title: New one-pot synthesis of N-fused isoquinoline derivatives by palladium-catalyzed C-H arylation: potent inhibitors of nucleotide pyrophosphatase-1 and -3.
abstract: Various N-fused isoquinoline derivatives were synthesized using a new one-pot reaction of 1-bromo-2-(2,2-difluorovinyl)benzenes with N-H group containing heterocycles followed by intramolecular palladium-catalyzed C-H arylation. The method described gives convenient access to diverse structures of N-fused polycyclic isoquinolines. Sixteen of the synthesized compounds were screened as potential human nucleotide pyrophosphatase/phosphodiesterase 1 and 3 (h-NPP-1 and h-NPP-3) inhibitors. The most effective h-NPP-1 inhibitor showed an IC50value as high as 0.36 ± 0.06 μM, whereas the most potent h-NPP-3 inhibitor posessed an inhibitory value of 0.48 ± 0.01 μM. Kinetic and molecular docking studies of both most effective inhibitors were carried out.
authors.affiliation: Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany. peter.langer@uni-rostock.de.
authors.forename: Elina
authors.initials: E
authors.lastname: Ausekle
authors.forename: Syeda Abida
authors.initials: SA
authors.lastname: Ejaz
authors.forename: Shafi Ullah
authors.initials: SU
authors.lastname: Khan
authors.forename: Peter
authors.initials: P
authors.lastname: Ehlers
authors.forename: Alexander
authors.initials: A
authors.lastname: Villinger
authors.forename: Joanna
authors.initials: J
authors.lastname: Lecka
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.forename: Jamshed
authors.initials: J
authors.lastname: Iqbal
authors.forename: Peter
authors.initials: P
authors.lastname: Langer
mesh_terms: D002384:Catalysis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D010165:Palladium; D011755:Pyrophosphatases; C021899:nucleotide pyrophosphatase; C039109:isoquinoline