Structural, Theoretical Analysis, and Molecular Docking of Two Benzamide Isomers. Halogen Bonding and Its Role in the Diverse Ways of Coupling with Protein Residues.

The crystal structures of two methoxyphenylbenzamide isomers are described, (Ph2Br) and (Ph3Br), with the general formula C14H12BrNO2. This structural study revealed the presence of N-H-O and C-H-O hydrogen bonds, Br-Br halogen bonds, C-H-π, and C-Br-π molecular contacts, showing in both compounds, a central C1-C7(O1)-N1(H1)-C8 amide segment, to be almost linear. The close proximity between the Br1 and O1 in Ph2Br showed that its interatomic distance was less than the sum of their VDW radii, generating an increase in the electrostatic potential in the O1 region, making possible the appearance of the so-called σ and π-holes on bromine. These specific conditions give rise to the formation of the Br-Br halogens bonds, which are united in a very interesting way, allowing the bond to extend by joining halogen atoms between different molecules forming an isosceles triangle with Br-Br distances equal to 3.5403(4) Å and 5.085 Å as its base. The presence of the carbonyl group in Ph2Br, an excellent acceptor of hydrogen and halogen bonds, led to competition between these bonds to organize crystal growth. The analysis of the compounds as pharmacophores showed that the bromine atom plays a key role in interactions with protein residues, reaching good ligand-protein interaction values comparable to the values presented by the parent inhibitor, Asciminib. In contact with the ALA356 residue, the bromine of Ph2Br participates with a higher contact geometry using the σ-hole, whereas the bromine of Ph3Br employs a more efficient contact geometry by taking advantage of its π-hole.

Synthesis, spectroscopic characterization, structural studies, thermal analysis and molecular docking of N-(2-methyl-5-nitrophenyl)-4-(pyridin-2-yl)pyrimidin-2-amine, a precursor for drug design against chronic myeloid leukemia.

The synthesis, crystal structure and spectroscopic and electronic properties of N-(2-methyl-5-nitrophenyl)-4-(pyridin-2-yl)pyrimidin-2-amine (NPPA), C16H13N5O2, a potential template for drug design against chronic myelogenous leukemia (CML), is reported. The design and construction of the target molecule were carried out starting from the guanidinium nitrate salt (previously synthesized) and the corresponding enaminone. X-ray diffraction analysis and a study of the Hirshfeld surfaces revealed important interactions between the nitro-group O atoms and the H atoms of the pyridine and pyrimidine rings. A crystalline ordering in layers, by the stacking of rings through interactions of the π-π type, was observed and confirmed by a study of the shape-index surfaces and dispersion energy calculations. Quantitative electrostatic potential studies revealed the most positive value of the molecule on regions close to the N-H groups (34.8 kcal mol-1); nevertheless, steric impediments and the planarity of the molecule do not allow the formation of hydrogen bonds from this group. This interaction is however activated when the molecule takes on a new extended conformation in the active pocket of the enzyme kinase (PDB ID 2hyy), interacting with protein residues that are fundamental in the inhibition process of CML. The most negative values of the molecule are seen in regions close to the nitro group (-35.4 and -34.0 kcal mol-1). A molecular docking study revealed an energy affinity of ΔG = -10.3 kcal mol-1 for NPPA which, despite not having a more negative value than the control molecule (Imatinib; ΔG = -12.8 kcal mol-1), shows great potential to be used as a template for new drugs against CML.

Synthesis, crystal structure, Hirshfeld surface analysis, MEP study and mol-ecular docking of N-{3-[(4-meth-oxy-phen-yl)carbamo-yl]phen-yl}-3-nitro-benzamide as a promising inhibitor of hfXa.

The title compound, C21H17N3O5, consists of three rings, A, B and C, linked by amide bonds with the benzene rings A and C being inclined to the mean plane of the central benzene ring B by 2.99 (18) and 4.57 (18)°, respectively. In the crystal, mol-ecules are linked via N-H⋯O and C-H⋯O hydrogen bonds, forming fused R 2 2(18), R 3 4(30), R 4 4(38) rings running along [0] and R 3 3(37) and R 3 3(15) rings along [001]. Hirshfeld analysis was undertaken to study the inter-molecular contacts in the crystal, showing that the most significant contacts are H⋯O/O⋯H (30.5%), H⋯C/C⋯H (28.2%) and H⋯H (29.0%). Two zones with positive (50.98 and 42.92 kcal mol-1) potentials and two zones with negative (-42.22 and -34.63 kcal mol-1) potentials promote the N-H⋯O inter-actions in the crystal. An evaluation of the mol-ecular coupling of the title compound and the protein with enzymatic properties known as human coagulation factor Xa (hfXa) showed the potential for coupling in three arrangements with a similar minimum binding energy, which differs by approximately 3 kcal mol-1 from the value for the mol-ecule Apixaban, which was used as a positive control inhibitor. This suggests the title compound exhibits inhibitory activity.

Synthesis, spectroscopic (FT-IR and UV-Vis), crystallographic and theoretical studies, and a molecular docking simulation of an imatinib-like template.

The aim of the present study was to report the crystal structure and spectroscopic, electronic, supramolecular and electrostatic properties of a new polymorph of 4-(pyridin-2-yl)pyrimidin-2-amine (C9H8N4). The compound was synthesized under microwave irradiation. The single-crystal X-ray structure analysis revealed an angle of 13.36 (8)° between the planes of the rings, as well as molecules linked by Nsp2-H...N hydrogen bonds forming dimers along the crystal. The material was analyzed by FT-IR vibrational spectroscopy, while a computational approach was used to elucidate the vibrational frequency couplings. The existence of Nsp2-H...N hydrogen bonds in the crystal was confirmed spectroscopically by the IR peaks from the N-H stretching vibration shifting to lower wavenumbers in the solid state relative to those in the gas phase. The supramolecular studies confirmed the formation of centrosymmetric R22(8) rings, which correspond to the formation of dimers that stack parallel to the b direction. Other weak C-H...π interactions, essential for crystal growth, were found. The UV-Vis spectroscopic analysis showed a donor-acceptor process, where the amino group acts as a donor and the pyridine and pyrimidine rings act as acceptors. The reactive sites of the molecule were identified and their quantitative values were defined using the electrostatic potential model proposed in the multifunctional wave function analyzer multiwfn. The calculated interaction energies between pairs of molecules were used to visualize the electrostatic terms as the leading factors against the dispersion factors in the crystal-growth process. The docking results showed that the amino group of the pyrimidine moiety was simultaneously anchored by hydrogen-bonding interactions with the Asp427 and His407 protein residues. This compound could be key for the realization of a series of syntheses of molecules that could be used as possible inhibitors of chronic myelogenous leukemia.

Catalyst- and solvent-free synthesis of 2-fluoro-N-(3-methylsulfanyl-1H-1,2,4-triazol-5-yl)benzamide through a microwave-assisted Fries rearrangement: X-ray structural and theoretical studies.

An efficient approach for the regioselective synthesis of (5-amino-3-methylsulfanyl-1H-1,2,4-triazol-1-yl)(2-fluorophenyl)methanone, C10H9FN4OS, (3), from the N-acylation of 3-amino-5-methylsulfanyl-1H-1,2,4-triazole, (1), with 2-fluorobenzoyl chloride has been developed. Heterocyclic amide (3) was used successfully as a strategic intermediate for the preparation of 2-fluoro-N-(3-methylsulfanyl-1H-1,2,4-triazol-5-yl)benzamide, C10H9FN4OS, (4), through a microwave-assisted Fries rearrangement under catalyst- and solvent-free conditions. Theoretical studies of the prototropy process of (1) and the Fries rearrangement of (3) to provide (4), involving the formation of an intimate ion pair as the key step, were carried out by density functional theory (DFT) calculations. The crystallographic analysis of the intermolecular interactions and the energy frameworks based on the effects of the different molecular conformations of (3) and (4) are described.

Intramolecular interactions, isomerization and vibrational frequencies of two paracetamol analogues: A spectroscopic and a computational approach.

The aim of this investigation was to determine the molecular properties and provide an interpretation of the vibrational mode couplings of these two paracetamol analogues: 2-bromo-2-methyl-N-(4-nitrophenyl)-propanamide and 2-bromo-2-methyl-N-p-tolyl-propanamide. E/Z isomers, keto/enol unimolecular rearrangement and prediction of the transition state structures in each mechanism were also assessed using the Density Functional Theory (DFT). The DFT estimates a high energy gap between E and Z isomers (9-11 kcal·mol(-1)), with barrier heights ranging from 16 to 19 kcal·mol(-1). In contrast, the barrier energies on the keto/enol isomerization are almost 10 kcal·mol(-1) higher than those estimated for the E/Z rearrangement. The kinetic rate constant was also determined for each reaction mechanism. Natural bond orbital analysis and the quantum theory of atoms in molecules were used to interpret the intramolecular hydrogen bonds and to understand the most important interactions that govern the stabilization of each isomer. Furthermore, an analysis of the atomic charge distribution using different population methodologies was also performed.

Crystal structure of 2-(4-chloro-benzamido)-benzoic acid.

In the title mol-ecule, C14H10ClNO3, the amide C=O bond is anti to the o-carb-oxy substituent in the adjacent benzene ring, a conformation that facilitates the formation of an intra-molecular amide-N-H⋯O(carbon-yl) hydrogen bond that closes an S(6) loop. The central amide segment is twisted away from the carb-oxy- and chloro-substituted benzene rings by 13.93 (17) and 15.26 (15)°, respectively. The most prominent supra-molecular inter-actions in the crystal packing are carb-oxy-lic acid-H⋯O(carbox-yl) hydrogen bonds that lead to centrosymmetric dimeric aggregates connected by eight-membered {⋯HOC=O}2 synthons.

Crystal structure of 2-fluoro-N-(1,3-thia-zol-2-yl)benzamide.

In the title compound, C10H7FN2OS, the mean plane of the central amide fragment (r.m.s. deviation = 0.048 Å) makes dihedral angles of 35.28 (8) and 10.14 (12)° with those of the fluoro-benzene and thia-zole rings, respectively. The thia-zole S and amide O atoms lie to the same side of the mol-ecule. In the crystal, pairs of N-H⋯N hydrogen bonds connect the mol-ecules into inversion dimers with R 2 (2)(8) motifs, and weak C-H⋯O inter-actions connect the mol-ecules into C(6) [001] chains. Together, the N-H⋯N and C-H⋯O hydrogen bonds generate (100) sheets.

Crystal structure of 3-chloro-N-(2-nitro-phen-yl)benzamide.

In the title compound, C13H9ClN2O3, the mean plane of the central amide fragment (r.m.s. deviation = 0.016 Å) subtends dihedral angles of 15.2 (2) and 8.2 (2)° with the chloro- and nitro-substituted benzene rings, respectively. An intra-molecular N-H⋯O hydrogen bond generates an S(6) ring. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen bonds, forming C(7) chains which propagate along [010], but no Cl⋯Cl short contacts are observed.

Crystal structure of 2-methyl-3-nitro-benzoic anhydride.

The title mol-ecule, C16H12N2O7, lies on a twofold rotation axis which bis-ects the central O atom. The dihedral angle between two symmetry-related benzene rings is 48.54 (9)°. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen bonds which generate C(13) chains running parallel to [31-1].

Crystal structure of 2-nitro-N-(2-nitro-phen-yl)benzamide.

In the title compound, C13H9N3O5, the mean plane of the non-H atoms of the central amide fragment C-N-C(=O)-C [r.m.s. deviation = 0.0442 Å] forms dihedral angles of 71.76 (6) and 24.29 (10)° with the C-bonded and N-bonded benzene rings, respectively. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds forming C(4) chains along [100]. Weak C-H⋯O contacts link the mol-ecules into (100) sheets containing edge-fused R 4 (4)(30) rings. Together, the N-H⋯O and C-H⋯O hydrogen bonds generate a three-dimensional network.

Crystal structure of 4-formyl-2-nitro-phenyl 4-chloro-2-nitro-benzoate.

In the title compound, C14H7ClN2O7, the central ester moiety is essentially planar, with an r.m.s. deviation of 0.0113 Å. The ester group is twisted away from the chloro- and formyl-substituted rings by 84.60 (9) and 88.55 (9)°, respectively. The crystal packing shows inter-molecular C-H⋯O inter-actions. These inter-actions generate R 2 (2)(20) and R 4 (4)(22) edge-fused rings parallel to (20-2).

Crystal structure of N-(2-hy-droxy-5-methyl-phen-yl)benzamide.

In the title compound, C14H13NO2, the mean plane of the non-H atoms of the central amide fragment C-N-C(=O)-C (r.m.s. deviation = 0.029 Å) forms dihedral angles of 5.63 (6) and 10.20 (5)° with the phenyl and hy-droxy-phenyl rings, respectively. A short intra-molecular N-H⋯O contact is present. In the crystal, the mol-ecules are linked by O-H⋯O hydrogen bonds to generate C(7) chains along [100]. The chains are reinforced by weak C-H⋯O contacts, which together with the O-H⋯O bonds lead to R 2 (2)(7) loops. Very weak N-H⋯O inter-actions link the mol-ecules into inversion dimers.

2-[(1-Oxidopyridin-4-yl)sulfan-yl]benzoic acid.

In the title compound, C12H9NO3S, the dihedral angle between the pyridine and benzene rings is 83.93 (7)°. In the crystal, pairs of O-H⋯O hydrogen bonds link the molecules, forming inversion dimers with graph-set notation R 2 (2)(22). These dimers are in turn linked by weak C-H⋯O hydrogen bonds along [100], forming R 2 (2)(8) rings.

2,4,6-Tri-nitro-phenyl 3-bromo-benzoate.

In the title picryl-substituted ester, C13H6BrN3O8, the mean plane of the central ester C-O-C(=O)-C fragment (r.m.s. deviation= 0.0186 Å) is rotated by 84.73 (7)° and 19.92 (12)° to the picryl and phenyl rings, respectively. In the crystal, the mol-ecules are linked by C-H⋯O inter-actions, forming centrosymmetric dimers enclosing R (2) 2(10) and R (2) 2(22) ring motifs along [001] and further helical chains of dimers enclosing R (2) 2(10) ring motifs along [010].

N-(2-Nitro-phen-yl)thio-phene-2-carbox-amide.

The title compound, C11H8N2O3S, shows two mol-ecules per asymmetric unit, with the dihedral angles between the benzene and thio-phene rings of 13.53 (6) and 8.50 (5)° being a notable difference between them. An intra-molecular N-H⋯O hydrogen-bond in each mol-ecule generates an S(6) ring motif. The crystal packing shows no classical hydrogen bonds with the mol-ecules being packed to form weak C-H⋯O and C-H⋯S inter-actions leading to R 2 (2)(9) and R 4 (4)(25) rings which are edge-shared, giving layers parallel to (010).

3-(Di-phenyl-amino)-isobenzo-furan-1(3H)-one.

In the title isobenzo-furan-one derivative, C20H15NO2, the planar fused-ring system (r.m.s. deviation for the 10 fitted atoms = 0.031 Å) forms dihedral angles of 63.58 (6) and 63.17 (8)° with the N-bound phenyl rings; the dihedral angle between the planes of these phenyl rings is 85.92 (7)°. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, involving both O atoms, forming helical supra-molecular chains along [001].

2,2'-(1,4-Phenyl-ene)bis-(propane-2,2-di-yl) bis-(benzodi-thio-ate).

The title compound, C26H26S4, shows a dihedral angle of 76.64 (15)° between the central and peripheral benzene rings. An inversion center is located at the centroid of the thio-benzoyl ring. In the crystal, weak C-H⋯S inter-actions form C(5) chains along [001]. There are no classical hydrogen bonds.

3,4-Di-methyl-phenyl benzoate.

In the title compound, C15H14O2, the terminal rings form a dihedral angle of 52.39 (4)°. The mean plane of the central ester group [r.m.s. deviation = 0.0488 Å] is twisted away from the benzene and phenyl rings by 60.10 (4) and 8.67 (9)°, respectively. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen bonds, forming C(6) chains which run along [100].

4-Formyl-2-nitro-phenyl benzoate.

In the title nitroaryl benzoate derivative, C14H9NO5, the aromatic rings form a dihedral angle of 46.37 (8)°. The central ester moiety, -C-(C=O)-O-, is essentially planar (r.m.s. deviation for all non-H atoms = 0.0283 Å) and forms a dihedral angle of 54.06 (9)° with the 4-formyl-2-nitro-phenyl ring and 7.99 (19)° with the benzoate ring. In the crystal, mol-ecules are inter-twined by weak C-H⋯O inter-actions, forming helical chains along [100].