Rational Design, Synthesis, Biological Evaluation, Homology and Docking Studies of Coumarin Derivatives as α1-Adrenoceptor Antagonists

According to a three-point pharmacophore for some uro-selective alpha(1)-adrenoceptor (AR) antagonists, a novel class of coumarin (=2H-1-benzopyran-2-one) derivatives have been successfully designed and synthesized with high efficacies for alpha(1)-AR. These synthesized coumarin derivatives exhibited high efficacies towards alpha(1)-AR in in vitro pharmacological assays. Compared with prazosin (pK(i) value of 8.77), among those coumarins, tolylpiperazine-substituted derivatives, 7 and 8, have comparable pK(i) values of 8.81 and 8.77, respectively. The trend in efficacies of these coumarin derivatives towards alpha(1A)-adrenoceptor was further rationalized by intensive molecular docking. Our work demonstrated that the designed coumarin derivatives can inhibit alpha(1)-AR in vitro. These findings will provide a guide for further studies of the medical therapy of benign prostatic hyperplasia (BPH).