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. 2012 Aug 22;3(11):914-9.
doi: 10.1021/ml3001825. eCollection 2012 Nov 8.

Neuroprotective Tri- and Tetracyclic BChE Inhibitors Releasing Reversible Inhibitors upon Carbamate Transfer

Fouad H Darras  1 , Beata Kling  1 , Jörg Heilmann  1 , Michael Decker  1
Affiliations

Neuroprotective Tri- and Tetracyclic BChE Inhibitors Releasing Reversible Inhibitors upon Carbamate Transfer

Fouad H Darras et al. ACS Med Chem Lett. .

Abstract

Tri- and tetracyclic nitrogen-bridgehead compounds were designed and synthesized to yield micromolar cholinesterase (ChE) inhibitors. Structure-activity relationships identified potent compounds with butyrylcholinesterase selectivity. These compounds were selected as starting points for the design and synthesis of carbamate-based (pseudo)irreversible inhibitors. Compounds with superior inhibitory activity and selectivity were obtained and kinetically characterized also with regard to the velocity of enzyme carbamoylation. Structural elements were identified and introduced that additionally showed neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation. We have identified potent and selective pseudoirreversible butyrylcholinesterase inhibitors that release reversible inhibitors with neuroprotective properties after carbamate transfer to the active site of cholinesterases.

Keywords: Alzheimer's disease; butyrylcholinesterase; carbamates; neuroprotection.

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Figures

Chart 1
Chart 1. Structures of the ChE Inhibiting Alkaloid Physostigmine, the Tetracyclic Lead Structure (5a, cf. Scheme 1), and the AD Drug Rivastigmine
Scheme 1
Scheme 1. Synthesis of Tetra- and Tricyclic N-Bridgehead Compounds
Reagents: (i) (Cl3CO)2CO, dry THF, 40–50 °C, 3 h. (ii) CH3I, N,N-diisopropylethylamine, N,N-dimethylacetamide, 40 °C, 24 h. (iii) Toluene/reflux, 24 h. (iv) LiAlH4, THF, 70 °C, 3 h. (v) Ethyl(methyl)carbamic chloride, NaH, THF, rt or isocyanate, Et3N, CH2Cl2, rt. (vi) Pyrrolidin-2-one, MW 100–200 W, 130 °C, 1 h. (vii) Benzylbromide, K2CO3, acetone, 70 °C, 24 h. (viii) CH3I, dioxane, 90 °C, 24 h. (ix) LiAlH4, THF, 70 °C, 3 h. (x) H2, Pd/C, ethanol, rt, 24 h. (xi) Isocyanate, CH2Cl2, Et3N, rt, 1–3 h.
Figure 1
Figure 1
(A) Time-dependent pattern of inhibition of BChE by compound 8b (10–50 nM). (B) Stability constants of the inhibitor–ChE complex (KC) and rate constants of carbamoyl–ChE formation (k3) of 8a,b and physostigmine, respectively.
Figure 2
Figure 2
Evaluation of neuroprotection of unsubstituted, phenolic, methoxy-substituted, and selected carbamyolated compounds at 10 μM against glutamate-induced oxidative stress on HT-22 cells (cf. the Supporting Information for details).
See this image and copyright information in PMC

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References

    1. Ballard C.; Gauthier S.; Corbett A.; Brayne C.; Aarsland D.; Jones E. Alzheimer's disease. Lancet 2011, 377, 1019–1031. - PubMed
    1. Takeda A.; Loveman E.; Clegg A.; Kirby J.; Picot J.; Payne E. C. A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease. Int. J. Geriatr. Psychiatry 2006, 21, 17–28. - PubMed
    1. Çokuğraş A. N. Butyrylcholinesterase: Structure and physiological importance. Turk. J. Biochem. 2003, 28, 54–61.
    1. Giacobini E. Cholinergic function and Alzheimer's disease. Int. J. Geriatr. Psychiatry 2003, 18Suppl. 1S1–S5. - PubMed
    1. Giacobini E.Drugs that target cholinesterases. In Cognitive Enhancing Drugs; Buccafusco J. J., Ed.; Birkhäuser: Basel, Boston, Berlin, 2004; pp 11–36.

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