Spectroscopic Investigations , DFT Calculations , and Molecular Docking Studies of the Anticonvulsant ( 2 E )-2-[ 3-( 1 H-Imidazol-1-yl )-1-phenylpropylidene ]-N-( 4-methylphenyl ) hydrazinecarboxamide

1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia 2Centre for Molecular and Biophysics Research, Department of Physics, Mar Ivanios College, Thiruvananthapuram, Kerala 695015, India 3Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), El Bohooth Street, Dokki, Giza 12622, Egypt

Literature screening indicated that computational studies on the (2E)-IPPMP molecule have not yet been reported.Therefore, detailed investigations of structural properties and vibrational spectral analysis of the (2E)-IPPMP molecule were carried out in the present study using density functional theory (DFT) computations.Moreover, the biological

Experimental
2.1.General.Melting point was recorded on a Gallenkamp melting point instrument and it is uncorrected.The Fourier transform infrared spectrum of MMIMI was recorded on a Perkin Elmer RXL spectrometer (Waltham, Massachusetts, USA) in the region 4000-400 cm −1 , with samples in the KBr pellet method.The resolution of the spectrum was 2 cm −1 .The FT-Raman spectrum was measured in the range 3500-50 cm −1 using a Bruker RFS 100/S FT-Raman spectrophotometer (Ettlingen, Germany) with a 1064 nm Nd:YAG laser source of 100 mW power (Göttingen, Germany).

Synthesis.
A solution containing N-(4-methylphenyl)hydrazinecarboxamide [12] (1.65 g, 10 mmol), 3-(1H-imidazol-1-yl)-1-phenylpropan-1-one (2.00 g, 10 mmol) [13], and a few drops of glacial acetic acid in ethanol (15 mL) was stirred at room temperature for 18 h.The reaction mixture was evaporated under reduced pressure and the residue was crystallized from ethanol to give 1.67 g (48%) of the title compound as colorless crystals (m.p. 476-478 K) which were suitable for single crystal X-ray analysis. 1H and 13 C NMR as well as the mass spectral data of the title compound 2 are in accordance with the previously reported ones [9].

Theoretical Calculations.
All DFT calculations of the (2E)-IPPMP molecule were performed using the Gaussian 09 program package [14] at the Becke3-Lee-Yang-Parr (B3LYP) level with a 6-311++G(d,p) basis set [15][16][17].The structural parameters were computed in the gas phase as well as in the liquid phase using a polarizable continuum model (PCM) method.In order to correct the overestimations arising from some negative factors such as basis set truncation effect, neglecting electron correlations, and anharmonicity characters of the vibrational modes, the calculated wavenumbers were scaled using a uniform scaling factor of 0.9673 [18,19].Theoretical NMR calculation was performed on the basis of the GIAO (gauge-independent atomic orbitals) theory method using a Gaussian program.

Results and Discussion
3.1.Synthesis.The target compound (2E)-IPPMP was obtained in a three-step reaction sequence as given in Scheme 1.

Structural Geometry Analysis.
The structure of the (2E)-IPPMP molecule was optimized using the B3LYP method with a 6-311++G(d,p) basis set.The optimized molecular structure of the isolated molecule is shown in Figure 1.The optimized geometrical parameters of the isolated (2E)-IPPMP molecule in the gas and water phases are given in Table 1.The calculated values were compared with the Xray diffraction results.In the (2E)-IPPMP molecule the two phenyl rings are bridged by a hydrazinecarboxamide skeleton containing an imidazole ring.The C-N bond lengths C 17 -N 16 (1.4179Å) and C 17 -N 19 (1.3792 Å) are shorter than the normal single C-N bond length 1.480 Å [20].This discrepancy is due to the conjugation of p-type electrons of the carbonyl group and nitrogen atom, allowing the electrons to smear out along the C-N bond.In the para-disubstituted phenyl ring, the calculated C 25 -H 44 (1.0789 Å) bond length is shorter than that of the other C-C bonds; also, O 18 ⋅ ⋅ ⋅ H 44 distance is 2.25 Å, which is significantly shorter than the van der Waals radius (2.72 Å) [21] between O and H atoms, which indicates the possibility of C-H⋅ ⋅ ⋅ O hydrogen bonding.The elongation of the C 20 -C 21 (1.4004Å) bond is due to the transfer of a lone pair of electrons from the amide nitrogen to the carbon atom.In the other phenyl ring, the C 5 -H 31  H 40 hinders the achievement of coplanarity.A small deviation was obtained within the calculated structural parameters in the gas and liquid phases, which were due to the solvent interactions over the solution phase calculations.

Natural Bond Orbital Analysis.
Natural bond orbital (NBO) analysis was performed using the NBO 3.1 program [22] as implemented in the Gaussian 09 program package for the DFT method.The corresponding results are presented in Table 2. NBO analysis has proved to be an effective tool for chemical interpretation of hyperconjugative interaction and electron density transfer (EDT) from a filled lone pair to an unfilled antibonding orbital in the hydrogen bonding system [23][24][25].potential energy distribution analysis using the VEDA4 program [26].The experimental infrared (IR) and Raman spectra are shown in Figures 2 and 3.The calculated vibrational wavenumbers, measured IR, and Raman band positions and their detailed assignments are given in Table 3.  [29].A medium band observed in IR at 1401 cm −1 is attributed to methylene scissoring mode.The twisting, wagging vibrations appear in the region 1422-719 cm −1 [30].

Phenyl Ring
The observed strong IR band at 1141 cm −1 and weak Raman band at 1177 cm −1 are assigned to CH 2 twisting modes for methylene.Wagging is observed in IR at 1352 cm −1 and Raman at 1361 cm −1 .

Secondary Amide Vibrations.
Carbonyl stretching vibration in a secondary amide is expected in the region 1680-1630 cm −1 [28] .A very strong band at 1654 cm −1 is assigned to C=O stretching.N-H stretching vibrations generally appear in the region 3370-3170 cm −1 .Observed IR and Raman bands at 3141 and 3140 cm −1 are attributed to N-H stretching.The in-plane N-H bending vibration usually appears from 1570 to 1515 cm −1 [28].The observed very strong IR band at 1523 cm −1 and weak Raman band at 1527 cm −1 are assigned to in-plane N-H bending vibration.
Observed Raman bands at 3121 and 3138 cm −1 and IR bands at 3119 and 3138 cm −1 are assigned to C-H stretching mode.The observed Raman band at 1338 cm −1 is attributed to C-C stretching mode [33].

Hydrazine Vibrations.
In accordance with earlier reports and in agreement with the calculation, a weak band observed at 3207 cm −1 is assigned to hydrazine N-H stretching [27,34].Observed bands in IR and Raman at 1089 and 1088 cm −1 are assigned to N-N stretching vibration.3.5.Frontier Molecular Orbital Energy Analysis.HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) are important in defining the reactivity of a chemical species.The energy of HOMO indicates nucleophilicity and LUMO indicates electrophilicity [35].HOMO is spread over the methyl phenyl, hydrazinecarboxamide fragment and LUMO is located on ph 2. This shows the charge transfer between the two rings through the hydrazinecarboxamide path.The HOMO (−6.61 eV) and LUMO (−1.61 eV) energies reflect the charge transfer within the molecule.The HOMO-LUMO energy gap is 4.46 eV.The frontier molecular orbital diagrams are shown in Figure 4.

Natural Population Analysis.
Natural population analysis provides an effective method to calculate atomic charges and electron distribution within a molecule [36].The net atomic charges of the (2E)-IPPMP molecule obtained by natural population analysis are plotted in Figure 5.All hydrogen atoms have a net positive charge.The atoms H 40 (0.3852e) and H 39 (0.3788e) show more positive charge than other hydrogen atoms due to their attachment with a nitrogen atom.Among the hydrogen atoms (∼0.2023e) of the phenyl ring, H 44  and 140.01 ppm.A carbonyl carbon signal was seen at 144.9 ppm and its computed one was obtained at 150.09 ppm.This deviation may occur due to the presence of amide⋅ ⋅ ⋅ amide interactions in the crystalline state.On the other hand, the computed 1 H chemical shift values for the title molecule showed good agreement with the experimental ones (Table 4).

Molecular Docking Analysis.
The title molecule (2E)-IPPMP was energy minimized based on the DFT method.Molecular docking was performed using AutoDock 4.2.A target protein (PDB ID: 1EOU) for antiepileptic agents was selected for the present docking analysis [37,38].The protein data bank file of the target protein was downloaded from the Research Collaboratory for Structural Bioinformatics (RCSB) database, with a resolution of 2.1 Å.Protein preparation was carried out by the following steps: (i) all water molecules were removed, (ii) hydrogen atoms were added to the crystal structure, (iii) Kollman charge was added, and (iv) a previously docked inhibitor (fructose-based sugar sulfamate RWJ-37497) was removed from the protein.Rigid protein and flexible ligand dockings were carried out using the AutoDock 4.2 program package [39] with the Lamarckian genetic algorithm, applying the following protocol: trials of 100 dockings, energy evaluations of 25000000, population size of 200, mutation rate of 0.02, crossover rate of 0.8, and elitism value of 1.The docking results were evaluated by sorting the docked conformations according to their predicted binding free energy.The protein-ligand interaction complex is given in Figure 6, displaying the conformer with the best predicted binding free energy (−7.94 kcal/mol).

Table 1 :
Structural geometry parameters of (2E)-IPPMP compared with their experimental X-ray diffraction results.
a (2) means energy of hyperconjugative interactions.bEnergy difference between donor and acceptor  and  NBO.c (, ) is the Fock matrix element between  and  NBO.(1.0825Å) bond is shorter than that of the other C-C bonds; also, N 15 ⋅ ⋅ ⋅ H 31 distance is 2.56 Å, which is significantly shorter than the van der Waals radius (2.75 Å) between N and H atoms, which indicates the possibility of C-H⋅ ⋅ ⋅ O hydrogen bonding.In addition, C 5 -C 6 (1.4024 Å) and C

Table 4 :
NMR chemicals shift values of13C and 1 H.
3.7.NMR Analysis.The scaled and experimental NMR ( 1 H and 13 C) chemical shift values for the (2E)-IPPMP molecule are presented in