Molecular design and synthesis of 1,4-disubstituted piperazines as α1-adrenergic receptor blockers

• Thieno[2,3-c]pyridines and thieno[2,3-d]pyrimidines were designed and synthesized.
• A pharmacophore model for the α1-ARs antagonists was generated and validated.
• Active hits were tested for their α1-ARs antagonistic activity on isolated rat aorta.
• Compounds IVb, IVc, VIb, Xb, Xia and XIb showed comparable activity to prazosin.

A new series of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid amide and 3,5,6,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one derivatives were designed, synthesized, their binding and functional properties as α1-adrenoreceptors blockers were evaluated. A new validated α1-adrenoreceptor blocker pharmacophore model (hypothesis) was generated using Discovery Studio 2.5. The compare-fit study for the designed molecules with the generated hypothesis was fulfilled and several compounds showed significant high fit values. Compounds IVa–c, VIIa–d, VIIIa–c, Xa–c, XIa–d have shown blocking activity ranging from 46.73% up to 94.74% compared to 99.17% for prazosin.

Compound XIb mapped to α1-AR antagonists pharmacophore and exhibited 94.74 inhibitory activity.Figure optionsDownload as PowerPoint slide