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Multi-target-directed ligands in design and discovery of potential drugs for Alzheimer’s disease

Barbara Malawska ,  Marek Bajda 

Jagiellonian University, Medical College, Department of Physicochemical Drug Analysis, Medyczna 9, Kraków 30-688, Poland

Abstract

Among the various drug discovery methods, a very promising modern approach relies on designing multiple ligands (DMLs). This methodology has been developed especially for drugs aimed at treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer’s disease (AD), currently the most common multi-factorial neurodegenerative disease. The physiopathology of AD is complex and still eludes full understanding. Severe neuron and synapse loss, formation of intracellular fibrils of polymerized tau protein and extracellular β-amyloid (Aβ) deposits are prominent in AD. In addition, there is some evidence pointing to the role of oxidative stress, metal ion disregulation, inflammation and cell cycle regulatory failure in AD pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease requires multi-target-directed compounds, which can be beneficial for AD treatment. Successful outcomes of applying the multi-target-directed ligand methodology will be presented. These include examples of new compounds obtained via combination of structurally active moieties interacting with different targets. Our study concerned on the synthesis and investigation of new hybrid molecules bearing two moieties: 1-benzylpiperidino-4-amino group and heterocyclic rings linked by alkyl chain as potential AChE dual binding site and (butyrylcholinesterase) BuChE inhibitors. Cholinesterases exert secondary functions among which the mediating the processing and deposition of Aβ peptide seems to be crucial for the development of the AD. Identification of the peripheral anionic binding site of AChE as a fragment responsible for binding with Aβ and resulting fibrillogenesis caused the interest in synthesis of dual binding site AChE inhibitors.

 

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Related papers

Presentation: Oral at VII Multidyscyplinarna Konferencja Nauki o Leku, by Barbara Malawska
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2010-03-09 13:59
Revised:   2010-03-09 14:22