title: Design, synthesis, and pharmacological profile of novel fused pyrazolo[4,3-d]pyridine and pyrazolo[3,4-b][1,8]naphthyridine isosteres: a new class of potent and selective acetylcholinesterase inhibitors.
abstract: A new family of tacrine (THA) analogues (7-9, 12), containing the azaheterocyclic pyrazolo[4,3-d]pyridine or pyrazolo[3,4-b][1,8]naphthyridine systems as isosteres of the quinoline ring of THA, has been synthesized. The compounds were tested in rat brain cholinesterases using Ellman's method, and all were fully efficacious in inhibiting the enzymes. Compounds 9 and 12b were the most potent against acetylcholinesterase (AChE), showing IC(50) of 6.0 and 6.4 microM, and were less active against rat brain butyrylcholinesterase, showing selectivity indexes of 5.3 and 20.9, respectively. Compounds 7-9 and 12 were also tested for their acute neurotoxicity in vitro, using cultured rat cortical cells. Compounds 7 and 8 were not significantly toxic; 9 was toxic at 500 microM, but not at 100 microM. The naphthyridine derivatives 12a and 12b showed a significant concentration-dependent neurotoxicity, being able to kill most cells at 500 microM. Molecular dynamic simulation using the X-ray crystal structure of AChE from Torpedo californica was used to explain the possible binding mode of these new THA isosteres.
authors.affiliation: Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, C. P. 68.006, 21944-910, Rio de Janeiro, RJ, Brazil. eliezer@ufrj.br
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Celso A
authors.initials: CA
authors.lastname: Camara
authors.forename: Hugo
authors.initials: H
authors.lastname: Verli
authors.forename: Leonora
authors.initials: L
authors.lastname: Brazil-Más
authors.forename: Newton G
authors.initials: NG
authors.lastname: Castro
authors.forename: Wagner M
authors.initials: WM
authors.lastname: Cintra
authors.forename: Yasco
authors.initials: Y
authors.lastname: Aracava
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014101:Torpedo
chemical_list: D002800:Cholinesterase Inhibitors; D009287:Naphthyridines; D018696:Neuroprotective Agents; D011720:Pyrazoles; D011725:Pyridines; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase