Experimental and Theoretical Biological Probing of Schiff Bases as Esterase Inhibitors: Structural, Spectral and Molecular Insights.

The present study was designed to evaluate the in vitro and in silico potential of the Schiff bases (Z)-4-ethoxy-N-((5-nitrothiophen-2-yl)methylene)benzenamine (1) and (Z)-2,4-diiodo-6-((2-methyl-3-nitrophenylimino)methyl)phenol (2). These Schiff bases were synthesized according to a reported method using ethanol as a solvent, and each reaction was monitored on a TLC until completion of the reaction. The structures of both compounds were elucidated using spectroscopic techniques such as UV-Vis, FTIR, 1H NMR and 13C NMR. Molecular structure was determined using single-crystal XRD, which revealed that compounds 1 and 2 were monoclinic and triclinic, respectively. Hirshfeld surface analysis (HS) and 2D fingerprint plots were used to determine the intermolecular interactions along the contact contribution in the crystalline molecules. The structures of both compounds were optimized through a hybrid functional method B3LYP using the 6-31G(d,p) basis set, and various structural parameters were studied. The experimental and theoretical parameters (bond angle and bond length) of the compounds were compared with each other and are in close agreement. The in vitro esterase potential of the synthesized compounds was checked using a spectrophotometric model, while in silico molecular docking studies were performed with AutoDock against two enzymes of the esterase family. The docking studies and the in vitro assessment predicted that such molecules could be used as enzyme inhibitors against the tested enzymes: acetylcholine esterase (AChE) and butyrylcholine esterase (BChE).

Synthesis, crystal structure, spectroscopic and computational investigations of the newly synthesized Schiff bases scaffold as enzyme inhibitor.

The current project was planned to access the enzyme inhibition potential of the synthesize imines; (E)-2-(2-hydroxy-4,5-dimethoxybenzylideneamino)benzonitrile 1 and (E)-2-(((3-hydroxy-4-methylphenyl)imino)methyl)-4-methoxyphenol 2 by the reported protocol of our continuous research and also assess their theoretical function in term of in silico action. The structural characterization of imines was done through advanced techniques i.e., FTIR, 1H NMR, 13C NMR, and UV spectroscopy. Moreover, a single X-Ray diffraction technique (SCXRD) was employed for real structural identification of imines dimensions, which revealed that compound 1 has a triclinic crystal system although 2 has a monoclinic one. A 2D fingerprint plot and Hirshfeld surface analysis (HS) was employed in the crystalline assembly of compounds to check intermolecular contacts and also their degree of contributions. Both compounds were optimized by B3LYP functional mode using a certain basis set (6-31G). The practical data (XRD) and theoretical data (DFT) of both molecules were compared and found between a sound coherence. Molecular docking studies in term of in silico assessment were conducted against enzymes of the esterase and alpha-glucosidase family. The docking outputs give a forecast about compounds that could be employed as protein inhibitors against analyzed protein surfaces.

Crystal structure and Hirshfeld surface analysis of dimethyl 3,3'-{[(1E,2E)-ethane-1,2-diyl-idene]bis(aza-nylyl-idene)}bis-(4-methyl-benzoate).

The title Schiff base compound, C20H20N2O4, synthesized by the condensation reaction of methyl 3-amino-4-methyl-benzoat and glyoxal in ethanol, crystallizes in the the monoclinic space group P21/n. The mol-ecule is Z-shaped with the C-N-C-C torsion angle being 47.58 (18)°. In the crystal, pairs of mol-ecules are linked via C-H⋯N hydrogen bonds, forming centrosymetric dimers with an R 2 2(8) ring motif; this connectivity leads to the formation of columns running along the a-axis direction. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to explore the inter-molecular inter-actions and revealed that the most significant contributions to the crystal packing are from H⋯H (49.4%), H⋯O/O⋯H (19.0%) and H⋯C/C⋯H (17.5%) contacts. Energy frameworks were constructed through different inter-molecular inter-action energies to investigate the stability of the compound. The net inter-action energies for the title compound were found to be electrostatic (E ele = -48.4 kJ mol-1), polarization (E pol = -9.7 kJ mol-1), dispersion (E dis = -186.9 kJ mol-1) and repulsion (E rep = 94.9 kJ mol-1) with a total inter-action energy, E tot, of -162.4 kJ mol-1.

Crystal structure and Hirshfeld surface analysis of 6,6'-((1E,1'E)-{[1,4-phenyl-enebis(methyl-ene)]bis(aza-nylyl-idene)}bis-(methane-ylyl-idene))bis-(2-meth-oxy-phenol).

The Schiff base compound, C24H24N2O4, was synthesized by the inter-action of 2-hy-droxy-3-meth-oxy benzaldehyde and 1,4-benzene dimethanamine in ethanol, and crystallizes in the monoclinic space group P21/n with Z' = 0.5. The mol-ecule is not planar, the 1,4-di-ethyl-benzene and the phenol rings are twisted with respect to each other, making a dihedral angle of 74.27 (5)°. The mol-ecular structure is stabilized by an O-H⋯N hydrogen bond, forming an S(6) ring motif. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, resulting in the formation of sheets parallel to the bc plane. A Hirshfeld surface analysis was undertaken to investigate the various inter-molecular contacts controlling the supra-molecular topology, suggesting the H⋯O (18%) contacts to be the most significant inter-actions, whereas the H⋯H (50.5%) and C⋯H (24.3%) inter-actions are less significant.

Crystal structure and Hirshfeld surface analysis of (Z)-2-{[(2,4-di-methyl-phen-yl)imino]-meth-yl}-4-methyl-phenol.

The title compound, C16H17NO, is a Schiff base that exists in the enol-imine tautomeric form and adopts a Z configuration. The mol-ecule is non-planar, with the twisted rings making a dihedral angle of 39.92 (4)°. The intra-molecular O-H⋯N hydrogen bond forms an S(6) ring motif. In the crystal, mol-ecules are linked by C-H⋯π inter-actions and very weak π-π stacking inter-actions also help to consolidate the crystal packing. A Hirshfeld surface analysis was performed to investigate the contributions of different inter-molecular contacts within the supra-molecular structure. The major contributions are from H⋯H (65%), C⋯H (19.2%) and O⋯H (6.6%) inter-actions.

Crystal structure, Hirshfeld surface analysis and DFT studies of (E)-4-methyl-2-{[(2-methyl-3-nitro-phen-yl)imino]-meth-yl}phenol.

The title compound, C15H14N2O3, was prepared by condensation of 2-hy-droxy-5-methyl-benzaldehyde and 2-methyl-3-nitro-phenyl-amine in ethanol. The configuration of the C=N bond is E. An intra-molecular O-H⋯N hydrogen bond is present, forming an S(6) ring motif and inducing the phenol ring and the Schiff base to be nearly coplanar [C-C-N-C torsion angle of 178.53 (13)°]. In the crystal, mol-ecules are linked by C-H⋯O inter-actions, forming chains along the b-axis direction. The Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H⋯H (37.2%), C⋯H (30.7%) and O⋯H (24.9%) inter-actions. The gas phase density functional theory (DFT) optimized structure at the B3LYP/ 6-311 G(d,p) level is compared to the experimentally determined mol-ecular structure in the solid state. The HOMO-LUMO behaviour was elucidated to determine the energy gap.

Synthesis, crystal structure and Hirshfeld surface analysis of 1,7-dimethyl-5a,6,11a,12-tetra-hydro-benzo[b]benzo[5,6][1,4]oxazino[2,3-e][1,4]oxazine.

Mol-ecules of the title compound, C16H16N2O2, occupy special positions on the twofold rotation axes. The heterocyclic ring adopts a slightly twisted envelope conformation with one of the two junction carbon atoms as the flap. The mean planes through the two halves of the mol-ecule form a dihedral angle of 72.01 (2)°. In the crystal, mol-ecules are linked by pairs of C-H⋯O and N-H⋯C contacts into layers parallel to (100). H⋯H contacts make the largest contribution to the Hirshfeld surface (58.9%).

Crystal structure, Hirshfeld surface analysis and DFT studies of 2-[(2-hy-droxy-5-methyl-benzyl-idene)amino]-benzo-nitrile.

The title compound, C15H12N2O, was synthesized by condensation reaction of 2-hy-droxy-5-methyl-benzaldehyde and 2-amino-benzo-nitrile, and crystallizes in the ortho-rhom-bic space group Pbca. The phenol ring is inclined to the benzo-nitrile ring by 25.65 (3)°. The configuration about the C=N bond is E, stabilized by a strong intra-molecular O-H⋯N hydrogen bond that forms an S(6) ring motif. In the crystal, C-H⋯O and C-H⋯N inter-actions lead to the formation of sheets perpendicular to the a axis. C-H⋯π inter-actions, forming polymeric chains along the a-axis direction, connect these sheets into a three-dimensional network. A Hirshfeld surface analysis indicates that the most important contributions for the packing arrangement are from H⋯H and C⋯H/H⋯C inter-actions. The density functional theory (DFT) optimized structure at the B3LYP/6-311 G(d,p) level is compared with the experimentally determined mol-ecular structure and the HOMO-LUMO energy gap is given.

Crystal structure, Hirshfeld surface analysis and DFT studies of (E)-2-{[(3-chloro-4-methyl-phen-yl)imino]-meth-yl}-4-methyl-phenol.

The title compound, C15H14ClNO, was synthesized by condensation reaction of 2-hy-droxy-5-methyl-benzaldehyde and 3-chloro-4-methyl-aniline, and crystallizes in the monoclinic space group P21/c. The 3-chloro-benzene ring is inclined to the phenol ring by 9.38 (11)°. The configuration about the C=N bond is E and an intra-molecular O-H⋯N hydrogen bond forms an S(6) ring motif. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the packing arrangement are from H⋯H (43.8%) and C⋯H/H⋯C (26.7%) inter-actions. The density functional theory (DFT) optimized structure at the B3LYP/ 6-311 G(d,p) level is compared with the experimentally determined mol-ecular structure and the HOMO-LUMO energy gap is provided.

Crystal structure, Hirshfeld surface analysis and DFT studies of 4-methyl-2-({[4-(tri-fluoro-meth-yl)phen-yl]imino}-meth-yl)phenol.

The title compound, C15H12F3NO, crystallizes with one mol-ecule in the asymmetric unit. The configuration of the C=N bond is E and there is an intra-molecular O-H⋯N hydrogen bond present, forming an S(6) ring motif. The dihedral angle between the mean planes of the phenol and the 4-tri-fluoro-methyl-phenyl rings is 44.77 (3)°. In the crystal, mol-ecules are linked by C-H⋯O inter-actions, forming polymeric chains extending along the a-axis direction. The Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from C⋯H/H⋯C (29.2%), H⋯H (28.6%), F⋯H/H⋯F (25.6%), O⋯H/H⋯O (5.7%) and F⋯F (4.6%) inter-actions. The density functional theory (DFT) optimized structure at the B3LYP/6-311 G(d,p) level is compared with the experimentally determined mol-ecular structure in the solid state. The HOMO-LUMO behaviour was elucidated to determine the energy gap. The crystal studied was refined as an inversion twin.

Crystal structure, Hirshfeld surface analysis and DFT studies of (E)-4-methyl-2-{[(4-methyl-phen-yl)imino]-meth-yl}phenol.

In the title compound, C15H15NO, the configuration of the C=N bond of the Schiff base is E, and an intra-molecular O-H⋯N hydrogen bond is observed, forming an intra-molecular S(6) ring motif. The phenol ring is inclined by 45.73 (2)° from the plane of the aniline ring. In the crystal, mol-ecules are linked along the b axis by O-H⋯N and C-H⋯O hydrogen bonds, forming polymeric chains. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the packing arrangement are from H⋯H (56.9%) and H⋯C/C⋯H (31.2%) inter-actions. The density functional theory (DFT) optimized structure at the B3LYP/ 6-311 G(d,p) level is compared with the experimentally determined mol-ecular structure, and the HOMO-LUMO energy gap is provided. The crystal studied was refined as an inversion twin.

Crystal structure and Hirshfeld surface analysis of 2-{[(4-iodo-phen-yl)imino]-meth-yl}-4-nitro-phenol.

The title compound, C13H9IN2O3, was synthesized by a condensation reaction between 2-hy-droxy-5-nitro-benzaldehyde and 4-iodo-aniline, and crystallizes in the ortho-rhom-bic space group Pna21. The 4-iodo-benzene ring is inclined to the phenol ring by a dihedral angle of 39.1 (2)°. The configuration about the C=N double bond is E. The crystal structure features C-H⋯O hydrogen-bonding inter-actions. A Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the packing arrangement are O⋯H/H⋯O (26.9%) and H⋯H (22.0%) inter-actions.

Two new zinc(II) and mercury(II) complexes based on N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide): synthesis, crystal structures and antibacterial activities.

Reaction of N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide), C20H18F2N4O2, (LF), with zinc chloride and mercury(II) chloride produced different types and shapes of neutral coordination complexes, namely, dichlorido[N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide)-κ2N,O]zinc(II), [ZnCl2(C20H18F2N4O2)], (1), and dichlorido[N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide)-κ4O,N,N',O']mercury(II), [HgCl2(C20H18F2N4O2)], (2). The organic ligand and its metal complexes are characterized using various techniques: IR, UV-Vis and nuclear magnetic resonance (NMR) spectroscopies, in addition to powder X-ray diffraction (PXRD), single-crystal X-ray crystallography and microelemental analysis. Depending upon the data from these analyses and measurements, a typical tetrahedral geometry was confirmed for zinc complex (1), in which the ZnII atom is located outside the bis(benzhydrazone) core. The HgII atom in (2) is found within the core and has a common octahedral structure. The in vitro antibacterial activities of the prepared compounds were evaluated against two different bacterial strains, i.e. gram positive Bacillus subtilis and gram negative Pseudomonas aeruginosa bacteria. The prepared compounds exhibited differentiated growth-inhibitory activities against these two bacterial strains based on the difference in their lipophilic nature and structural features.

A3B type unsymmetrical and amphiphilic phthalocyanines: Synthesis, characterization, thermal stability and aggregation studies.

This study reports the preparation, analysis, aggregation statuses and thermal properties of five phthalocyanines. The preparation of all molecules includes two steps: the first step is the preparation of phthalocyanine precursor molecules (A and B coded phthalonitriles); the second step is the synthesis of one metal-free and four metalled phthalocyanines (A3B-Co, A3B-Cu, A3B-H, A3B-Ni, and A3B-Zn coded compounds). Compound A holds a hydrophobic chain (cetyl alcohol); compound B holds a hydrophilic chain (tetraethylene glycol). Phthalocyanines include three hydrophobic chains and one hydrophilic chain (A3B type phthalocyanine). Characterization methods which were used to determine the structure of these compounds are Fourier Transform Infrared (FTIR), Proton Nuclear Magnetic Resonance (1H NMR), Carbon-13 Nuclear Magnetic Resonance (13C NMR), and Ultraviolet Visible (UV Vis) spectroscopies and elemental analysis. The phthalocyanines have high stability up to 260 °C as a minimum value. Aggregation statuses of the phthalocyanines change to the metal from the metal or to the solvent from the solvent.

(E)-3-{[(2-Bromo-3-methyl-phen-yl)imino]-meth-yl}benzene-1,2-diol: crystal structure and Hirshfeld surface analysis.

The title compound, C14H12BrNO2, was synthesized by the condensation reaction of 2,3-di-hydroxy-benzaldehyde and 2-bromo-3-methyl-aniline. It crystallizes in the centrosymmetric triclinic space group P . The configuration about the C=N bond is E. The dihedral angle between the planes of the 5-(2-bromo-3-methyl-phenyl ring and the catechol ring is 2.80 (17)°. In the crystal, O-H⋯O hydrogen-bond inter-actions consolidate the crystal packing.

Crystal structure and DFT study of (E)-2-chloro-4-{[2-(2,4-di-nitro-phen-yl)hydrazin-1-yl-idene]meth-yl}phenol aceto-nitrile hemisolvate.

The title Schiff base compound, C13H9ClN4O5·0.5CH3CN, crystallizes as an aceto-nitrile hemisolvate; the solvent mol-ecule being located on a twofold rotation axis. The mol-ecule is nearly planar, with a dihedral angle between the two benzene rings of 3.7 (2)°. The configuration about the C=N bond is E, and there is an intra-molecular N-H⋯Onitro hydrogen bond present forming an S(6) ring motif. In the crystal, mol-ecules are linked by O-H⋯O and N-H⋯O hydrogen bonds, forming layers lying parallel to (10). The layers are linked by C-H⋯Cl hydrogen bonds, forming a supra-molecular framework. Within the framework there are offset π-π stacking inter-actions [inter-centroid distance = 3.833 (2) Å] present involving inversion-related mol-ecules. The DFT study shows that the HOMO and LUMO are localized in the plane extending from the phenol ring to the 2,4-di-nitro-benzene ring, and the HOMO-LUMO gap is found to be 0.13061 a.u.

Crystal structure and Hirshfeld surface analysis of (Z)-6-[(2-hy-droxy-4-methyl-anilino)-methyl-idene]-4-methyl-cyclo-hexa-2,4-dien-1-one.

The title compound, C15H15NO2, is a Schiff base that exists in the keto-enamine tautomeric form and adopts a Z configuration. The mol-ecule is almost planar, with the two phenyl rings twisted relative to each other by 9.60 (18)°. There is an intra-molecular N-H⋯O hydrogen bond present forming an S(6) ring motif. In the crystal, pairs of O-H⋯O hydrogen bonds link adjacent mol-ecules into inversion dimers with an R 2 2(18) ring motif. The dimers are linked by very weak π-π inter-actions, forming layers parallel to (01). Hirshfeld surface analysis, two-dimensional fingerprint plots and the mol-ecular electrostatic potential surfaces were used to analyse the inter-molecular inter-actions, indicating that the most important contributions for the crystal packing are from H⋯H (55.2%), C⋯H/H⋯C (22.3%) and O⋯H/H⋯O (13.6%) inter-actions.

Crystal structure and Hirshfeld surface analysis of (Z)-6-[(2-hy-droxy-5-nitro-anilino)methyl-idene]-4-methyl-cyclo-hexa-2,4-dien-1-one.

The title compound, C14H12N2O4, is a Schiff base that exists in the keto-enamine tautomeric form and adopts a Z configuration. The mol-ecule is almost planar, the rings making a dihedral angle of 4.99 (7)°. The mol-ecular structure is stabilized by an intra-molecular N-H⋯O hydrogen bond forming an S(6) ring motif. In the crystal, inversion-related mol-ecules are linked by pairs of O-H⋯O hydrogen bonds, forming dimers with an R 2 2(18) ring motif. The dimers are linked by pairs of C-H⋯O contacts with an R 2 2(10) ring motif, forming ribbons extended along the [20] direction. Hirshfeld surface analysis, two-dimensional fingerprint plots and the mol-ecular electrostatic potential surfaces were used to analyse the inter-molecular inter-actions present in the crystal, indicating that the most important contributions for the crystal packing are from H⋯H (33.9%), O⋯H/H⋯O (29.8%) and C⋯H/H⋯C (17.3%) inter-actions.

Crystal structure, DFT and MEP study of (E)-2-[(2-hy-droxy-5-meth-oxy-benzyl-idene)amino]-benzo-nitrile.

The asymmetric unit of the title compound, C15H12N2O2, contains two crystallographically independent mol-ecules in which the dihedral angles between the benzene rings in each are 13.26 (5) and 7.87 (5)°. An intra-molecular O-H⋯N hydrogen bonds results in the formation of an S(6) ring motif. In the crystal, mol-ecules are linked by weak C-H⋯O and C-H⋯N hydrogen bonds, forming layers parallel to (011). In addition, π-π stacking inter-actions with centroid-centroid distances in the range 3.693 (2)-3.931 (2) Šcomplete the three-dimensional network.

(Z)-3-({[3-Meth-oxy-5-(tri-fluoro-meth-yl)phen-yl]imino}meth-yl)benzene-1,2-diol.

The title compound, C15H12F3NO3, crystallizes with one mol-ecule in the asymmetric unit. The mean planes of the two phenyl rings of the Schiff base moiety, bearing the OH groups and the imine group, respectively, are inclined to each other by 4.91 (1)°. In the crystal, mol-ecules are linked via pairs of bifurcated O-H⋯O hydrogen bonds between the phenol OH groups, forming inversion dimers with an R 1 2(5) ring motif. The structure exhibits also intra-molecular O-H⋯N and C-H⋯F hydrogen-bonding inter-actions. Hirshfeld surfaces analysis and two-dimensional fingerprint plots were applied to qu-antify the inter-molecular inter-actions. The three F atoms of the tri-fluoro-methyl group are disordered over two sets of sites, with occupancy factors of 0.578 (8) and 0.422 (8). The crystal studied was refined as an inversion twin.