title: Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives.
abstract: The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1-6, by Friedländer-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1-6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H-benzo[b]pyrazolo[4,3-g][1,8]naphthyridin-3-yl)acetamide (5) [IC(50) (EeAChE) = 0.069 ± 0.006 μM; IC(50) (eqBuChE) = 6.3 ± 0.6 μM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K(i) = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences, UL, Faculty of Pharmacy, University of Lisbon, Av Prof Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Silva
authors.forename: Mourad
authors.initials: M
authors.lastname: Chioua
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: M
authors.initials: M
authors.lastname: Carmo Carreiras
authors.forename: María-Luisa
authors.initials: ML
authors.lastname: Jimeno
authors.forename: Eduarda
authors.initials: E
authors.lastname: Mendes
authors.forename: Cristóbal de Los
authors.initials: Cde L
authors.lastname: Ríos
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006736:Horses; D020128:Inhibitory Concentration 50; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D011720:Pyrazoles