Crystal structure, in silico molecular docking, DFT analysis and ADMET studies of N-(2-methoxy-benzyl)-acetamide European Journal of Chemistry 13 (4) (2022) 440-450 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2022 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.13.4.440-450.2303 European Journal of Chemistry View Journal Online View Article Online Crystal structure, in silico molecular docking, DFT analysis and ADMET studies of N-(2-methoxy-benzyl)-acetamide Suganya Murugan 1, Prasanth Gunasekaran 2, Jayasudha Nehru 1, Anaglit Catherine Paul 1, Necmi Dege 3, Emine Berrin Cinar 3, Savaridasson Jose Kavitha 1, Kasthuri Balasubramani 4, Kaliyaperumal Thanigaimani 5, Venkatachalam Rajakannan 2 and Madhukar Hemamalini 1,* 1 Department of Chemistry, Faculty of Science, Mother Teresa Women’s University, Kodaikanal, 624101, India 2 Centre of Advanced Study in Crystallography and Biophysics, Faculty of Science, University of Madras, Chennai, 600025, India 3 Department of Physics, Faculty of Science, Ondokuz Mayis University, Samsun, 55200, Turkey 4 Department of Chemistry, Faculty of Science, Government Arts College (Autonomous), Thanthonrimalai, Karur, 639005, India 5 Department of Chemistry, Faculty of Science, Government Arts College, Trichy, 620022, India * Corresponding author at: Department of Chemistry, Faculty of Science, Mother Teresa Women’s University, Kodaikanal, 624101, India. e-mail: hemamalini2k3@yahoo.com (M. Hemamalini). 10.5155/eurjchem.13.4.440-450.2303 Received: 08 July 2022 Received in revised form: 01 September 2022 Accepted: 09 September 2022 Published online: 31 December 2022 Printed: 31 December 2022 In this work, N-(2-methoxy-benzyl)-acetamide (2MBA) was synthesized from an amide derivative and it was characterized by FT-IR and NMR spectroscopy techniques. The crystal structure of 2MBA was also validated via single-crystal X-ray diffraction analysis. Crystal data for C10H13NO2 for 2MBA: Monoclinic, space group P21/n (no. 14), a = 9.1264(6) Å, b = 9.3375(7) Å, c = 11.9385(8) Å, β = 95.745(5)°, V = 1012.26(12) Å3, Z = 4, μ(MoKα) = 0.082 mm-1, Dcalc = 1.176 g/cm3, 5632 reflections measured (5.368° ≤ 2Θ ≤ 51.992°), 1990 unique (Rint = 0.0377, Rsigma = 0.0314) which were used in all calculations. The final R1 was 0.0583 (I > 2σ(I)) and wR2 was 0.1444 (all data). The intermolecular interactions in 2MBA were theoretically examined by Hirshfeld surface analysis and 2D fingerprint plots. Moreover, the HOMO and LUMO energy gaps of 2MBA was calculated by DFT calculation with the B3LYP/6- 311G++(d,p) method. The electron-withdrawing and donating sites of the 2MBA were confirmed via molecular electrostatic potential surface analysis. The present study discusses the title compound not only highlighted the crystallographic data but also revealed good molecular interactions together with an anticancer drug target, which is a targeting PARP protein, which was an important drug target in the treatment of breast cancer. PARP protein Crystal structure Molecular docking Density functional theory Hirshfeld surface analysis Molecular electrostatic potential Cite this: Eur. J. Chem. 2022, 13(4), 440-450 Journal website: www.eurjchem.com 1. Introduction Medicinal chemistry plays an important role in the development of drugs for curing, maintaining, and improving the health of humans. The significance of the amidation reactions (C=O with N-H), including peptide bond-forming reactions, is one of the most fundamental transformations in organic chemistry and the pharmaceutical industry. The rising costs of waste disposal have prompted researchers to look for new methods for amide bond formation that avoid the forma- tion of unwanted materials while increasing atom economy [1- 3]. Recent literature studies revealed that acetamide and various amide derivatives showed many biological activities such as antifungal, antibacterial, antioxidant, anticancer, anti- inflammatory, anti-arthritic, anticancer, and anthelmintic acti- vities [4-7]. Numerous acetamide derivatives have been repor- ted to be active as antimicrobial agents [8]. To explore the effect of the 2MBA compound on breast cancer, we use the molecular docking methodology for the evaluation of molecular-level interactions with the important class of drug targets in breast cancer treatment [9]. The ADMET properties [10] and the effect of the amide compound against cancer were predicted using Swiss ADME and Way2Drug servers [11], and the molecular docking of the 2MBA compound with drug targets was carried out through Autodock Tools 4.2 [12]. 2MBA was docked with a total of four drug targets PARP1, PARP2, Tankyrase 1, and Tankyrase 2, belonging to the PARP protein family [13]. The results are compared with data on drugs, olaparib and talazoparib, which are available for treatment to inhibit molecular targets [14]. This work explains crystallization, structure refinement, Hirshfeld surface analysis, density functional theory calculations, and molecular docking as an important study on the 2MBA compound [15]. 2. Experimental 2.1. Instrumentation ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.13.4.440-450.2303 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.13.4.440-450.2303 mailto:hemamalini2k3@yahoo.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.13.4.440-450.2303&domain=pdf&date_stamp=2022-12-31 Murugan et al. / European Journal of Chemistry 13 (4) (2022) 440-450 441 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.440-450.2303 Table 1. Crystal data and structure refinement parameters for 2MBA. Empirical formula C10H13NO2 Formula weight 179.21 Temperature (K) 296(2) Crystal system Monoclinic Space group P21/n a, (Å) 9.1264(6) b, (Å) 9.3375(7) c, (Å) 11.9385(8) β (°) 95.745(5) Volume (Å3) 1012.26(12) Z 4 ρcalc (g/cm3) 1.176 μ (mm-1) 0.082 F(000) 384.0 Crystal size (mm3) 0.78 × 0.657 × 0.48 Radiation MoKα (λ = 0.71073) 2Θ range for data collection (°) 5.368 to 51.992 Index ranges -11 ≤ h ≤ 11, -11 ≤ k ≤ 11, -14 ≤ l ≤ 13 Reflections collected 5632 Independent reflections 1990 [Rint = 0.0377, Rsigma = 0.0314] Data/restraints/parameters 1990/0/120 Goodness-of-fit on F2 1.073 Final R indexes [I≥2σ (I)] R1 = 0.0583, wR2 = 0.1304 Final R indexes [all data] R1 = 0.0870, wR2 = 0.1444 Largest diff. peak/hole (e.Å-3) 0.16/-0.17 CCDC Number 2145614 O NH2 Ethanol Reflux O N H O HO O Scheme 1. Synthesis of N-(2-methoxy-benzyl)-acetamide (2MBA). The FT-IR spectrum was recorded in a FTIR Perking Elmer Spectrum400 spectrophotometer using the KBr pellet method. The solution state 1H NMR and 13C NMR spectrum were recorded on a Bruker Advance III HD Nanobay 400 MHz FT- NMR spectrometer. The sample was analyzed in deuterated DMSO and the chemical shifts were relative to tetramethyl- silane (TMS) as reference [16,17]. 2.2. Synthesis of N-(2-methoxy-benzyl)-acetamide (2MBA) All the chemicals and solvents used in this investigation were of analytical reagent grade. 2-Methoxy-benzylamine and acetic acid were purchased from Merck and were used without further purification. 2-Methoxy-benzylamine (1 mmol, 0.0343 g) and acetic acid (1 mmol, 0.0150 g) were dissolved in 25 mL of ethanol and the solution mixture was heated very slowly and refluxed for 6 h with constant stirring. The reaction mixture was then cooled to room temperature and the obtained precipitate was filtered [15]. The precipitate was recrystallized with ethanol. Finally, the acquired product N-(2-methoxy-benzyl)- acetamide is shown in Scheme 1. N-(2-Methoxy-benzyl)-acetamide (2MBA): Color: White/ needle shape. Yield: 76%. M.p.: 80-85 °C. FT-IR (KBr, ν, cm-1): 1603 (C=O), 3015 (C-H), 3289 (N-H). 1H NMR (400 MHz, DMSO- d6, δ, ppm): 1.02 (s, 3H, CH3), 3.79 (s, 3H, O-CH3), 4.20 (s, 2H, CH2), 6.90 (t, 1H, Ar-H), 6.96 (d, 1H, Ar-H), 7.10 (d, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 8.08 (s, 1H, NH). 13C NMR (100 MHz, DMSO- d6, δ, ppm): 176.70, 157.02, 128.34, 127.68, 127.49, 120.57, 110.87, 37.28, 34.43, 20.11. 2.3. Single crystal structure determination Single crystal X-ray diffraction analysis was carried out on STOE IPDS diffractometer using a MoKα radiation (λ = 0.71073 Å) at 296(2) K. The softwares used for crystal structure analysis: to data collection, APEX3 [18]; to cell refinement and data reduction, SAINT [19]; to solve the structure, SHELXS-97 [20,21], to refine the structure, SHELXL-97 [20,21], to molecu- lar graphics and publication material, OLEX2 [22] and ORTEP3 [23]. The crystal data and structure refinement parameter details are given in Table 1. All H atoms were positioned geometrically (N-H = 0.86 Å and C-H = 0.93-0.97 Å were refined using a riding model, with Uiso(H) = 1.2 or 1.5Ueq(C, O). 2.4. Hirshfeld surface analysis To analyze the intermolecular interactions in the crystal structure, Hirshfeld surfaces were mapped with dnorm, and their associated 2D fingerprint was plotted using Crystal Explorer 17.5 [24]. 2.5. Computational study Theoretical calculations were obtained by density func- tional theory (DFT) with the B3LYP/6-311G++(d,p) basis set using the Gaussian 09W program [25]. Additionally, the HOMO- LUMO energies and molecular electrostatic potential were calculated with the same level of theory. In silico ADME screening using the SwissADME website (http://www.swissad me.ch/index.php) to evaluate individual ADME behavior, such as physiochemical properties, lipophilicity, water solubility, pharmacokinetics, drug likeness and BOILED Egg properties of 2MBA [26-29]. The biological activity of the title compound was predicted using the free online webserver WAY2DRUG (http://www.way2drug.com/index.php) to predict the effect of the compound against different biological assays [11]. From the results of predicted biological activity, the breast cancer target proteins were selected for molecular docking and the title compound was docked with Poly (ADP-Ribose) polymerases (PARP), a group of potential drug targets in cancer therapy [30]. The crystal structures of important PARP class proteins such as PARP-1 (PDB: 7KK2), PARP-2 (PDB: 4TVJ), Tankyrase-1 (PDB: 7KKM), Tankyrase-2 (PDB: 3KR7) were downloaded from the RCSB database [13,14]. http://www.way2drug.com/index.php 442 Murugan et al. / European Journal of Chemistry 13 (4) (2022) 440-450 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.440-450.2303 Table 2. Bond lengths (Å) and bond angles (°) for 2MBA. Atom Atom Length Atom Atom Length X-ray DFT X-ray DFT O1 C5 1.366(2) 1.374 C6 C7 1.510(3) 1.514 O1 C10 1.419(3) 1.423 C5 C4 1.373(3) 1.394 O2 C8 1.231(2) 1.222 C8 C9 1.496(3) 1.519 N1 C8 1.324(3) 1.365 C1 C2 1.382(3) 1.396 N1 C7 1.441(3) 1.460 C4 C3 1.381(3) 1.397 C6 C5 1.387(3) 1.407 C2 C3 1.363(4) 1.388 C6 C1 1.376(3) 1.391 Atom Atom Atom Angle Atom Atom Atom Angle X-ray DFT X-ray DFT C5 O1 C10 117.51(19) 118.65 O2 C8 N1 122.4(2) 123.06 C8 N1 C7 122.99(17) 122.77 O2 C8 C9 121.7(2) 121.50 C5 C6 C7 118.98(17) 120.15 N1 C8 C9 115.94(19) 115.42 C1 C6 C5 118.02(18) 118.02 C6 C1 C2 121.2(2) 121.43 C1 C6 C7 122.99(18) 121.43 N1 C7 C6 114.75(17) 113.43 O1 C5 C6 115.08(18) 115.32 C5 C4 C3 119.3(2) 119.55 O1 C5 C4 123.62(19) 123.92 C3 C2 C1 119.6(2) 119.35 C4 C5 C6 121.29(19) 120.74 C2 C3 C4 120.5(2) 120.50 Table 3. Hydrogen bond interaction of the title compound. D-H···A d(D-H), Å d(H···A), Å d(D···A), Å ∠ D-H···A, ° Symmetry N1-H1A···O2 0.86 1.99 2.836(2) 169.1 3/2-x, -1/2+y, 1/2-z Figure 1. The asymmetric unit of N-(2-methoxy-benzyl)-acetamide. Figure 2. The package of N-(2-methoxy-benzyl)-acetamide. AUTODOCK TOOLS 4.2 software [12] was used for molecular docking and the grid box parameters was adjusted in the active site residues of protein targets and the results were analyzed [31] and compared with the co-crystal structures of the olaparib and talazoparib drugs [13,14] using PyMol [32], Ligplot [33] and Poseview [34,35]. 3. Results and discussion 3.1. Single crystal structure analysis The ORTEP view of 2MBA is shown in Figure 1 with a dihedral angle of 86.18(13)° between the benzene ring and the mean plane of the carboxamide group C-C(O)-N. The N1-C8, C8- O2, and C8-C9 bond lengths are 1.324(3), 1.231(2), and 1.496(3) Å, respectively (Table 2). The C8-O2 bond distance in the amide group shows a partial double-bond character and is similar in length to those found in the crystal structure of the 3- acetoxy-2-methyl-N-(4-nitrophenyl) benzamide, (1.215(2) Å [36]. The benzene ring, C1-C2-C3-C4-C5-C6, is planar with an RMS deviation of -0.004(2) Å at C1. The torsion angles of C7-N1- C8-O2 and C7-N1-C8-C9 -0.1(3) and -179.6(2)° compared with theoretical values of -4.15 and 176.4°, respectively. From the theoretical values, it was found that calculated values of bond length and bond angles slightly difference from the experimental values, by the DFT-B3LYP/6-311G++(d,p) basis set as shown in Table 2. In the crystal structure, neighboring molecules are linked by strong N1-H1A···O2 hydrogen bonds (3/2-x, -1/2+y, 1/2-z), forming supramolecular chains along the b-axis direction (Figure 2 and Table 3). 3.2. Hirshfeld surface analysis The Hirshfeld surface (HS) analysis provides qualitative and quantitative details about intermolecular close contacts in molecular crystals. Murugan et al. / European Journal of Chemistry 13 (4) (2022) 440-450 443 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.440-450.2303 Table 4. Energy values of 2MBA. Color N Symop R Electron density Eele Epol Edis Erep Etot 2 x+1/2, -y+1/2, z+1/2 7.49 B3LYP/6-31G(d,p) -4.2 -1.9 -11.0 7.7 -10.6 2 x, y, z 9.13 B3LYP/6-31G(d,p) -6.3 -2.1 -11.3 5.5 -14.7 2 -x+1/2, y+1/2, -z+1/2 6.64 B3LYP/6-31G(d,p) -1.0 -1.1 -17.8 5.8 -13.7 2 x+1/2, -y+1/2, z+1/2 8.19 B3LYP/6-31G(d,p) -4.3 -1.7 -12.7 5.6 -13.4 1 -x, -y, -z 6.50 B3LYP/6-31G(d,p) -0.7 -0.9 -18.7 7.1 -13.3 1 -x, -y, -z 6.37 B3LYP/6-31G(d,p) -0.3 -1.1 -19.3 9.1 -12.3 2 -x+1/2, y+1/2, -z+1/2 6.42 B3LYP/6-31G(d,p) -43.3 -11.4 -24.2 49.7 -44.6 1 -x, -y, -z 11.56 B3LYP/6-31G(d,p) -1.1 -0.1 -1.8 0.2 -2.6 (a) (b) (c) (d) (e) (f) Figure 3. (a) Hirshfeld surface plots over de, (b) di, (c) dnorm, (c) Shape index, (e) Curvedness and (f) Fragment patch. The distances can be defined as de (distance from the nearest nucleus inside to the surface) and di (distance from the nearest nucleus outside to the surface) as shown in Figures 3a and 3b. The dnorm surface shown in Figure 3c (range of -0.5942 to 1.5253 a.u.) represents a red spot of intensity and shows the presence of dominant interactions. Figure 3d shows the shape index map produced within the range -1 to 1 Å. The convex blue portions indicate hydrogen donor groups, while the concave red parts represent hydrogen acceptor groups. The nonexis- tence of contiguous red and blue triangles on the shape-index plot indicates the absence of π-π interactions. The curvedness map, generated in the range -4.0 to 4.0 Å, as shown in Figure 3e, depicts enormous areas of green with no flat (i.e., planar) surface area, while the blue patches show areas of curvature. The fragment patch plot ranging from 0 to 13.0000 a.u. provides the neighbor coordination environment based on the color of the patch shown in Figure 3f. The overall two-dimensional fingerprint (FPs) with the largest contacts of H···H interaction contributes 61.6% to the surface, followed by C···H/H···C contacts at 18.9% which are important contributors to structural stability via hydrogen bonding, O···H/H···O contacts at 18.1%, and the shortest contacts of N···H/H···N interaction at 1.4% shown in Figure 4. The total interaction energy is obtained by the combination of the electrostatic energy Eele, the exchange repulsion energy Erep, the polarization energy Epol, and the dispersion energy Edis were performed by the CE-B3LYP/6-31G(d,p) method. In Table 4, the highest interaction energy Etot = -44.6 kJ/mol (shown by purple color) from the centroid of the selected 2MBA associated with symmetry operation (-x+1/2, y+1/2, -z+1/2) and the molecular distance R = 6.42 Å. Whereas the lowest interaction energy Etot = -2.6 kJ/mol (shown by pink color) with the symmetry code (-x, -y, -z) and the molecular distance R = 11.56 Å (Figure 5) [37]. The Etot for the inter- molecular interaction N1-H1A···O2 is 169.1° (Table 3). 3.3. DFT studies The quantum chemical calculations of 2MBA have been performed by DFT/B3LYP/6-311G++(d,p) basis set, using the Gaussian 09W program [25]. The optimized molecular structure is shown in Figure 6 and the related geometrical para- meters are given in Table 2. 3.3.1. Frontier molecular orbitals Frontier molecular orbitals (FMOs), the highest occupied molecular orbital (HOMO), and the lowest unoccupied molecular orbital (LUMO) are the most significant parameters for quantum chemistry, electrical properties, and molecule interactions with other species. 444 Murugan et al. / European Journal of Chemistry 13 (4) (2022) 440-450 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.440-450.2303 (a) (b) (c) (d) (e) Figure 4. Two-dimensional fingerprint plot for the title compound showing the contributions of individual types of interactions: (a) all intermolecular contacts, (b) C···H contacts, (c) O···H/H···O contacts, (d) H···H contacts, and (e) N···H/H···N contacts. Figure 5. Energy frameworks of 2MBA. The chemical reactivity descriptors [38] such as EHOMO ionization potential (A), ELUMO electron affinity, chemical hardness (η), chemical potential (μ), softness (S), electro- negativity (χ), nucleophilicity index (ε) and electrophilicity index (ω) of the 2MBA molecule shown in Table 5. The energy gap for 2MBA is 5.7795 eV. Therefore, the molecule is highly polarizable and highly reactive (Figure 7). 3.3.2. Molecular electrostatic potential The molecular electrostatic potential (MEP) map is an important tool for explaining the electrostatic interactions. In order to find the most active regions of the molecule, the molecular electrostatic potential map surfaces were taken into consideration. The negative area, which is considered a nucleophilic site, is usually colored red (the strongest repulsion), whereas the negative region, which is the preferred electrophilic site, is colored blue (the strongest attraction). The green-colored patch on the map shows a neutral potential. From the MEP map as shown in Figure 8, it is evident that most of the reactive and negative region is around the methoxy group. The electrons present in this area could be readily provided to the acceptor species [39]. Murugan et al. / European Journal of Chemistry 13 (4) (2022) 440-450 445 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.440-450.2303 Table 5. Calculated frontier molecular orbital analysis and chemical reactivity descriptors of the 2MBA. Parameters Equations Values EHOMO HOMO -6.4014 ELUMO LUMO -0.6219 I Minus of HOMO 6.4014 eV A Minus of LUMO 0.62190 eV Egap ∆E = (I-A) 5.7795 eV Chemical hardness η = (I-A)/2] 2.88975 eV Chemical potential µ = -(I+A)/2) 3.51165 eV Electronegativity χ = (-μ) -3.51165eV Softness S = (1/η) 0.34605 1/eV Electrophilicity index ω = (μ2/2η) 2.1337 eV Nucleophilicity index ε = 1/ω 0.4687 eV Dipole moment µ 5.2885 Figure 6. DFT optimized structure of 2MBA. ELUMO = -0.6219 eV ↕ Egap = 5.7795 eV EHOMO = -6.4014 eV Figure 7. The graphical presentation of the HOMO-LUMO of 2MBA. Figure 8. The MEP surfaces of 2MBA by using DFT/B3LYP/6311G++(d,p). 446 Murugan et al. / European Journal of Chemistry 13 (4) (2022) 440-450 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.440-450.2303 (a) (b) Figure 9. Molecular interaction analysis of ligand with Tankyrase-1. (a) Three-dimensional representation of molecular interaction of title compound with tankyrase-1 (PDB: 7KKM) (Tankyrase-1: cartoon pale blue, hydrogen, and hydrophobic interacting residues: orange lines, ligand: cyan stick) and (b) Two- dimensional representation of molecular interaction of title compound with Tankyrase-1 (PDB: 7KKM) active site residues. (Dotted line-hydrogen bonds, arc structures-residues involved in hydrophobic interaction). (a) (b) Figure 10. Molecular interaction analysis of ligand with Tankyrase-2. (a) Three-dimensional representation of molecular interaction of title compound with Tankyrase-2 (PDB: 3KR7) and (b) Two-dimensional representation of molecular interaction of title compound with Tankyrase-2 (PDB: 3KR7) active site residues. (Dotted line-hydrogen bonds, arc structures-residues involved in hydrophobic interaction). 3.4. Molecular docking The in-silico analysis of the cell line activity of the title compound using the Way2Drug server shows maximum activity toward the MDA-MB-453 cell line belonging to breast adenocarcinoma (Table 6). The 2MBA molecule was analyzed for PARP protein inhibition activity through molecular docking; the function of the PARP protein was to play an important role in the single-strand DNA repair mechanism, where it binds with NAD+ to produce ADP-ribose-monomers. PARP (Poly ADP ribose polymerase) inhibitors were an important class of medications used in the treatment of advanced or metastatic breast cancer with individuals having HER2-negative BRCA gene mutations [40-42]. The docking results of 2MBA with the PARP protein exhibit better interactions with the catalytic site residues of Tankyrase-1 and Tankyrase-2. The 2MBA/ Tankyrase-2 complex has a binding energy of -6.27 kcal/mol, which was the least binding energy compared to the Tankyrase- 1, PARP-1, and PARP-2 complexes. 2MBA have hydrogen bon- ding with one of the catalytic residues TYR1060 and hydro- phobic interaction with the other two catalytic residues (HIS 1031, Glu 1138), and one π-π interaction with the ring of TYR 1071 of Tankyrase-2 protein. Like Tankyrase-2, the 2MBA has two hydrogen bonds with catalytic residue TYR1213, and the other hydrogen bond interaction is with residue GLY 1185 (Figure 9-11). There is no interaction observed with the catalytic residues of PARP-1 protein and the 2MBA interacts only through hydrophobic interaction with two catalytic residues of PARP-2 protein (Tables 7 and 8). 3.5. Swiss ADME studies The values of physicochemical properties of 2MBA mole- cule show have a polar surface area of 38.33 Ų with 50.52 refractive indexes and fraction Csp3 (Table 9). The lipophilicity analysis of the 2MBA molecule shows a consensus Log Po/w value of 1.48 which shows that it passes one of the important ADMET properties. The three different solubility index calculations show a moderate solubility character in water. The pharmacokinetic properties of the title compound show high gastrointestinal absorption with no observed P-glycoprotein binding affinity and the blood-brain barrier crossing property with all cytochrome P isoform inhibition properties. The amide 2MBA shows no violation against Lipinski’s rule, GOSE rule, VEBER rule, EGAN, and MUEGGE rule, which indicated its good drug likeliness properties with a bioavailability score of 0.55 [29]. Murugan et al. / European Journal of Chemistry 13 (4) (2022) 440-450 447 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.440-450.2303 Table 6. 2MBA activity against the cell lines predicted by the Way2Drug server. Pa* Pi* Cell line Cell line full name Tissue Tumor type 0.443 0.034 MDA-MB-453 Breast adenocarcinoma Breast Adenocarcinoma 0.372 0.087 NALM-6 Adult B acute lymphoblastic leukemia Hematopoietic and lymphoid tissue Leukemia 0.341 0.079 U-266 Plasma cell myeloma Blood Myeloma 0.378 0.135 Hs 683 Oligodendroglioma Brain Glioma 0.332 0.104 CFPAC-1 Pancreatic carcinoma Pancreas Carcinoma 0.258 0.085 LS174T Colon adeno carcinoma Colon Adenocarcinoma 0.260 0.092 MKN-7 Gastric carcinoma Stomach Carcinoma 0.179 0.021 U2OS Osteosarcoma Bone Sarcoma 0.245 0.087 CCRF-CEM Childhood T acute lymphoblastic leukemia Blood Leukemia 0.263 0.136 HOS Osteosarcoma Bone Sarcoma 0.248 0.123 HOP-18 Non-small cell lung carcinoma Lung Carcinoma 0.158 0.035 SK-BR-3 Breast adenocarcinoma Breast Adenocarcinoma 0.249 0.128 NCI-H1299 Non-small cell lung carcinoma Lung Carcinoma 0.198 0.077 Ovarian carcinoma cells Ovarian adenocarcinoma Ovarium Adenocarcinoma 0.109 0.017 MOLT-3 T-lymphoblastic leukemia Blood Leukemia 0.133 0.044 D54 Glioblastoma Brain Glioblastoma 0.091 0.020 JAM Ovarian cystadenocarcinoma Ovarium Adenocarcinoma 0.157 0.090 Jurkat Acute leukemic T-cells Blood Leukemia 0.095 0.028 KETR3 Renal carcinoma Kidney Carcinoma 0.086 0.020 DO4 Melanoma Skin Melanoma 0.136 0.074 SH-SY5Y Bone marrow neuroblastoma Brain Neuroblastoma 0.211 0.153 NCI-H69 Small cell lung carcinoma Lung Carcinoma 0.120 0.062 NSCLC Non-small cell lung carcinoma Lung Carcinoma 0.064 0.020 UMUC3 Bladder carcinoma Urinary tract Carcinoma 0.233 0.195 MCF7 Breast carcinoma Breast Carcinoma 0.223 0.187 Hs-578T Invasive ductal breast carcinoma Breast Carcinoma 0.128 0.094 LXFL 529 Non-small cell lung carcinoma Lung Carcinoma 0.057 0.028 CEM-SS Childhood T acute lymphoblastic leukemia Blood Leukemia 0.027 0.005 NT2 Embryonal carcinoma Germ cell. Fibroblast Carcinoma 0.063 0.050 SW1353 Bone chondrosarcoma Bone Sarcoma 0.052 0.039 TCC-SUP Bladder carcinoma Urinary tract Carcinoma 0.101 0.089 MeWo Melanoma Skin Melanoma 0.081 0.075 DAN-G Human pancreas adenocarcinoma cell line Pancreas Adenocarcinoma 0.056 0.050 UMSCC22B Hypopharyngeal squamous cell carcinoma Upper aerodigestive tract Carcinoma 0.138 0.133 MAXF401 Breast carcinoma Breast Carcinoma 0.176 0.171 M19-MEL Melanoma Skin Melanoma 0.030 0.026 BE-NQ Colon adenocarcinoma Colon Adenocarcinoma 0.024 0.023 C180-13S Ovarian carcinoma Ovarium Carcinoma 0.207 0.206 PC-6 Small cell lung carcinoma Lung Carcinoma Table 7. Protein target details, grid box parameters and molecular docking results. PDB ID Name Grid box coordinates (x, y, z) Grid box size (x, y, z) Binding energy (kcal/mol) Inhibition constant (μM) Intermolecular energy (kcal/mol) VDW desolv. energy (kcal/mol) 3KR7 Tankyrase-2 9.736, 3.712, 12.826 22, 40, 42 -6.27 25.27 -7.17 -7.12 7KKM Tankyrase-1 1.207, 8.131, 19.136 40, 44, 36 -5.99 40.88 -6.88 -6.81 7KK2 PARP-1 -6.923, 3.070, 9.444 50, 40, 50 -5.67 69.76 -6.57 -6.24 4TVJ PARP-2 20.389, 0.872, 22.411 58, 32, 40 -5.19 155.61 -6.09 -6.01 Table 8. Information about the hydrogen, hydrophobic interaction, and pi-pi interaction. Name Hydrogen bonds Hydrophobic interaction Pi-Pi interaction Tankyrase-2 Tyr 1060 Lys1067, His1048, Phe1030, Glu1138, Gly1032, Ser1068, Phe1061, Ala1062, Tyr1060, His1031, Gly1058 Tyr1071 Tankyrase-1 Tyr 1213, Gly 1185 Lys1220, Glu1291, Phe1214, Ala1215, Ser1221, His1184, Ser1186. Tyr1224 PARP-1 Arg 878, Asp 770 Tyr710, Pro 881, Leu769, Ala880, Asp766, Ile879, Ile872, Leu877 - PARP-2 Gly 429 Tyr462, Glu558, His428, Ser470, Ala464, Ser430 Tyr473 Table 9. Physio-chemical properties of 2MBA Physicochemical properties Lipophilicity Water solubility Pharmacokinetics Formula C10H13NO2 Log Po/w (iLOGP) 2.09 Log S (ESOL) -1.74 GI absorption High Molecular weight, g/mol 179.22 Log Po/w (XLOGP3) 1.13 Solubility 3.26 mg/mL BBB permeant Yes Num. heavy atoms 13 Log Po/w (WLOGP) 1.18 Class Very soluble P-gp substrate No Num. arom. heavy atoms 6 Log Po/w (MLOGP) 1.27 Log S (Ali) -1.53 CYP1A2 inhibitor Yes Fraction Csp3 0.30 Log Po/w (SILICOS-IT) 1.74 Solubility 5.30 mg/mL CYP2C19 inhibitor No Num. rotatable bonds 4 Consensus Log Po/w 1.48 Class Very soluble CYP2C9 inhibitor No Num. H-bond acceptors 2 Log S (SILICOS-IT) -3.32 CYP2D6 inhibitor No Num. H-bond donors 1 Solubility 0.0866 mg/mL CYP3A4 inhibitor No Molar Refractivity 50.52 Class Soluble Log Kp (skin permeation) -6.59 cm/s TPSA 38.33 Ų The nil alertness in PAINS and BRENK rule with a synthetic accessibility score of 1.13 shows a possible drug-likeness property of 2MBA. Bioavailability radar of the molecule (Figure 12a) prepared from the SWISSADME server. The pink area represents the optimal range for each property such as lipophilicity (XLOGP3 -0.7 to +5.0), Molecular weight (150 to 500 g/mol), polarity: TPSA (20 to130 Å2), solubility (Log S not more than 6), saturation (fraction of carbons in the sp3 hybridization not less than 0.25), and flexibility (no more than 9 rotatable bonds). Here, our molecule values cover an optimal area of all properties showing good drug likeliness character. BOILED-EGG (WLOGP vs TPSA) plot of 2MBA is given in Figure 12b. The red dot structure shows that 2MBA is not an inhibitor of P-glycoprotein, and its presence inside the yellow yolk region explains its high penetration capability of the blood-brain barrier. The future work will focus on altering the molecule character to improve the water solubility with less cytochrome P isoforms inhibition. https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614187 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL2366315 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL612596 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL613506 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614097 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614355 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL615023 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL382 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614736 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614809 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL613834 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL612255 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614667 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614176 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL612247 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL613987 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL397 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614637 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614287 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614910 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614805 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL612554 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL612799 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL387 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614645 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614110 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614548 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614205 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614944 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL615010 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL613300 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614033 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL612798 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL612703 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614019 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614702 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL613540 https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL614235 448 Murugan et al. / European Journal of Chemistry 13 (4) (2022) 440-450 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.440-450.2303 Complex (a) Complex (b) 4TKG (c) 7KKM (d) Figure 11. Molecular interactions of the ligand with Tankyrase-1 and Tankyrase-2 compared with molecular interactions of drugs olaparib and talazoparib complexed crystal structure. (a) Hydrogen and hydrophobic interaction plot generated using LIGPLOT for the title ligand docked with Tankyrase-2 (PDB: 3KR7) (Dotted line-hydrogen bonds, arc structures-residues), (b) Hydrogen and hydrophobic interaction plot generated using LIGPLOT for the ligand docked with Tankyrase-1, (PDB: 7KKM) (Dotted line-hydrogen bonds, arc structures-residues), (c) Hydrogen and hydrophobic interaction plot generated using LIGPLOT for drug olaparib with Tankyrase-2 crystal structure downloaded from RCSB (PDB: 4TKG) (Dotted line-hydrogen bonds, arc structures-residues involved in hydrophobic interaction), (d) Hydrogen and hydrophobic interaction plot generated using LIGPLOT for drug talazoparib with Tankyrase-1 crystal structure downloaded from RCSB (PDB: 7KKM) (Dotted line-hydrogen bonds, arc structures-residues involved in hydrophobic interaction). (a) (b) Figure 12. (a) Bioavailability radar and (b) BOILED-EGG plot of 2MBA. Murugan et al. / European Journal of Chemistry 13 (4) (2022) 440-450 449 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.440-450.2303 4. Conclusions In the present work, N-(2-methoxy-benzyl)acetamide deri- ved from 2-methoxybenzylamine and acetic acid was success- fully synthesized. The obtained compound was characterized by using spectroscopic analysis, such as FT-IR and NMR studies. Our findings also characterize the FMO and MEP concepts that were successfully applied in 2MBA to confirm the experimental results. Non-covalent supramolecular interactions in the crystal structure were quantified through Hirshfeld dnorm surfaces and 2D fingerprint plots to predict the percentage interactions. The quantum chemical parameters such as chemical hardness, softness electronegativity, HOMO-LUMO energy gap, ELUMO, and EHOMO provide important clues about the biological activity of the amide 2MBA have been calculated with the B3LYP/6- 311G++(d,p) method. In addition, a positive result of kinase inhibition was implicated by a molecular docking study against anticancer activity. Furthermore, drug-likeness and pharmaco- dynamics data revealed that 2MBA completed ADME require- ments and has good drug score values. The molecular docking results show the interaction of compounds like olaparib and talazoparib drug compounds and the interaction of the compound with Tankyrase-1 and Tankyrase-2 has been potential evidence to proceed the further studies on the compound for future cancer-based activity. Acknowledgments Madhukar Hemamalini thanks the Science and Engineering Research Board Science, International Research Experience (SERB-IRE) for financial support; Ref. No. SIR/2022/000011. Anaglit Catherine Paul thanks Mother Teresa Women’s University, Tamil Nadu, India, for financial support. Supporting information CCDC-2145614 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by e-mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: All ethical guidelines have been adhered. Sample availability: Sample of the 2MBA is available from the author. CRediT authorship contribution statement Conceptualization: Madhukar Hemamalini; Methodology: Suganya Murugan, Jayasudha Nehru; Software: Venkatachalam Rajakannan, Prasanth Gunasekaran, Necmi Dege, Emine Berrin Cinar; Validation: Madhukar Hemamalini, Venkatachalam Rajakannan, Savaridasson Jose Kavitha; Formal Analysis: Suganya Murugan, Anaglit Catherine Paul, Jayasudha Nehru; Investigation: Kaliyaperumal Thanigaimani; Resources: Madhukar Hemamalini; Data Curation: Necmi Dege, Emine Berrin Cinar; Writing - Original Draft: Madhukar Hemamalini, Suganya Murugan; Writing - Review and Editing: Savaridasson Jose Kavitha, Madhukar Hemamalini; Visualization: Suganya Murugan, Anaglit Catherine Paul; Funding acquisition: Madhukar Hemamalini, Anaglit Catherine Paul; Supervision: Madhukar Hemamalini; Project Administration: Madhukar Hemamalini. ORCID and Email Suganya Murugan sugan.chemistns@gmail.com https://orcid.org/0000-0001-9707-9998 Prasanth Gunasekaran prasanthbiophysics@gmail.com https://orcid.org/0000-0001-9996-2960 Jayasudha Nehru sujijaya145@gmail.com https://orcid.org/0000-0003-4694-5328 Anaglit Catherine Paul acatherine.paul@gmail.com https://orcid.org/0000-0002-5217-1616 Necmi Dege necmid@omu.edu.tr https://orcid.org/0000-0003-0660-4721 Emine Berrin Cinar emineberrin.cinar@omu.edu.tr https://orcid.org/0000-0001-7617-3459 Savaridasson Jose Kavitha josekavitha@gmail.com https://orcid.org/0000-0002-6513-2210 Kasthuri Balasubramani manavaibala@gmail.com https://orcid.org/0000-0003-1724-9999 Kaliyaperumal Thanigaimani thanigaimani81@gmail.com https://orcid.org/0000-0002-4384-7848 Venkatachalam Rajakannan vrajakannan@gmail.com https://orcid.org/0000-0002-4129-9227 Madhukar Hemamalini hemamalini2k3@yahoo.com hemamalini.ch@motherteresawomensuniv.ac.in https://orcid.org/0000-0001-8233-9451 References [1]. Humphrey, J. 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The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). https://www.pymol.org/ http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Instrumentation 2.2. Synthesis of N-(2-methoxy-benzyl)-acetamide (2MBA) 2.3. Single crystal structure determination 2.4. Hirshfeld surface analysis 2.5. Computational study 3. Results and discussion 3.1. Single crystal structure analysis 3.2. Hirshfeld surface analysis 3.3. DFT studies 3.3.1. Frontier molecular orbitals 3.3.2. Molecular electrostatic potential 3.4. Molecular docking 3.5. Swiss ADME studies 4. Conclusions Acknowledgments Supporting information Disclosure statement CRediT authorship contribution statement ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField18: PrintField19: PrintField110: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: PrintField28: PrintField29: PrintField210: