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

Abstract Subtype-selective α 1 -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 1 -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 1D subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α 1B -AR (pA 2 7.13) with a poor selectivity for α 1A and α 1D subtypes. Compound 1 exhibited enhanced antagonistic effect on α 1D subtype (pA 2 7.06) and excellent selectivity for α 1D over α 1B (α 1D /α 1B ratio = 79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α 1 receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α 1D -selective antagonists.