title: Towards new neuroprotective agents: design and synthesis of 4H-thieno[2,3-c] isoquinolin-5-one derivatives as potent PARP-1 inhibitors.
abstract: An excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme able to catalyze the transfer of ADP-ribose from NAD to acceptor proteins, is involved in the progression of neuronal damage after brain insult. Potent and selective PARP-1 inhibitors have neuroprotective properties in experimental models of brain ischemia. As a follow up of our previous structure-activity relationship study and in search for novel potent PARP-1 inhibitors, a series of 4H-thieno[2,3-c]-isoquinolin-5-one derivatives was designed and synthesized. Tested for their ability to inhibit PARP-1, these novel derivatives showed high inhibitory potency. The unsubstituted derivative TIQ was selected for further characterization and found to be endowed with strong neuroprotective properties in models of cerebral ischemia.
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000209:etiology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020768:Middle Cerebral Artery; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry; D051381:Rats; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013876:Thiophenes; C475227:thieno(2,3-c)isoquinolin-5-one; D011065:Poly(ADP-ribose) Polymerases