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 CHBrNO. 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.