Design, synthesis, crystal structure, biological evaluation and molecular docking studies of carbazole-arylpiperazine derivatives.

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.