Indole-arylpiperazine derivatives have exhibited good selectivity for the α 1A -adrenoceptor, but the structure-activity-binding mechanism relationship remains unclear. In the current study, three compounds (1, 2 and 3) were investigated through single-crystal X-ray diffraction analysis, density functional theory (DFT) calculations and molecular docking using a homology model of the α 1A receptor. Compounds 1 and 3 form H-bonds networks to stabilize their three-dimensional structures, while C-H¨¨¨π interactions play a significant role in the packing of 2. Based on DFT-optimized conformations, the HOMO-LUMO energy gaps and molecular electrostatic potential (MEP) were theoretically calculated at the B3LYP/6-311G (d, p) level of theory. Chemical reactivity increases in the order of 3 < 2 < 1, and the maximum positive region of the MEP maps is mainly localized over the NH group. The binding mechanisms of ligand-α 1A -adrenoceptor complexes were illustrated by molecular docking. Binding to Gln177 of the second extracellular loop region via hydrogen bonds is likely to be essential for α 1A-selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of α 1A antagonists with high selectivity.

Subtype-selective α-adrenoceptor (AR) antagonists display optimum therapeutic efficacies for the treatment of benign prostatic hyperplasia (BPH). In this study, we designed and synthesized novel carbazole-arylpiperazines derivatives (1 and 2) on the basis of the proposed pharmacophore model for α-AR antagonists. Structural properties were investigated using single-crystal X-ray diffraction analysis. Comparison of crystal structures with ligand-based pharmacophore models revealed that the two agents may possess antagonistic effects on α subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α-AR (pA 7.13) with a poor selectivity for α and α subtypes. Compound 1 exhibited enhanced antagonistic effect on α subtype (pA 7.06) and excellent selectivity for α over α (α/α ratio=79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α-selective antagonists.

No abstract

A series of novel arylpiperazine derivatives was synthesized. The in vitro cytotoxic activities of all synthesized compounds against three human prostate cancer cell lines (PC-3, LNCaP, and DU145) were evaluated by a CCK-8 assay. Compounds 8, 10, 13, 17, and 20 exhibited strong cytotoxic activities against the tested cancer cell lines (IC 50 <3 μmol/L). In addition, these compounds exhibited weak cytotoxic effects on human epithelial prostate normal cells WPMY-1. The structure-activity relationship (SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data.

No abstract