title: Synthesis, biological evaluation, and molecular modeling of new 3-(cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) Oxime (GEBR-7b) related phosphodiesterase 4D (PDE4D) inhibitors.
abstract: A new series of 3-(cyclopentyloxy)-4-methoxyphenyl derivatives, structurally related to our hit GEBR-4a (1) and GEBR-7b (2), has been designed by changing length and functionality of the chain linking the catecholic moiety to the terminal cycloamine portion. Among the numerous molecules synthesized, compounds 8, 10a, and 10b showed increased potency as PDE4D enzyme inhibitors with respect to 2 and a good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, without both cytotoxic and genotoxic effects. The ability to enhance cAMP level in neuronal cells was assessed for compound 8. SAR considerations, also confirmed by in silico docking simulations, evidenced that both chain and amino terminal function characterized by higher hydrophilicity are required for a good and selective inhibitor-catalytic pocket interaction.
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa , Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.forename: Matteo
authors.initials: M
authors.lastname: Massa
authors.forename: Massimo
authors.initials: M
authors.lastname: Rocca
authors.forename: Chiara
authors.initials: C
authors.lastname: Rotolo
authors.forename: Sara
authors.initials: S
authors.lastname: Guariento
authors.forename: Daniela
authors.initials: D
authors.lastname: Rivera
authors.forename: Roberta
authors.initials: R
authors.lastname: Ricciarelli
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fedele
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
mesh_terms: D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007097:Imines / Q000737:chemistry*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009025:Morpholines / Q000737:chemistry*; D009474:Neurons / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C570687:GEBR-7b; D007097:Imines; D009025:Morpholines; D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517355:PDE4A protein, human; C517360:PDE4B protein, human; C517361:PDE4C protein, human; C517376:PDE4D protein, human