title: Structure-Based Design of Novel Tetrahydro-Beta-Carboline Derivatives with a Hydrophilic Side Chain as Potential Phosphodiesterase Inhibitors.
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 the6R,12aRisomer 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 theSconfiguration.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. ahmed.elhady@guc.edu.eg.
authors.forename: Ahmed K
authors.initials: AK
authors.lastname: Elhady
authors.affiliation: Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36608, USA. sara_sigler@hotmail.com.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Sigler
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. nazih.noureldin@guc.edu.eg.
authors.forename: Nazih
authors.initials: N
authors.lastname: Noureldin
authors.affiliation: Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36608, USA. jcanzoneri@adtpharma.com.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Canzoneri
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. nermin.salah@guc.edu.eg.
authors.forename: Nermin S
authors.initials: NS
authors.lastname: Ahmed
authors.affiliation: Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36608, USA. gpiazza@health.southalabama.edu.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. ashraf.abadi@guc.edu.eg.
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
keywords: Terahydro-beta-carboline; phosphodiesterase 5 inhibitors; stereochemistry; structure-based design