Structure-Based Design of Novel Tetrahydro-Beta-Carboline Derivatives with a Hydrophilic Side Chain as Potential
Ahmed K Elhady1, Sara C Sigler2, Nazih Noureldin3
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. ahmed.elhady@guc.edu.eg.
Abstract:
Tadalafil is a clinically approved phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction and pulmonary arterial hypertension. It contains two chiral carbons, and the marketed isomer is the 6R, 12aR isomer with a methyl substituent on the terminal nitrogen of the piperazinedione ring. In this report, tadalafil analogues with an extended hydrophilic side chain on the piperazine nitrogen were designed to interact with particular hydrophilic residues in the binding pocket. This leads to analogues with moderate inhibitory activity on phosphodiesterase-5, even for isomers in which chiral carbons are of the S configuration.
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