-C3: 121.3/121.3; C9-C10-C11: 109.0/110.1.

Figure 1.

Figure 1

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The unit cell viewing (a) numbering of the atoms in capped stick model (b) the secondary intermolecular interaction places and bond lengths (c) of the title compound.

3.2. Molecular electrostatic potential and Mulliken atomic charges

Molecular electrostatic potential (MEP) is a 3D mapping of the whole electron density in a molecule. It is a powerful method for determining the nucleophilic and electrophilic attack regions of a molecule. In MEP, the distribution of electrons is represented by colors. The color distribution can change in a red-blue gradient. The red regions show the most negative electrostatic potential. The blue regions show the most positive, and the green regions show the zero electrostatic potential in a molecule. While the red atoms, group of atoms, or regions are open to electrophilic attack, the blue regions are open to nucleophilic attack. The MEP map for our compound was calculated at the B3LYP/6-31G (d, p) level of theory and shown in Figure 2 with the three mapping models. As can be seen in Figure 2, the red regions spread over the oxygen atoms of the nitro group, and there are no dark blue regions showing strong nucleophilic attack positions in the molecule. The cyan regions were slightly gathered on the piperidinyl (C6H5N) ring and methyl (-CH3) group, and therefore, these regions can be evaluated as weak nucleophilic attack positions, while the oxygens atoms of the nitro group can be evaluated as strong electrophilic positions. The other positions of the molecule are green, have zero electrostatic potential; thus, these regions are not reactive. When the Mulliken charges of the title compound (Figure 3) were examined, the five atoms with the most negative and positive charges can be listed as follows: O3 (−0.565) > N2 (−0.557) > N3 (−0.488) > O2 (−0.407) > O1 (−0.405) and N1 (0.364) > C18 (0.330) > C5 (0.269) > C2 (0.237) > C13 (0.197).

Figure 2.

Figure 2

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Molecular electrostatic potential map of the title compound.

Figure 3.

Figure 3

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Mulliken atomic charge distribution map of the title compound: with numbered style (left), with colored style (right).

3.3. Molecular orbital analysis and global reactivity descriptors

The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), also called frontier molecular orbitals (FMOs), are the most critical orbitals in a molecule. The HOMO is an electron donor, while the LUMO is an electron acceptor. The energy of these orbitals and frontier orbital gap (or energy gap) plays a vital role in determining the chemical reactivity, kinetic stability [44–46], and electrical, optical, and physical properties [47] of a molecule. The global reactivity descriptors, including electron affinity, chemical hardness and softness, electronegativity, chemical potential, electrophilicity index, and charge transfer index can also be calculated using the energy values of these orbitals. The small energy gap between HOMO and LUMO indicates high chemical reactivity, low stability, softness [48], and easy charge transfer [49]; the large energy gap indicates low chemical reactivity, high kinetic stability [50], hardness [51], and hard charge transfer [49]. To investigate the above properties, we examined the FMOs of the compound in the gas phase. The calculations were performed at the B3LYP/6-31G (d, p) level of theory. HOMO-LUMO orbitals of the studied compound are shown in Figure 4. HOMO orbitals spread over all surfaces of the molecule except for some methylene groups in the piperidinyl ring; LUMO orbitals spread over imine, nitrobenzene, and nitrogen in the piperidinyl ring. Global reactivity descriptors were calculated using the HOMO and LUMO energies and are listed in Table 1. For the title molecule, the energy values of the HOMO, the LUMO, and the energy gap were found to be −5.629, −2.053, and 3.576 eV, respectively. Other global reactivity parameters can be seen in Table 1. The molecule has the smallest value of the energy gap among the similar studies we have performed previously [52–54]. From the calculated results, we can draw these conclusions about our compound: (i) The lowest value of the frontier orbital gap of the title molecule among the similar compounds [52–54] indicates that the molecule has high chemical reactivity, low chemical and kinetic stability, easy charge transfer, high polarizability, and softness. (ii) A high electrophilicity index (4.125) indicates a high electrophilic nature and good biological activity, while a relatively high softness value (0.279) indicates an increased probability of toxicity [55]. (iii) The effect of HOMO, LUMO, and energy gap values of the compounds on biological activity has been reported [56]. Low values of energy gap and LUMO lead to increased biological activity. This is due to the low energy required for electronic excitation and the strong charge transfer interaction between donor and acceptor atoms [57–59].

Figure 4.

Figure 4

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HOMO, HOMO-1, LUMO, LUMO+1 orbitals, energy values of the orbitals and band gaps of the title compound.

Table 1.

Calculated global reactivity descriptors.

Parameters Values (eV)
EHOMO −5.629
ELUMO −2.053
Energy band gap (ΔE = ELUMO−EHOMO) 3.576
Ionization potential (I = − EHOMO) 5.629
Electron affinity (A = − ELUMO) 2.053
Chemical hardness (η = (I−A)/2) 1.788
Chemical softness (σ = 1/2η) 0.279
Electronegativity (χ = (I+A)/2) 3.841
Chemical potential (μ = −(I+A)/2) −3.841
Electrophilicity index (ω = μ2/2η) 4.125
Maximum charge transfer index (ΔNmax = −μ/η) 2.148
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3.4. Hirshfeld surfaces and fingerprint analysis

To learn about the intermolecular interaction species in the molecule and their quantitative contributions, we performed Hirshfeld surface and 2D fingerprint analyses. For the above purpose, Crystal Explorer 17.5 software requires the CIF file of the compound. The calculated Hirshfeld surfaces of the title compound are shown in Figure 5 in six different maps, including dnorm, di, de, fragment patch, curvedness, and shape index. In the dnorm mapped surface, red dots show the interaction distance shorter than the sum van der Waals (vdW) radii of two atoms. White regions show the close interactions to the vdW radii, and finally, the more extended contacts from the sum of vdW radii are represented by blue areas [60]. On the dnorm surface, the bright red spot is on the O2 atom, indicating the presence of hydrogen bonding at this atom. Fingerprint plots showing the percentage contributions of each interaction type are shown in Figure 6 (If the contribution is greater than or equal to 1%). The largest contribution to the percentage of secondary interactions is the hydrogen···hydrogen (50.8%) interaction, a type of vdW force. The second largest contribution is the hydrogen bonding interactions between oxygen and hydrogen (20.2%). The other contributors are C···H (14.7%), C···C (6.1%), and N···H (5.8%).

Figure 5.

Figure 5

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The title compound (middle) and its Hirshfeld surfaces (around).

Figure 6.

Figure 6

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Intermolecular interactions and their relative contributions with the fingerprint plots (showed only bigger than 1% ones).

3.5. Docking studies

Docking experiments were performed on the active residues of the SARS-CoV-2 main protease to determine the inhibitory activity of the synthesized compound. The 3D crystal structure of the main protease with the native N3 inhibitor (PDB entry: 6LU7 [61]) was retrieved from the RSCB PDB website (https://www.rcsb.org/). Before the docking experiments, the protein and ligand structures were prepared by removing water, adding polar hydrogens, merging nonpolar hydrogen atoms, and adding charges using the AutoDock and Autodock tools. The grid box has centered on the active residues [62], and the grid dimensions are given in Figures 7 and S3. The docking experiments were performed using the Lamarckian genetic algorithm. In the docking experiments, we used a semiflexible docking method (rigid target/flexible ligand).

Figure 7.

Figure 7

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The active sites in the grid box and grid box settings.

N3 is a peptidomimetic inhibitor of the main protease of SARS-CoV and SARS-CoV-2 [61,63]. It was used for comparison in this study. Both the native ligand N3 inhibitor and query compound were docked to the active sites of the target protein. Docking results of the title compound, including binding modes, interacting residues, and binding free energy, are given in Figure 7. The docking experiment was repeated ten times for the title compound. Docking scores were determined with a standard deviation of 0.057. The median value of the docking experiments was determined and accepted as the final docking score (−8.10 kcal/mol). The ligand efficiency was found to be −0.32. The calculated docking parameters for ten docking experiments are shown in Figure S4. The most stable conformations of the reference N3 inhibitor and query compound (Figure 8a), the top ten conformations produced in the active pocket of SARS-CoV-2 main protease (Figure 8b), and the whole protein surface, including the reference molecule and query compound (Figure 8c), were shown in Figure 8. According to the docking results, the query compound has higher binding energy than the reference N3 inhibitor. In our study, the binding energies of the native ligand N3 and the query compound were calculated to be −7.11 and −8.10 kcal/mol, respectively. Query compound is bound to the target protein via both hydrophobic interactions (LEU167: 3.91 Å, GLN192: 3.67 Å, GLN189: 3.33 Å) and hydrogen bond (TYR54: 2.11 Å) (Figure 9). We compared the results of our study with those of the other studies (Table 2). For Mpro (3CLpro) of SARS-CoV-2, the studies listed in Table 2 show the chemical class studied against Mpro, common functional groups with our compound, software, docking scores, and interaction status with the catalytic dyad of Mpro. Although our docking score is high, no interaction with the catalytic dyad of Mpro was detected in our complex interactions. Therefore, the title compound may not provide the desired inhibitory effect on the Mpro of SARS-CoV-2.

Figure 8.

Figure 8

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Docking positions of the reference N3 and query compound (a), ten positions produced of query compound in the active site of Mpro (b), the whole surface viewing of Mpro (c).

Figure 9.

Figure 9

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Docking position of the title compound in the active site of Mpro, and the secondary interaction species formed with the active residues.

Table 2.

Comparative docking studies performed with Mpro (3CLpro) of SARS-CoV-2.

PDB ID Compound class Compound code with the highest docking score Common groups with the title compound Software Docking score (kcal/mol) Interaction with the catalytic dyad
Our study (S0) 6LU7 Schiff base Title compound Aromatic ring, alicyclic ring, imine group, nitro group, methoxy group, and tertiary amine AutoDock −8.10 No
S1 [94] 6LU7 Coumarin derivatives 10a Two aromatic rings Autodock and AutoDock Vina −7.0 and −8.6 Yes
S2 [95] 7BQY Coumarin derivatives 14 Aromatic ring and imine group MOE −7.47 Not reported
S3 [96] 6LU7 Crinipellin and Alliacol-B derivatives Compound 5 One alicyclic ring AutoDock −7.3 No
S4 [97] 6LU7 Azo-imidazole derivatives L5 Methoxy, two aromatic rings, imine group AutoDock Vina −8.1 Yes
S5 [98] 7BQY Schiff bases ZG-7 Not reported MOE −8.79 Not reported
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3.6. Druglike nature, medicinal chemistry and druggability

We examined some essential physical and biological parameters in medicinal chemistry using the SwissADME [40] web tool developed by the Swiss Institute of Bioinformatics. These parameters compose of six sections (Table 3), including physicochemical properties, lipophilicity, solubility, pharmacokinetics, drug-likeness, and medicinal chemistry. Druggability predictions (Figure 10) of the title compound to determine the biological targets were performed using SwissTargetPrediction [64]. In Table 3, the pink-colored area of the polygon on the left shows the suitable physicochemical space for oral bioavailability, the white area shows the unsuitable space, and the red lines sign out the position of our compound in the whole space. This hexagon is related to lipophilicity (LIPO), size (SIZE), polarity (POLAR), solubility (INSOLU), unsaturation (INSATU), and flexibility (FLEX) and is calculated by using appropriate domain borders of parameters, including XLOGP, molecular weight, topological polar surface area (TPSA), Log S, fraction of sp3, and number of rotatable bonds, respectively. As it can see from the red outline of the polygon, our compound has settled in the range suitable for oral bioavailability. When the BOILED-Egg model of the title molecule is examined from Figure 11, it can see that the molecule has a good intestinal absorption and can cross the blood-brain barrier. Cytochrome P450 enzyme families (CYPs) influence the pharmacokinetics of a drug. We investigated 5 CYPs, including CYP1A2, CYP2C19, CYP2C9, CYP2C6, and CYP3A4, which are related to the 80% of the metabolism of drugs in clinical use [65]. According to the predictions, the title compound is a potential CYPs inhibitor for five CYPs. This inhibitory effect means that our compound as a drug molecule candidate suppresses CYPs enzyme activity and decreases the metabolic rate in human liver, so the pharmacokinetic properties might not reach the desired efficiency.

Table 3.

Some calculated drug-like properties of the title compound.

graphic file with name turkjchem-46-5-1548f14.jpg graphic file with name turkjchem-46-5-1548f15.jpg
Physicochemical properties Pharmacokinetics
Formula C19H21N3O3 GI absorption High
Molecular weight 339.39 BBB permeant Yes
Num. heavy atoms 25 P-gp substrate No
Num. arom. heavy atoms 12 CYP1A2 inhibitor Yes
Fraction Csp3 0.32 CYP2C19 inhibitor Yes
Num. Rotatable bonds 5 CYP2C9 inhibitor Yes
H-bond acceptors 4 CYP2D6 inhibitor Yes
H-bond donors 0 CYP3A4 inhibitor Yes
Molar reactivity 104.90 Log Kp (skin permeation) −5.54 cm/s
TPSA 70.65 Å2
Lipophilicity Drug-likeness
Log Po/w (İLOGP) 3.05 Lipinski Yes, 0 violation
Log Po/w (XLOGP) 3.99 Ghose Yes
Log Po/w (WLOGP) 3.96 Veber Yes
Log Po/w (MLOGP) 2.07 Egan Yes
Log Po/w (SILICOS_IT) 2.29 Muegge Yes
Consensus Log Po/w 3.07 Bioavailability score 0.55
Medicinal chemistry
PAINS 1 alert: anil_di_alk_A
Brenk 3 alerts: imine_1, nitro_group, oxygen-nitrogen_single bond
Leadlikeness No, 1 violation: XLOGP > 3.5
Synthetic accessibility 2.98
Water solubility
Log S (ESOL) −4.48
Solubility 1.12 × E-02 mg/mL; 3.29 × E-05 mol/L
Class Moderately soluble
Log S (Ali) −5.18
Solubility 2.27 × E-03 mg/mL; 6.68 × E-06 mol/L
Class Moderately soluble
Log S (SILICOS-IT) −5.21
Solubility 2.11 × E-03 mg/mL; 6.21 × E-06 mol/L
Class Moderately soluble
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Figure 10.

Figure 10

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Druggability prediction results supplied from SwissTargetPrediction tool.

Figure 11.

Figure 11

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Representation of the toxicity results with the radar chart.

Drug-likeness was derived from the structures and properties of existing drugs and drug candidates. Before drug discovery, it is important to filter out unsuitable compounds [66]. This term was defined by Lipinski as meeting some proposed criteria for drug candidates [67]. Lipinski states that poor absorption and permeation are more likely in the following situations: i) Molecular weight is higher than 500. ii) LogP value is higher than 5. iii) Hydrogen bond acceptors are higher than 10. iv) Hydrogen bond donors are higher than 5 [68]. After Lipinski, different rules for drug-likeness were given by Ghose (160 ≤ MW ≤ 480; −0.4 ≤ WLOGP ≤ 5.6; −40 ≤ MR ≤ 130; 20 ≤ atoms ≤ 70) [69]; Veber (Rotatable bonds ≤ 10; TPSA ≤ 140) [70]; Egan (WLOGP ≤ 5.88; TPSA ≤ 131.6) [71]; Muegge (200 ≤ MW ≤ 600; −2 ≤ WLOGP ≤ 5; TPSA ≤ 150; number of rings ≤ 7; number of carbons > 4; number of heteroatoms >1; rotatable bonds ≤ 15; hydrogen bond acceptor ≤ 10; hydrogen bond donor ≤ 5) [72]. According to the mentioned rules, our molecule does not violate the above drug-likeness rules. We also investigated druggability predictions for our compound. The calculation results (Figure 10) show that our compound can inhibit the following enzyme classes in the top 15 lists: protease, kinase, phosphodiesterase, family A G protein couplet-receptor, oxidoreductase, voltage-gated ion channel, and cytochrome P450.

3.7. Potential multitarget identification with fingerprint methods

To improve the information about the bioactivity properties of our compound, we used a web server, the polypharmacology browser (PPB), www.gdb.unibe.ch. This web server is used to identify potential targets of a compound based on six different fingerprints and some combinations. The results of PPB are given according to the various algorithms: atom pair fingerprint (APfp), extended atom pair fingerprint (Xfp), molecular quantum numbers (MQN), scalar fingerprint counting the occurrence of characters in SMILES (SMIfp), (SMIfp), substructure fingerprint (Sfp), and extended connectivity fingerprint (ECfp4). APfp works with molecular shape; Xfp perceives pharmacophores; MQN perceives atoms, bonds, polarity, ring features, constitution, topology, and molecular shape; SMIfp uses rings, aromaticity, and polarity; Sfp works with the detailed substructures; ECfp4 uses the combination of detailed substructures and pharmacophores [41]. We tabulated the top 20 targets selected by the six fingerprinting algorithms for our compound. The results were ordered by the calculated cumulative density (p-values) for each target in Table 4. The red hexagon in this table indicates that the specified fingerprint algorithm did not find a target; the green hexagon indicates a lower p-value (from 0.01 to 0) and a lower probability for the target; the blue hexagon indicates potential targets for which the p-value is greater than 0.01. Provided that the estimated p-value is greater than 0.01, we indicate the exact p-values. The ChEMBL-ID and common names of the targets, and the explanation of each target are listed in Table 4. The results show that our compound has a similar fingerprint to the molecules with the indicated number on the right side of Table 4, which have strong biological activity on the indicated targets in the ChEMBL database. These targets can cause various diseases, such as malaria: Plasmodium falciparum/ChEMBL364 [73]; cancer: EHMT2/ChEMBL6032 [74]: GMNN/ChEMBL1293278 [75], ALD1AH1/ChEMBL3577 [76]; diabetes: HLP1R/ChEMBL1784 [77]; multiple sclerosis: RORC/ChEMBL1293231 [78, 79], Alzheimer’s disease: MAPT/ChEMBL1293224 [80]; spinocerebellar ataxia: ChEMBL1795085/ATXN2 [81]; HIV-1 infection: APOBEC3G/ChEMBL1741217 [82], APOBEC3F/ChEMBL2007626 [83]; laminopathies: LMNA/ChEMBL1293235 [84]; glioblastomas, chondrosarcomas, and acute myeloid leukemias (AML): IDH1/ChEMBL2007625 [85, 86]; LDL-derived cholesterol, Nieamann-Pick disease type C, and Ebola virus infection: NPC1/ChEMBL1293277 [87]; liver cancer: RAB9A/ChEMBL1293294 [88]. Our compound could interact with the listed targets as a potential ligand molecule and act as an inhibitor against target-related diseases mentioned above.

Table 4.

The potential targets of the title compound calculated by PPB.

Rank ChEMBL-ID ChEMBL-name APfp Xfp MQN SMIfp Sfp ECfp4 No of mols
1 ChEMBL364 ORGANISM_NOGN Inline graphic 0.233 Inline graphic 0.113 graphic file with name turkjchem-46-5-1548f17.jpg Inline graphic0.032 Inline graphic 0.236 Inline graphic0.036 16
2 ChEMBL6032 EHMT2 Inline graphic 0.533 Inline graphic 0.114 graphic file with name turkjchem-46-5-1548f17.jpg Inline graphic 0.117 Inline graphic 0.233 Inline graphic 0.025 11
3 ChEMBL1784 GLP1R graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic0.109 graphic file with name turkjchem-46-5-1548f17.jpg Inline graphic0.030 Inline graphic0.207 Inline graphic0.021 17
4 ChEMBL1293278 GMNN graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.119 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.032 Inline graphic 0.234 Inline graphic 0.013 19
5 ChEMBL1293231 RORC Inline graphic 0.264 Inline graphic 0.109 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.105 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.065 6
6 ChEMBL1741220 BAZ2B graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.241 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.06 Inline graphic 0.232 Inline graphic 0.013 5
7 ChEMBL1293224 MAPT Inline graphic 0.504 graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f17.jpg Inline graphic 0.083 Inline graphic 0.160 Inline graphic 0.018 9
8 ChEMBL1795085 ATXN2 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.301 Inline graphic 0.262 Inline graphic 0.108 Inline graphic 0.297 Inline graphic18 12
9 ChEMBL1741209 ATAD5 Inline graphic 0.523 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.012 graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.028 12
10 ChEMBL614818 CELL-LINE_NOGN Inline graphic 0.556 Inline graphic 0.121 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.032 graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg 11
11 ChEMBL1741217 APOBEC3G graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.079 graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.012 13
12 ChEMBL1293235 LMNA graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.092 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.029 8
13 ChEMBL4377 GNAS graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.111 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.035 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.030 5
14 ChEMBL614358 CELL-LINE_NOGN graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.018 graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg 11
15 ChEMBL1293258 SMAD3 graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.011 graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg 2
16 ChEMBL2007625 IDH1 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.109 graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg 12
17 ChEMBL3577 ALDH1A1 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.264 graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.199 graphic file with name turkjchem-46-5-1548f18.jpg 3
18 ChEMBL1293277 NPC1 Inline graphic 0.439 Inline graphic 0.234 Inline graphic 0.054 Inline graphic 0.078 graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.081 4
19 ChEMBL1293294 RAB9A Inline graphic 0.465 Inline graphic 0.286 Inline graphic 0.059 graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg Inline graphic 0.083 4
20 ChEMBL2007626 APOBEC3F graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg graphic file with name turkjchem-46-5-1548f18.jpg 6
graphic file with name turkjchem-46-5-1548f18.jpg Target not found by fingerprint.
graphic file with name turkjchem-46-5-1548f17.jpg p-value stretching from 0.01 to 0.
graphic file with name turkjchem-46-5-1548f16.jpg p-value > 0.01.
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ORGANISM_NOGN: Plasmodium falciparum; EHMT2: Histone-lysine_N-methyltransferase_H3_lysine-9_specific_3; GLP1R: Glucagon-like_peptide_1_receptor; GMNN: Geminin; RORC: Nuclear_receptor_ROR-gamma; BAZ2B: Bromodomain_adjacent_to_zinc_finger_domain_protein_2B; MAPT: Microtubule-associated_protein_tau; ATXN2: Ataxin-2; ATAD5: ATPase_family_AAA_domain-containing_protein_5; CELL-LINE_NOGN: HEK293; APOBEC3G: DNA_dC->dU-editing_enzyme_APOBEC-3G; LMNA: Prelamin-A/C; GNAS: Guanine_nucleotide-binding_protein_G(s)_subunit_alpha; CELL-LINE_NOGN: BJ; SMAD3: Mothers against decapentaplegic homolog_3; IDH1: Isocitrate_dehydrogenase_[NADP]_cytoplasmic; ALDH1A1: Aldehyde_dehydrogenase_1A1; NPC1: Niemann-Pick_C1_protein; RAB9A: Ras-related_protein_Rab-9A; APOBEC3F: DNA_dC->dU-editing_enzyme_APOBEC-3F.

3.8 Toxicity analysis

Two web servers, ProTox-II and pkCSM were used to determine the toxicity parameters of the title compound. The calculated toxicity endpoints and models are shown in Table 5 and Figure 11 (ProTox-II) and Table 6 (pkCSM). From Table 5 and Figure 11, we can see that the title compound is classified as mutagenic and carcinogenic with a probability of 79% and 61%, respectively. From Table 6, we can see that the title compound has two alerts related to AMES mutagenicity and hepatoxicity. In summary, we can define the title compound as mutagenic, carcinogenic, and hepatotoxic. These toxic effects are generally reported as structural warnings for compounds with the nitro substituent [89–92]. Despite these known facts for the toxicophoric nitro groups, many drugs containing the nitro group, such as flutamide and niclosamide, have been approved by the FDA, and the nitro group plays a direct role in the efficacy of a drug molecule [92]; therefore, we cannot exclude the compounds containing the nitro group, and can still consider them as drug candidates.

Table 5.

Toxicity results of the title compound calculated by ProTox-II.

Toxicity model report
Classification Target Shorthand Prediction Probability
Organ toxicity Hepatotoxicity dili Inactive 0.68
Toxicity end points Carcinogenicity carcino Active 0.61
Toxicity end points Immunotoxicity immuno Inactive 0.82
Toxicity end points Mutagenicity mutagen Active 0.79
Toxicity end points Cytotoxicity cyto Inactive 0.60
Tox21-Nuclear receptor signaling pathways Aryl hydrocarbon receptor (AhR) nr_ahr Inactive 0.69
Tox21-Nuclear receptor signaling pathways Androgen receptor (AR) nr_ar Inactive 0.90
Tox21-Nuclear receptor signaling pathways Androgen receptor (AR)-ligand binding domain (AR-LBD) nr_ar_Ibd Inactive 0.97
Tox21-Nuclear receptor signaling pathways Aromatase nr_aromatase Inactive 0.72
Tox21-Nuclear receptor signaling pathways Estrogen receptor (ER) nr_er Inactive 0.87
Tox21-Nuclear receptor signaling pathways Estrogen receptor (ER)-ligand binding domain (AR-LBD) ner_er_Ibd Inactive 0.98
Tox21-Nuclear receptor signaling pathways Peroxisome proliferator activated receptor gamma (PPAR-Gamma) nr_ppar_gamma Inactive 0.98
Tox21-Stress response pathways Nuclear factor (erythroid-derived 2)-like2/antioxidant responsive element (nrf2/ARE) ar_are Inactive 0.86
Tox21-Stress response pathways Heat shock factor response element (HSE) sr_hse Inactive 0.86
Tox21-Stress response pathways Mitochondrial membrane potential (MMP) sr_mmp Inactive 0.52
Tox21-Stress response pathways Phosphoprotein (tumor suppressor) p53 sr_p53 Inactive 0.89
Tox21-Stress response pathways ATPase family AAA domain-containing protein 5 (ATAD5) sr_atad5 Inactive 0.88
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Table 6.

Some toxicity parameters and results calculated by pkCSM of the title compound

pkCSM toxicity report.
AMES toxicity Yes Categorical (Yes/No)
Max. tolerated dose (human) 0.076 Numeric (log mg/kg/day)
Herg I inhibitor No Categorical (Yes/No)
Herg II inhibitor No Categorical (Yes/No)
Oral Rat Acute Toxicity (LD50) 2.549 Numeric (mol/kg)
Oral Rat Chronic Toxicity (LOAEL) 1.383 Numeric (log mg/kg_bw/day)
Hepatotoxicity Yes Categorical (Yes/No)
Skin sensitization No Categorical (Yes/No)
T. Pyriformis toxicity 1.417 Numeric (log ug/L)
Minnow toxicity −1.982 Numeric (log mM)
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3.9. Gastrointestinal absorption and brain penetration

We examined the title compound to determine human intestinal absorption (HIA) and blood-brain barrier (BBB) penetration, two crucial pharmacokinetic properties in drug discovery. These properties were investigated using the Brain Or IntestinaL EstimateD permeation method (BOILED-Egg) developed by Daina and Zoete [93]. This model uses two physicochemical parameters, WLOGP and TPSA. It simultaneously predicts the intestinal absorption and brain access of the molecules. For our compound, the estimated model is shown in Figure 12, in which the yellow area (yolk) shows that the compounds can passively penetrate through the blood-brain barrier. The white region signifies a physicochemical space where the gastrointestinal system can absorb the molecules. In this graph, the white and yellow areas are not mutually exclusive. The small red cycle in the yolk shows that our compound can passively cross the blood-brain barrier and be absorbed by the human gastrointestinal tract. As a result, the molecule is active in the BBB, and the gastrointestinal tract can absorb it.

Figure 12.

Figure 12

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BOILED-Egg Model of query compound: the red cycle in the yolk signs out both good gastrointestinal absorption and blood-brain barrier permeability.

4. Conclusion

A Schiff base compound was synthesized via a condensation reaction between an aromatic aldehyde and amine molecule. The single crystal was analyzed using the X-ray diffraction method. The mentioned compound has space group P21/n and crystallized in monoclinic system. The monomeric units are four in the unit cell (Z = 4).

  1. The molecular electrostatic potential map and Mulliken charges have revealed the most positive and the most negative regions of the molecule. The oxygen (O3) of the anisole ring and the nitrogen (N3) in the imine group are the most negatively charged atoms. The oxygen atoms (O1 and O2) of the nitro substituent are open positions for the electrophilic attack.

  2. Molecular orbital analysis provided information on the intramolecular charge transfer, molecular softness, stability, reactivity, and toxicity. The energies of the energy gap, HOMO, and LUMO orbitals were calculated to be −5.629, −2.053, and 3.576 eV, respectively. As a result, charge transfer between the HOMO and LUMO orbitals occurs easily; the title compound has high chemical reactivity, biological activity, polarizability, probably high toxicity, and low kinetic and chemical stability.

  3. Molecular stability is mainly established by H···H interaction, followed by O···H, C···H, C···C and N···H interactions and others.

  4. Docking experiments were performed to determine the inhibitory effect of the candidate molecule. The title compound and reference inhibitor were docked to the COVID-19 main protease (Mpro). Our docking calculations showed that the binding energy of the complex of query compound/SARS-CoV-2 (−8.10 kcal/mol) is higher than that of the complex of N3/SARS-CoV-2 (− 7.11 kcal/mol). Therefore, the title compound is a potent candidate for inhibition of the main protease.

  5. The title compound settled in the suit drug domain region according to the SwissADME algorithm and obeyed the known drug-likeness rules (Lipinski, Veber, Ghose, Egan, Muegge). pkCSM and ProTox-II tools uncovered mutagenic, carcinogenic, and hepatotoxic predictions on the title compound. Metabolism of the molecule in liver is likely to be low, as it was found to be an inhibitor of 5CYPs. There is no concern regarding human intestinal absorption and brain permeability.

Supplementary information

Table S1.

Single-crystal X-ray data of the title compound and the refinement parameters.

Crystal data
CCDC deposition number 2082426
Chemical formula C19H21N3O3
Formula weight 339.39
Temperature (K) 296
Wavelength (Å) 0.71073
Crystal system Monoclinic
Space group P21/n
Unit cell parameters
a≠b≠c (Å) 10.1685(16), 13.3628(15), 13.416(2)
α=γ≠β (°) 90.00, 90.00, 107.854 (12)
Crystal size (mm) 0.71 × 0.48 × 0.24
Z 4
Volume, V (Å3) 1735.2(4)
μ (mm−1) 0.09
F (000) 720
θ min-max (°) 12.6–35.1
Calculated density (Mgm−3) 1.299
Color and shape Yellow, prism
Data collection
Diffractometer STOE IPDS 2
θ min-max for data collection (°) 2.6–26.0
Index ranges; h, k, l −10→12, −13→16, −16→16
Measurement method Scans
Reflections collected 9358
Independent reflections 3398
Reflections with I> 2σ(I) 2080
Absorption correction Integration ((X-RED32; Stoe and Cie, 2002)
Tmin-max 0.948–0.979
Rint 0.049
Refinement
Refinement method Full matrix least squares on F2
Parameters 227
R [F2 > 2σ(F2)] 0.041
wR(F2) 0.094
GooF=S 0.91
Δρmin-max (e Å−3) −0.13, 0.14
w = 1/[σ2(Fo2) + (0.0638P)2 + 0.3411P], where P = (Fo2 + 2Fc2)/3, (Δ/σ)max < 0.001,
Extinction correction: SHELXL-2014/7 (Sheldrick 2014).
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Table S2.

The calculated and measured bond length values of the title compound.

Bond length B3LYP Exp.
O3—C18 1.3713 1.382 (2)
O3—C19 1.4213 1.429 (2)
N2—C5 1.4083 1.406 (2)
N2—C8 1.4673 1.473 (2)
N2—C12 1.4783 1.479 (2)
N3—C7 1.2824 1.277 (2)
N3—C13 1.4006 1.418 (2)
O1—N1 1.2316 1.235 (2)
N1—O2 1.2337 1.230 (2)
N1—C2 1.4647 1.465 (2)
C7—C6 1.4747 1.480 (2)
C7—H7 1.0908 0.9300
C6—C1 1.3989 1.396 (2)
C6—C5 1.425 1.427 (2)
C5—C4 1.4108 1.412 (2)
C13—C14 1.4032 1.404 (2)
C13—C18 1.4214 1.414 (2)
C14—C15 1.3919 1.380 (3)
C14—H14 1.0851 0.9300
C2—C3 1.3954 1.384 (3)
C2—C1 1.3876 1.385 (2)
C18—C17 1.3983 1.390 (3)
C12—C11 1.5304 1.517 (3)
C12—H12A 1.1055 0.9700
C12—H12B 1.0908 0.9700
C1—H1 1.0823 0.9300
C4—C3 1.3868 1.378 (3)
C4—H4 1.0828 0.9300
C3—H3A 1.0827 0.9300
C17—C16 1.3965 1.389 (3)
C17—H17 1.0832 0.9300
C8—C9 1.532 1.517 (3)
C8—H8A 1.0834 0.9700
C8—H8B 1.1062 0.9700
C11—C10 1.5337 1.529 (3)
C11—H11A 1.0966 0.9700
C11—H11B 1.0968 0.9700
C15—C16 1.3928 1.379 (3)
C15—H15 1.0852 0.9300
C16—H16 1.0858 0.9300
C9—C10 1.5329 1.521 (3)
C9—H9A 1.0968 0.9700
C9—H9B 1.096 0.9700
C10—H10A 1.0956 0.9700
C10—H10B 1.0991 0.9700
C19—H19A 1.0972 0.9600
C19—H19B 1.0966 0.9600
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Table S3.

The calculated and measured bond angle values of the title compound.

Bond angle B3LYP Exp.
C18—O3—C19 117.9116 117.61 (15)
C5—N2—C8 117.3559 117.57 (14)
C5—N2—C12 116.3752 117.31 (13)
C8—N2—C12 112.0595 111.20 (13)
C7—N3—C13 123.512 123.96 (15)
O2—N1—O1 124.406 122.87 (18)
O2—N1—C2 117.6418 118.15 (19)
O1—N1—C2 117.9521 118.96 (16)
N3—C7—C6 120.3003 119.71 (15)
N3—C7—H7 123.2613 120.1
C6—C7—H7 116.3552 120.1
C1—C6—C5 119.3966 119.37 (16)
C1—C6—C7 118.9256 117.49 (15)
C5—C6—C7 121.5157 122.78 (15)
N2—C5—C4 121.3611 120.96 (16)
N2—C5—C6 120.0819 120.74 (15)
C4—C5—C6 118.5476 118.25 (17)
C14—C13—C18 118.0087 117.35 (16)
C14—C13—N3 115.9861 115.56 (15)
C18—C13—N3 125.8697 127.02 (15)
C15—C14—C13 122.0243 122.75 (17)
C15—C14—H14 121.0932 118.6
C13—C14—H14 116.8814 118.6
C3—C2—C1 121.3513 121.30 (17)
C3—C2—N1 119.1791 119.95 (17)
C1—C2—N1 119.4628 118.71 (17)
O3—C18—C17 123.0735 123.13 (16)
O3—C18—C13 117.1253 116.91 (15)
C17—C18—C13 119.7842 119.93 (17)
N2—C12—C11 111.0694 110.75 (14)
N2—C12—H12A 109.4321 109.5
C11—C12—H12A 109.5931 109.5
N2—C12—H12B 109.1818 109.5
C11—C12—H12B 110.2807 109.5
H12A—C12—H12B 107.1988 108.1
C2—C1—C6 120.2402 120.23 (17)
C2—C1—H1 120.6299 119.9
C6—C1—H1 119.0941 119.9
C3—C4—C5 121.5246 121.42 (18)
C3—C4—H4 118.6577 119.3
C5—C4—H4 119.7861 119.3
C4—C3—C2 118.8524 119.43 (17)
C4—C3—H3A 121.5638 120.3
C2—C3—H3A 119.5709 120.3
C16—C17—C18 120.6792 120.48 (18)
C16—C17—H17 119.2051 119.8
C18—C17—H17 120.113 119.8
N2—C8—C9 110.5135 110.87 (16)
N2—C8—H8A 108.377 109.5
C9—C8—H8A 109.9995 109.5
N2—C8—H8B 111.3825 109.5
C9—C8—H8B 109.0347 109.5
H8A—C8—H8B 107.4803 108.1
C12—C11—C10 111.2726 110.75 (17)
C12—C11—H11A 108.8787 109.5
C10—C11—H11A 110.5794 109.5
C12—C11—H11B 108.756 109.5
C10—C11—H11B 109.8197 109.5
H11A—C11—H11B 107.4352 108.1
C16—C15—C14 119.259 118.63 (18)
C16—C15—H15 120.6244 120.7
C14—C15—H15 120.1082 120.7
C15—C16—C17 120.185 120.83 (18)
C15—C16—H16 120.5368 119.6
C17—C16—H16 119.2749 119.6
C8—C9—C10 111.096 111.76 (15)
C8—C9—H9A 108.7378 109.3
C10—C9—H9A 109.829 109.3
C8—C9—H9B 108.9651 109.3
C10—C9—H9B 110.8098 109.3
H9A—C9—H9B 107.3022 107.9
C9—C10—C11 110.1514 109.04 (16)
C9—C10—H10A 110.6369 109.9
C11—C10—H10A 110.646 109.9
C9—C10—H10B 109.3121 109.9
C11—C10—H10B 109.3268 109.9
H10A—C10—H10B 106.691 108.3
O3—C19—H19A 111.7356 109.5
O3—C19—H19B 111.4225 109.5
H19A—C19—H19B 109.1408 109.5
O3—C19—H19C 106.0313 109.5
H19A—C19—H19C 108.9719 109.5
H19B—C19—H19C 109.457 109.5
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Table S4.

The calculated and measured dihedral angle values of the title compound.

Dihedral angle B3LYP Exp.
C13—N3—C7—C6 −177.4069 −173.59 (14)
N3—C7—C6—C1 11.9856 23.1 (2)
N3—C7—C6—C5 −172.6713 −163.85 (14)
C8—N2—C5—C4 −21.2475 14.0 (2)
C12—N2—C5—C4 −115.5165 −122.78 (17)
C8—N2—C5—C6 −157.6223 −163.30 (14)
C12—N2—C5—C6 65.6137 59.93 (19)
C1—C6—C5—N2 −177.6607 178.00 (13)
C7—C6—C5—N2 7.0177 5.1 (2)
C1—C6—C5—C4 3.4379 0.6 (2)
C7—C6—C5—C4 −171.8837 −172.28 (14)
C7—N3—C13—C14 −146.5829 150.97 (16)
C7—N3—C13—C18 −37.755 −32.2 (2)
C18—C13—C14—C15 2.8046 1.4 (2)
N3—C13—C14—C15 178.8237 178.52 (15)
O2—N1—C2—C3 −0.6199 −7.2 (2)
O1—N1—C2—C3 179.2988 171.88 (17)
O2—N1—C2—C1 178.4461 170.37 (16)
O1—N1—C2—C1 −1.6352 −10.5 (2)
C19—O3—C18—C17 10.6209 −3.2 (3)
C19—O3—C18—C13 −167.8739 178.78 (16)
C14—C13—C18—O3 177.2472 177.67 (14)
N3—C13—C18—O3 1.6641 0.9 (2)
C14—C13—C18—C17 −1.2993 −0.5 (2)
N3—C13—C18—C17 −176.8826 −177.24 (16)
C5—N2—C12—C11 −162.6825 −161.74 (15)
C8—N2—C12—C11 −58.3476 58.9 (2)
C3—C2—C1—C6 −0.4093 0.1 (2)
N1—C2—C1—C6 −179.4544 −177.44 (14)
C5—C6—C1—C2 −2.1637 −0.6 (2)
C7—C6—C1—C2 173.2798 172.71 (14)
N2—C5—C4—C3 178.8666 −177.59 (15)
C6—C5—C4—C3 −2.2467 −0.2 (2)
C5—C4—C3—C2 −0.2714 −0.2 (2)
C1—C2—C3—C4 1.6429 0.3 (2)
N1—C2—C3—C4 −179.3094 177.82 (14)
O3—C18—C17—C16 −179.1932 −179.03 (17)
C13—C18—C17—C16 −0.7367 −1.0 (3)
C5—N2—C8—C9 162.3447 163.00 (14)
C12—N2—C8—C9 −59.1211 −57.74 (19)
N2—C12—C11—C10 −54.8559 −57.9 (2)
C13—C14—C15—C16 −2.2182 −0.7 (3)
C14—C15—C16—C17 0.0843 −0.8 (3)
C18—C17—C16—C15 1.3698 1.7 (3)
N2—C8—C9—C10 56.8131 56.3 (2)
C8—C9—C10—C11 −53.6878 −54.6 (2)
C12—C11—C10—C9 52.7361 55.2 (2)
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Figure S1.

FTIR spectrum of the title compound.

turkjchem-46-5-1548s1.tif (153.4KB, tif)
Figure S2.

UV-Vis spectrum of the title compound.

turkjchem-46-5-1548s2.tif (124.2KB, tif)
Figure S3.

Grid box including the active residues in Mpro of SARS-CoV-2.

turkjchem-46-5-1548s3.tif (930.5KB, tif)
Figure S4.

The comparative docking results of reference inhibitor N3 and query compound.

Acknowledgment

This study was supported by Scientific Researching Projects Fund of Ondokuz Mayıs University, Samsun, Turkey (Project no: PYO.FEN.1906.19.001).

Appendix A. Supplementary data

CCDC 2082426 contains the supplementary crystallographic data for the title compound. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.

Funding Statement

This study was supported by Scientific Researching Projects Fund of Ondokuz Mayıs University, Samsun, Turkey (Project no: PYO.FEN.1906.19.001).

Footnotes

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1.

Single-crystal X-ray data of the title compound and the refinement parameters.

Crystal data
CCDC deposition number 2082426
Chemical formula C19H21N3O3
Formula weight 339.39
Temperature (K) 296
Wavelength (Å) 0.71073
Crystal system Monoclinic
Space group P21/n
Unit cell parameters
a≠b≠c (Å) 10.1685(16), 13.3628(15), 13.416(2)
α=γ≠β (°) 90.00, 90.00, 107.854 (12)
Crystal size (mm) 0.71 × 0.48 × 0.24
Z 4
Volume, V (Å3) 1735.2(4)
μ (mm−1) 0.09
F (000) 720
θ min-max (°) 12.6–35.1
Calculated density (Mgm−3) 1.299
Color and shape Yellow, prism
Data collection
Diffractometer STOE IPDS 2
θ min-max for data collection (°) 2.6–26.0
Index ranges; h, k, l −10→12, −13→16, −16→16
Measurement method Scans
Reflections collected 9358
Independent reflections 3398
Reflections with I> 2σ(I) 2080
Absorption correction Integration ((X-RED32; Stoe and Cie, 2002)
Tmin-max 0.948–0.979
Rint 0.049
Refinement
Refinement method Full matrix least squares on F2
Parameters 227
R [F2 > 2σ(F2)] 0.041
wR(F2) 0.094
GooF=S 0.91
Δρmin-max (e Å−3) −0.13, 0.14
w = 1/[σ2(Fo2) + (0.0638P)2 + 0.3411P], where P = (Fo2 + 2Fc2)/3, (Δ/σ)max < 0.001,
Extinction correction: SHELXL-2014/7 (Sheldrick 2014).
Open in a new tab

Table S2.

The calculated and measured bond length values of the title compound.

Bond length B3LYP Exp.
O3—C18 1.3713 1.382 (2)
O3—C19 1.4213 1.429 (2)
N2—C5 1.4083 1.406 (2)
N2—C8 1.4673 1.473 (2)
N2—C12 1.4783 1.479 (2)
N3—C7 1.2824 1.277 (2)
N3—C13 1.4006 1.418 (2)
O1—N1 1.2316 1.235 (2)
N1—O2 1.2337 1.230 (2)
N1—C2 1.4647 1.465 (2)
C7—C6 1.4747 1.480 (2)
C7—H7 1.0908 0.9300
C6—C1 1.3989 1.396 (2)
C6—C5 1.425 1.427 (2)
C5—C4 1.4108 1.412 (2)
C13—C14 1.4032 1.404 (2)
C13—C18 1.4214 1.414 (2)
C14—C15 1.3919 1.380 (3)
C14—H14 1.0851 0.9300
C2—C3 1.3954 1.384 (3)
C2—C1 1.3876 1.385 (2)
C18—C17 1.3983 1.390 (3)
C12—C11 1.5304 1.517 (3)
C12—H12A 1.1055 0.9700
C12—H12B 1.0908 0.9700
C1—H1 1.0823 0.9300
C4—C3 1.3868 1.378 (3)
C4—H4 1.0828 0.9300
C3—H3A 1.0827 0.9300
C17—C16 1.3965 1.389 (3)
C17—H17 1.0832 0.9300
C8—C9 1.532 1.517 (3)
C8—H8A 1.0834 0.9700
C8—H8B 1.1062 0.9700
C11—C10 1.5337 1.529 (3)
C11—H11A 1.0966 0.9700
C11—H11B 1.0968 0.9700
C15—C16 1.3928 1.379 (3)
C15—H15 1.0852 0.9300
C16—H16 1.0858 0.9300
C9—C10 1.5329 1.521 (3)
C9—H9A 1.0968 0.9700
C9—H9B 1.096 0.9700
C10—H10A 1.0956 0.9700
C10—H10B 1.0991 0.9700
C19—H19A 1.0972 0.9600
C19—H19B 1.0966 0.9600
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Table S3.

The calculated and measured bond angle values of the title compound.

Bond angle B3LYP Exp.
C18—O3—C19 117.9116 117.61 (15)
C5—N2—C8 117.3559 117.57 (14)
C5—N2—C12 116.3752 117.31 (13)
C8—N2—C12 112.0595 111.20 (13)
C7—N3—C13 123.512 123.96 (15)
O2—N1—O1 124.406 122.87 (18)
O2—N1—C2 117.6418 118.15 (19)
O1—N1—C2 117.9521 118.96 (16)
N3—C7—C6 120.3003 119.71 (15)
N3—C7—H7 123.2613 120.1
C6—C7—H7 116.3552 120.1
C1—C6—C5 119.3966 119.37 (16)
C1—C6—C7 118.9256 117.49 (15)
C5—C6—C7 121.5157 122.78 (15)
N2—C5—C4 121.3611 120.96 (16)
N2—C5—C6 120.0819 120.74 (15)
C4—C5—C6 118.5476 118.25 (17)
C14—C13—C18 118.0087 117.35 (16)
C14—C13—N3 115.9861 115.56 (15)
C18—C13—N3 125.8697 127.02 (15)
C15—C14—C13 122.0243 122.75 (17)
C15—C14—H14 121.0932 118.6
C13—C14—H14 116.8814 118.6
C3—C2—C1 121.3513 121.30 (17)
C3—C2—N1 119.1791 119.95 (17)
C1—C2—N1 119.4628 118.71 (17)
O3—C18—C17 123.0735 123.13 (16)
O3—C18—C13 117.1253 116.91 (15)
C17—C18—C13 119.7842 119.93 (17)
N2—C12—C11 111.0694 110.75 (14)
N2—C12—H12A 109.4321 109.5
C11—C12—H12A 109.5931 109.5
N2—C12—H12B 109.1818 109.5
C11—C12—H12B 110.2807 109.5
H12A—C12—H12B 107.1988 108.1
C2—C1—C6 120.2402 120.23 (17)
C2—C1—H1 120.6299 119.9
C6—C1—H1 119.0941 119.9
C3—C4—C5 121.5246 121.42 (18)
C3—C4—H4 118.6577 119.3
C5—C4—H4 119.7861 119.3
C4—C3—C2 118.8524 119.43 (17)
C4—C3—H3A 121.5638 120.3
C2—C3—H3A 119.5709 120.3
C16—C17—C18 120.6792 120.48 (18)
C16—C17—H17 119.2051 119.8
C18—C17—H17 120.113 119.8
N2—C8—C9 110.5135 110.87 (16)
N2—C8—H8A 108.377 109.5
C9—C8—H8A 109.9995 109.5
N2—C8—H8B 111.3825 109.5
C9—C8—H8B 109.0347 109.5
H8A—C8—H8B 107.4803 108.1
C12—C11—C10 111.2726 110.75 (17)
C12—C11—H11A 108.8787 109.5
C10—C11—H11A 110.5794 109.5
C12—C11—H11B 108.756 109.5
C10—C11—H11B 109.8197 109.5
H11A—C11—H11B 107.4352 108.1
C16—C15—C14 119.259 118.63 (18)
C16—C15—H15 120.6244 120.7
C14—C15—H15 120.1082 120.7
C15—C16—C17 120.185 120.83 (18)
C15—C16—H16 120.5368 119.6
C17—C16—H16 119.2749 119.6
C8—C9—C10 111.096 111.76 (15)
C8—C9—H9A 108.7378 109.3
C10—C9—H9A 109.829 109.3
C8—C9—H9B 108.9651 109.3
C10—C9—H9B 110.8098 109.3
H9A—C9—H9B 107.3022 107.9
C9—C10—C11 110.1514 109.04 (16)
C9—C10—H10A 110.6369 109.9
C11—C10—H10A 110.646 109.9
C9—C10—H10B 109.3121 109.9
C11—C10—H10B 109.3268 109.9
H10A—C10—H10B 106.691 108.3
O3—C19—H19A 111.7356 109.5
O3—C19—H19B 111.4225 109.5
H19A—C19—H19B 109.1408 109.5
O3—C19—H19C 106.0313 109.5
H19A—C19—H19C 108.9719 109.5
H19B—C19—H19C 109.457 109.5
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Table S4.

The calculated and measured dihedral angle values of the title compound.

Dihedral angle B3LYP Exp.
C13—N3—C7—C6 −177.4069 −173.59 (14)
N3—C7—C6—C1 11.9856 23.1 (2)
N3—C7—C6—C5 −172.6713 −163.85 (14)
C8—N2—C5—C4 −21.2475 14.0 (2)
C12—N2—C5—C4 −115.5165 −122.78 (17)
C8—N2—C5—C6 −157.6223 −163.30 (14)
C12—N2—C5—C6 65.6137 59.93 (19)
C1—C6—C5—N2 −177.6607 178.00 (13)
C7—C6—C5—N2 7.0177 5.1 (2)
C1—C6—C5—C4 3.4379 0.6 (2)
C7—C6—C5—C4 −171.8837 −172.28 (14)
C7—N3—C13—C14 −146.5829 150.97 (16)
C7—N3—C13—C18 −37.755 −32.2 (2)
C18—C13—C14—C15 2.8046 1.4 (2)
N3—C13—C14—C15 178.8237 178.52 (15)
O2—N1—C2—C3 −0.6199 −7.2 (2)
O1—N1—C2—C3 179.2988 171.88 (17)
O2—N1—C2—C1 178.4461 170.37 (16)
O1—N1—C2—C1 −1.6352 −10.5 (2)
C19—O3—C18—C17 10.6209 −3.2 (3)
C19—O3—C18—C13 −167.8739 178.78 (16)
C14—C13—C18—O3 177.2472 177.67 (14)
N3—C13—C18—O3 1.6641 0.9 (2)
C14—C13—C18—C17 −1.2993 −0.5 (2)
N3—C13—C18—C17 −176.8826 −177.24 (16)
C5—N2—C12—C11 −162.6825 −161.74 (15)
C8—N2—C12—C11 −58.3476 58.9 (2)
C3—C2—C1—C6 −0.4093 0.1 (2)
N1—C2—C1—C6 −179.4544 −177.44 (14)
C5—C6—C1—C2 −2.1637 −0.6 (2)
C7—C6—C1—C2 173.2798 172.71 (14)
N2—C5—C4—C3 178.8666 −177.59 (15)
C6—C5—C4—C3 −2.2467 −0.2 (2)
C5—C4—C3—C2 −0.2714 −0.2 (2)
C1—C2—C3—C4 1.6429 0.3 (2)
N1—C2—C3—C4 −179.3094 177.82 (14)
O3—C18—C17—C16 −179.1932 −179.03 (17)
C13—C18—C17—C16 −0.7367 −1.0 (3)
C5—N2—C8—C9 162.3447 163.00 (14)
C12—N2—C8—C9 −59.1211 −57.74 (19)
N2—C12—C11—C10 −54.8559 −57.9 (2)
C13—C14—C15—C16 −2.2182 −0.7 (3)
C14—C15—C16—C17 0.0843 −0.8 (3)
C18—C17—C16—C15 1.3698 1.7 (3)
N2—C8—C9—C10 56.8131 56.3 (2)
C8—C9—C10—C11 −53.6878 −54.6 (2)
C12—C11—C10—C9 52.7361 55.2 (2)
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Figure S1.

FTIR spectrum of the title compound.

turkjchem-46-5-1548s1.tif (153.4KB, tif)
Figure S2.

UV-Vis spectrum of the title compound.

turkjchem-46-5-1548s2.tif (124.2KB, tif)
Figure S3.

Grid box including the active residues in Mpro of SARS-CoV-2.

turkjchem-46-5-1548s3.tif (930.5KB, tif)
Figure S4.

The comparative docking results of reference inhibitor N3 and query compound.

turkjchem-46-5-1548s4.tif (4.5MB, tif)

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