Multitarget Strategy to Address Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and Computational Studies of Coumarin-Based Derivatives.
Alzheimer's disease (AD) is a major public health challenge that faces an aging global population. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease-modifying therapies. Following the multitarget-directed ligand approach, a small library of coumarin-based derivatives was designed and synthesized as a follow-up to our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern at the 6- or 7-position was modified by introducing alkyl chains of variable lengths and with different terminal amino functional groups. 3-(4-{[Benzyl(ethyl)amino]methyl}phenyl)-6-({5-[(7-methoxy-6H-indeno[2,1-b]quinolin-11-yl)amino]pentyl}oxy)-2H-chromen-2-one, bearing the bulkiest amine, emerged as a non-neurotoxic dual acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitor, potentially suitable for the treatment of the middle stage of AD. Furthermore, the introduction of a diethylamino spacer, as in 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-6-{[5-(diethylamino)pentyl]oxy}-2H-chromen-2-one and 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one, led to nanomolar human AChE inhibitors endowed with significant inhibitory activity toward Aβ42 self-aggregation, whereas the reference compound was completely ineffective. Furthermore, 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one also showed promising neuroprotective behavior, which makes it a potential candidate for development into a disease-modifying agent.
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Serena
S
Montanari
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Manuela
M
Bartolini
Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy.
Paolo
P
Neviani
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Federica
F
Belluti
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Silvia
S
Gobbi
Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy.
Letizia
L
Pruccoli
Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy.
Andrea
A
Tarozzi
CompuNet, Italian Institute of Technology, via Morego 30, 16163, Genova, Italy.
Federico
F
Falchi
Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy.
Vincenza
V
Andrisano
Faculty of Chemistry, Biological & Chemical Research Centre, University of Warsaw, Pasteura 1, 02093, Warsaw, Poland.
Przemysław
P
Miszta
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.|CompuNet, Italian Institute of Technology, via Morego 30, 16163, Genova, Italy.
Andrea
A
Cavalli
Faculty of Chemistry, Biological & Chemical Research Centre, University of Warsaw, Pasteura 1, 02093, Warsaw, Poland.
Sławomir
S
Filipek
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Alessandra
A
Bisi
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. angela.rampa@unibo.it.
Angela
A
Rampa
D000110:Acetylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D001596:Benzylamines / Q000737:chemistry / Q000627:therapeutic use; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
C475423:AP 2238; D016229:Amyloid beta-Peptides; D001596:Benzylamines; D002800:Cholinesterase Inhibitors; D003374:Coumarins; D008024:Ligands; D010446:Peptide Fragments; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
Alzheimer's disease; coumarins; cytotoxicity; inhibitors; multitarget-directed ligands