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ACS Med Chem Lett. 2013 Oct 6;4(12):1178-82. doi: 10.1021/ml4002908. eCollection 2013 Dec 12.

Multifunctional cholinesterase and amyloid Beta fibrillization modulators. Synthesis and biological investigation.

Author information

1
European Research Centre for Drug Discovery and Development-NatSynDrugs and Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena , via Aldo Moro 2, 53100 Siena, Italy ; European Research Centre for Drug Discovery and Development-NatSynDrugs and Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena , via Aldo Moro 2, 53100 Siena, Italy.
2
Division of Biochemistry, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910 , United States.
3
Institute for Basic Research in Developmental Disabilities , Forest Hill Road, Staten Island, New York 10314, United States.
4
Dipartimento di Scienze del Farmaco, University of Pavia , viale Taramelli 12, 27100 Pavia, Italy.
5
Department of Pathology, Fondazione IRCCS, Policlinico S. Matteo and University of Pavia , 27100 Pavia, Italy.
6
Department of Pharmacy and Biotechnolgy, University of Bologna , via Belmeloro 6, 40126 Bologna, Italy.
7
Department for Life Quality Studies, University of Bologna , Corso di Augusto 237, 47900 Rimini, Italy.
8
European Research Centre for Drug Discovery and Development-NatSynDrugs and Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena , via Aldo Moro 2, 53100 Siena, Italy ; Dipartimento di Farmacia, University of Napoli Federico II , via D. Montesano 49, 80131 Napoli, Italy.

Abstract

In order to identify novel Alzheimer's modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (Aβ). Accordingly, compounds 2a-c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with Aβ aggregation and with the Aβ self-oligomerization process (2a). Compounds 2a-c in complex with TcAChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site. These moieties are likely responsible for the observed reduction of hAChE-induced Aβ aggregation since they physically hamper Aβ binding to the enzyme surface. Moreover, 2a was able to significantly interfere with Aβ self-oligomerization, while 2b,c showed improved inhibition of hAChE-induced Aβ aggregation.

KEYWORDS:

Alzheimer’s disease; Cholinesterase inhibitors; amyloid beta oligomers; amyloid beta-peptides; bivalent ligands; multifunctional tools

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