Structural determinants influencing halogen bonding: a case study on azinesulfonamide analogs of aripiprazole as 5-HT(1A), 5-HT(7), and D(2) receptor ligands.

A series of azinesulfonamide derivatives of long-chain arylpiperazines with variable-length alkylene spacers between sulfonamide and 4-arylpiperazine moiety is designed, synthesized, and biologically evaluated. In vitro methods are used to determine their affinity for serotonin 5-HT(1A), 5-HT(6), 5-HT(7), and dopamine D(2) receptors. X-ray analysis, two-dimensional NMR conformational studies, and docking into the 5-HT(1A) and 5-HT(7) receptor models are then conducted to investigate the conformational preferences of selected serotonin receptor ligands in different environments. The bent conformation of tetramethylene derivatives is found in a solid state, in dimethyl sulfoxide, and as a global energy minimum during conformational analysis in a simulated water environment. Furthermore, ligand geometry in top-scored complexes is also bent, with one torsion angle in the spacer (τ(2)) in synclinal conformation. Molecular docking studies indicate the role of halogen bonding in complexes of the most potent ligands and target receptors.