Synthesis, inhibitory activity of cholinesterases, and neuroprotective profile of novel 1,8-naphthyridine derivatives.
1,8-Naphthyridine derivatives related to 17 (ITH4012), a neuroprotective compound reported by our research group, have been synthesized. In general, they have shown better inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) than most tacrine derivatives previously synthesized in our laboratory. The compounds presented an interesting neuroprotective profile in SH-SY5Y neuroblastoma cells stressed with rotenone/oligomycin A. Moreover, compound 14 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) also caused protection in cells stressed with okadaic acid (OA) or amyloid beta 1-42 peptide (Abeta(1-42)). Interestingly, compound 14 prevented the OA-induced PP2A inhibition, one of the enzymes implicated in tau dephosphorylation. This compound also exhibited neuroprotection against neurotoxicity elicited by oxygen and glucose deprivation in hippocampal slices. Because these stressors caused neuronal damage related to physiopathological hallmarks found in the brain of Alzheimer's disease (AD) patients, we conclude that compound 14 deserves further in vivo studies in AD models to test its therapeutic potential in this disease.
de Los Ríos
Cristóbal
C
Departamento de Farmacologia y Terapeutica, Facultad de Medicina, Instituto Teofilo Hernando, Universidad Autonoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain. cristobal.delosrios@uam.es
Egea
Javier
J
Marco-Contelles
José
J
León
Rafael
R
Samadi
Abdelouahid
A
Iriepa
Isabel
I
Moraleda
Ignacio
I
Gálvez
Enrique
E
García
Antonio G
AG
López
Manuela G
MG
Villarroya
Mercedes
M
Romero
Alejandro
A
D000110:Acetylcholinesterase / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry; D002118:Calcium / Q000378:metabolism; D020134:Catalytic Domain; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003603:Cytotoxins / Q000494:pharmacology; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors; D004593:Electrophorus; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007536:Isomerism; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D009840:Oligomycins / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D003603:Cytotoxins; D045222:Electron Transport Chain Complex Proteins; D009287:Naphthyridines; D018696:Neuroprotective Agents; D009840:Oligomycins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C551006:ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo(b)(1,8)naphthyridine-3-carboxylate; D012402:Rotenone; C031004:oligomycin A; D019319:Okadaic Acid; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D054648:Protein Phosphatase 2; D005947:Glucose; D010100:Oxygen; D002118:Calcium