Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives

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 Friedlander-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) [IC50 (EeAChE) = 0.069 +/- 0.006 mu M; IC50 (eqBuChE) = 6.3 +/- 0.6 mu M]. 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. (C) 2011 Elsevier Masson SAS. All rights reserved.