Download [1]Bolognesi, ML Polypharmacology in a single drug: multitarget

Multi-target-directed ligands in Alzheimer's disease treatment
Sarah Sameza,b, Alessandro Pesaresia, Manuela Bartolinic, Xiaoming Zhad, Maria Laura Bolognesic and
Doriano Lambaa
a
Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park - Basovizza, S.S. 14 - Km 163.5, I-34149
Trieste, Italy
b
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, Via L. Giorgieri 1, I-34127 Trieste, Italy
c
Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Belmeloro 6, I-40126
Bologna, Italy
d
Jiangsu Center for Drug Screening, China Pharmaceutical University, 210009 Nanjing, P.R. China
Among the various drug discovery methods, a very promising modern approach consists in designing multitarget-directed ligands (MTDLs). This methodology has been specifically developed for treatment of
disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently
the most common multifactorial neurodegenerative disease. AD is related to increased levels of the
amyloid β peptide (Aβ) and the hyperphosphorylated tau protein, along with loss of neurons and synapses.
Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation,
inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the
development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed
compounds which can be beneficial for AD treatment. We report on the structure-activity relationships of
two novel multitarget anti-Alzheimer compounds designed by combining a tacrine fragment and a juglone
(I) [2] or benzofuran (II) function respectively with a linker of a suitable length. In vitro, both compounds
displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block
amyloid-βaggregation. The X-ray analysis of the Torpedo californica AChE – inhibitor complexes allowed a
structure-based rationale for the outstanding activity data.
[1]Bolognesi, M. L. Polypharmacology in a single drug: multitarget drugs. Curr. Med. Chem. 2013, 20, 1639-1645.
[2]Nepovimova E, Uliassi E, Korabecny J, Peña-Altamira LE, Samez S, Pesaresi A, Garcia GE, Bartolini M, Andrisano V,
Bergamini C, Fato R, Lamba D, Roberti M, Kuca K, Monti B, Bolognesi ML. Multitarget drug design strategy: quinone-tacrine
hybrids designed to block amyloid-beta aggregation and to exert anticholinesterase and antioxidant effects. J. Med. Chem.
2014, DOI: 10.1021/jm5010804