title: Multifunctional cholinesterase and amyloid Beta fibrillization modulators. Synthesis and biological investigation.
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.
authors.affiliation: 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.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.affiliation: 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.
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.affiliation: 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.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.affiliation: 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.
authors.forename: Samuele
authors.initials: S
authors.lastname: Maramai
authors.affiliation: 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.
authors.forename: Egeria
authors.initials: E
authors.lastname: Guarino
authors.affiliation: 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.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Panico
authors.affiliation: Division of Biochemistry, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910 , United States.
authors.forename: Ashima
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Institute for Basic Research in Developmental Disabilities , Forest Hill Road, Staten Island, New York 10314, United States.
authors.forename: Ved
authors.initials: V
authors.lastname: Chauhan
authors.affiliation: Dipartimento di Scienze del Farmaco, University of Pavia , viale Taramelli 12, 27100 Pavia, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Colombo
authors.affiliation: Department of Pathology, Fondazione IRCCS, Policlinico S. Matteo and University of Pavia , 27100 Pavia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Verga
authors.affiliation: Dipartimento di Scienze del Farmaco, University of Pavia , viale Taramelli 12, 27100 Pavia, Italy.
authors.forename: Ersilia
authors.initials: E
authors.lastname: De Lorenzi
authors.affiliation: Department of Pharmacy and Biotechnolgy, University of Bologna , via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.affiliation: Department for Life Quality Studies, University of Bologna , Corso di Augusto 237, 47900 Rimini, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.affiliation: 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.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: 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.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
keywords: Alzheimer’s disease; Cholinesterase inhibitors; amyloid beta oligomers; amyloid beta-peptides; bivalent ligands; multifunctional tools