Plenary Lecture 3

Title: Navigating the chemical Space of multitarget-directed ligands:
From hybrids to fragments in alzheimer’s disease

Professor Maria Laura Bolognesi

University of Bologna, Italy


Lecture Summary: Boomed in the 2000,1 multitarget drug discovery is still one of the hottest topics and most active research areas in neurodegenerative diseases and, particularly, in Alzheimer’s disease (AD). All of the evidence we have accumulated so far corroborates the initial conviction that modulating multiple networked targets with a single chemical entity is an asset in treating a complex disorder of the elderly, such as AD. On this basis, multitarget ligands directed at molecular targets intertwined in the AD pathogenic cascade have been increasingly sought after in the last two decades. Many new hits have been identified, some have been evaluated as pre-clinical leads, however, none have so far reached clinical trials. Indeed, how to design high-quality hit and lead compounds, with a high level of clinical developability, is still a formidable challenge to medicinal chemists. This is mainly due to the still unsolved question of achieving a balanced activity at the selected multiple targets, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are at the extremes, with their particular pros and cons.2 In this presentation, my aim is to provide an overview on what we have recently accomplished in the development of both hybrid- and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, oxidative stress, metal chelation, BACE-1 and GSK-3β).3-5 In addition, I will attempt to identify the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL from bench to bedside.


Acknowledgments: MLB thanks MIUR and University of Bologna for the financial support. MLB is supported by a grant of Visiting Professor (PVE–CNPq #401864/2013-8) from the programme “Ciência sem Fronteiras”, Brazil.


References: [1] Cavalli, A.; Bolognesi, M. L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. J Med Chem 2008, 51, 347-72.

2 Prati F.; Cavalli A.; Bolognesi, M.L. Molecules 2016, 21, pii: E466.

3 Prati, F.; De Simone, A.; Bisignano, P.; Armirotti, A.; Summa, M.; Pizzirani, D.; Scarpelli, R.; Perez, D. I.; Andrisano, V.; Perez-Castillo, A.; Monti, B.; Massenzio, F.; Polito, L.; Racchi, M.; Favia, A. D.; Bottegoni, G.; Martinez, A.; Bolognesi, M. L.*; Cavalli, A. Multitarget drug discovery for Alzheimer's disease: triazinones as BACE-1 and GSK-3β inhibitors. Angew Chem Int Ed Engl 2015, 54, 1578-1582.

4 Prati, F.; Bergamini, C.; Fato, R.; Soukup, O.; Korábečný, J.; Andrisano, V.; Bartolini, M.; Bolognesi, M.L. Novel 8-Hydroxyquinoline Derivatives as Multitarget Compounds for the Treatment of Alzheimer's Disease. ChemMedChem 2016, 11, 1284-1295.

5 Prati, F.; De Simone, A.; Armirotti, A.; Summa, M.; Pizzirani, D.; Scarpelli, R.; Bertozzi, S. M.; Perez, D. I.; Andrisano, V.; Perez-Castillo, A.; Monti, B.; Massenzio, F.; Polito, L.; Racchi, M.; Sabatino, P.; Bottegoni, G.; Martinez, A.; Cavalli, A.; Bolognesi, M. L. ACS Chem Neurosci 2015, 6, 1665-1682.