title: Synthesis, Molecular Modeling, and Biological Evaluation of Novel Tetrahydro-β-Carboline Hydantoin and Tetrahydro-β-Carboline Thiohydantoin Derivatives as Phosphodiesterase 5 Inhibitors.
abstract: Two series of fused tetrahydro-β-carboline hydantoin and tetrahydro-β-carboline thiohydantoin derivatives with a pendant 2,4-dimethoxyphenyl at position 5 were synthesized, and chiral carbons at positions 5 and 11a swing from R,R to R,S, S,R, and S,S. The prepared analogues were evaluated for their capacity to inhibit phosphodiesterase 5 (PDE5) isozyme. The R absolute configuration of C-5 in the β-carboline hydantoin derivatives was found to be essential for the PDE5 inhibition. Chiral carbon derived from amino acid even if of the S configuration (L-tryptophan) may lead to equiactive or more active isomers than those derived from amino acid with the R configuration (D-tryptophan). This expands the horizon from which efficient PDE5 inhibitors can be derived and may offer an economic advantage. The thiohydantoin derivatives were less active than their hydantoin congeners.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical/Medicinal Chemistry, Friedrich-Schiller University, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: Division of Drug Discovery, Department of Biochemistry and Molecular Biology, Southern Research Institute, The University of Alabama at Birmingham, 2000 Ninth Avenue South, Birmingham, AL 35205, USA.
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.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abdel-Halim
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
authors.forename: Mohamed S M
authors.initials: MS
authors.lastname: Ali