On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi- and tricyclic (hetero)aromatic systems were studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC50 values for most of them (e. g. 15: IC50 vs BChE = 0.15 μM; SI = 47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e. g. 46: IC50 vs AChE = 0.35 μM; SI = 0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer's disease, and may, therefore, represent hits for the development of interesting single-entity multitarget drugs.
Quinolizidinyl derivatives of Bi- and tricyclic systems as potent inhibitors of Acetyl- and butyrylcholinesterase with potential in Alzheimer's disease / B. Tasso, M. Catto, O. Nicolotti, F. Novelli, M. Tonelli, I. Giangreco, L. Pisani, A. Sparatore, V. Boido, A. Carotti, F. Sparatore. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 46:6(2011 Jun), pp. 2170-2184.
Quinolizidinyl derivatives of Bi- and tricyclic systems as potent inhibitors of Acetyl- and butyrylcholinesterase with potential in Alzheimer's disease
A. Sparatore;
2011
Abstract
On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi- and tricyclic (hetero)aromatic systems were studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC50 values for most of them (e. g. 15: IC50 vs BChE = 0.15 μM; SI = 47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e. g. 46: IC50 vs AChE = 0.35 μM; SI = 0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer's disease, and may, therefore, represent hits for the development of interesting single-entity multitarget drugs.File | Dimensione | Formato | |
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