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

Subtype-selective alpha(1)-adrenoceptor (AR) antagonists display optimum therapeutic efficacies for the treatment of benign prostatic hyperplasia (BPH). In this study, we designed and synthesized novel carbazolearylpiperazines derivatives (1 and 2) on the basis of the proposed pharmacophore model for alpha(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 alpha(1D) subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on alpha(1B)-AR (pA(2) 7.13) with a poor selectivity for alpha(1A) and alpha(1D) subtypes. Compound 1 exhibited enhanced antagonistic effect on a(1D) subtype (pA(2) 7.06) and excellent selectivity for alpha(1D) over alpha(1B) (alpha(1D)/alpha(1B) ratio = 79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of alpha(1) receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of alpha(1D)-selective antagonists. (C) 2016 Elsevier Ltd. All rights reserved.