title: Design and Synthesis of Substituted Pyridazinone-1-Acetylhydrazones as Novel Phosphodiesterase 4 Inhibitors.
abstract: A series of novel pyridazin-6-one-1-acetylhydrazone hybrids were rationally designed to inhibit phosphodiesterase 4 (PDE4B). The prepared compounds were evaluated for their in vitro ability to inhibit the PDE4B enzyme; several of these compounds showed moderate activity compared to the reference drug, rolipram. Compounds 6, 12, and 14 emerged as the most potent inhibitors in this series. The [3-(4-methoxyphenyl)-6-oxo-5,6-dihydro-4H-pyridazin-1-yl]acetic acid [1-(3,4,5-trimethoxyphenyl)ethylidene]hydrazide (12) showed an IC50 value of 13 μM against PDE4B. Docking of 6, 12, and 14 into the active site of PDE4B illustrates their possible binding mode and provides insights for further optimization of this drug scaffold.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt.
authors.forename: Hamdy M
authors.initials: HM
authors.lastname: Abdel-Rahman
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdel-Aziz
authors.affiliation: Department of Biology, Chemistry and Mathematics, University of Montevallo, Montevallo, AL, USA.
authors.forename: Heather N
authors.initials: HN
authors.lastname: Tinsley
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Gary
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Canzoneri
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
mesh_terms: D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry*; D062105:Molecular Docking Simulation; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: C000613234:(3-(4-methoxyphenyl)-6-oxo-5,6-dihydro-4H-pyridazin-1-yl)acetic acid (1-(3,4,5-trimethoxyphenyl)ethylidene)hydrazide; D006835:Hydrazones; D058988:Phosphodiesterase 4 Inhibitors; D011724:Pyridazines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: Docking; N-Acylhydrazones; PDE4B inhibitors; Pyridazinones