Design, synthesis, crystal structure, biological evaluation and molecular docking studies of carbazole-arylpiperazine derivatives.
Subtype-selective α1-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 α1-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 α1Dsubtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α1B-AR (pA27.13) with a poor selectivity for α1Aand α1Dsubtypes. Compound 1 exhibited enhanced antagonistic effect on α1Dsubtype (pA27.06) and excellent selectivity for α1Dover α1B(α1D/α1Bratio=79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α1receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α1D-selective antagonists.
School of Pharmaceutical Sciences, Jinan University, Guangzhou 510632, China.
Wei
W
Xu
Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China.
Junjun
J
Huang
Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China.
Binhao
B
Shao
Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China.
Xingjie
X
Xu
School of Pharmaceutical Sciences, Jinan University, Guangzhou 510632, China. Electronic address: rwjiang2008@126.com.
Renwang
R
Jiang
Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China. Electronic address: mryuanmu838@sina.com.
Mu
M
Yuan
D018674:Adrenergic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D018674:Adrenergic Antagonists; D002227:Carbazoles; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; C041514:carbazole
Arylpiperazine; Molecular docking; Pharmacophore model; X-ray crystallography; α(1)-Adrenoceptor antagonists