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.