COST Chemistry Action D34 ‘Molecular Targeting
and Drug Design in Neurological and Bacterial
Diseases'
-
1
Universite Catholique de Louvain, Belgium
COST Chemistry Action D34 ‘Molecular Targeting and Drug Design in Neurological and Bacterial Diseases’ can be considered as two independent activities, which are both characterized by a synthetic approach to the design of new candidate drugs and their subsequent biological evaluation. The first is focused on drug targeting in bacterial diseases, while the second, focused on drug targeting in neurological diseases, is represented by three Working Groups, D34/0003, 0005 and 0006, coordinated by Mercedes Unzeta (Barcelona), Roberta Ward (Louvain-la-Neuve) and Robert Crichton (Louvain-la-Neuve). Neurodegenerative diseases, are a major cause of concern, and are expected to affect more and more of our increasingly ageing population. There is a growing consensus that they are caused by ROS (reactive oxygen species) generated in specific regions of the brain, often catalyzed by redox-active transition metal ions.
D34/0003 aims to design and synthesize novel polyfunctional compounds based on a propargylamine structure and to validate them biologically in experimental models of neurodegenerative diseases. A number of bifunctional inhibitors of monoamine oxidase and acetylcholinesterase (Figure 1) have been tested for their inhibition of MAOA and MAOB and of AChE and BuChE. Compounds of the furo- and pyrroloquinone class and furo- and pyrrolopyridine class as well as a series of oxazole, furan and pyrrole derivatives have also been tested.
WG D34/0005 has evaluated specific taurine analogues (Figure 2), which are able to traverse cell membranes independently of the taurine transporter and exert greater antiinflammatory action within the cell than taurine at a comparable dose. Two families of taurine and homotaurine analogues have been investigated in vivo and in vitro for their antiinflammatory action: the 1,4-dihydropyridine derivatives tauropyrone, and homotauropyrone, and the β− and γ−sultams. Upon hydrolysis they yield taurine and homotaurine. In addition the N-acetyl derivatives of the sultams have been studied. These should have enhanced penetration of the blood brain barrier and an increased rate at which the prodrug is hydrolysed to release its active form within the cell.
D34/0006 develops targeted chelators (Figure 3) to protect against oxidative stress in animal and cellular models of neurological diseases. New classes of iron and copper chelators and iron biosensors are synthesized and their metal binding capacity determined by physicochemical techniques. The chelators are then tested in vitro using neuromelanin, and in vivo for their protection against oxidative stress in cultured macrophages and glial cells using the 6-hydroxydopamine animal model of Parkinson’s disease. Proof of concept that two commercially available iron chelators can effectively cross the blood-brain barrier has been established
Extensive collaboration between D34/0005 and D34/0006 has resulted in a reliable assay for highly reactive oxygen species which has been validated during in vivo microdialysis, In further collaboration between the two WGs, an elegant rat model of inflammatory-induced neurotoxicity has been produced by ‘binge drinking’ of ethanol, mimicking the weekend paralytic, weekday sober, behaviour of many young adults.
Conference:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.
Presentation Type:
Oral Presentation
Topic:
Presentations
Citation:
Crichton
RR
(2010). COST Chemistry Action D34 ‘Molecular Targeting
and Drug Design in Neurological and Bacterial
Diseases'.
Front. Pharmacol.
Conference Abstract:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU.
doi: 10.3389/conf.fphar.2010.02.00019
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Received:
10 Mar 2010;
Published Online:
10 Mar 2010.
*
Correspondence:
Robert R Crichton, Universite Catholique de Louvain, Louvain, Belgium, robert.crichton@uclouvain.be