Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds.
The complex etiology of Alzheimer's disease (AD) prompts scientists to develop multifunctional compounds to combat causes and symptoms of such neurodegeneration. To this aim we designed, synthesized, and tested a series of compounds by introducing halophenylalkylamidic functions on the scaffold of AP2238, which is a dual binding site acetylcholinesterase inhibitor. The inhibitory activity was successfully extended to the beta-site amyloid precursor protein cleavage enzyme, leading to the discovery of a potent inhibitor of this enzyme (3) and affording multifunctional compounds (2, 6, 8) for the treatment of AD.
Piazzi
Lorna
L
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. lorna.piazzi@unibo.it
Cavalli
Andrea
A
Colizzi
Francesco
F
Belluti
Federica
F
Bartolini
Manuela
M
Mancini
Francesca
F
Recanatini
Maurizio
M
Andrisano
Vincenza
V
Rampa
Angela
A
D000544:Alzheimer Disease / Q000188:drug therapy*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000577:Amides; D002800:Cholinesterase Inhibitors; D003374:Coumarins; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human