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1.
Neurodegener Dis ; 10(1-4): 96-9, 2012.
Article in English | MEDLINE | ID: mdl-22236498

ABSTRACT

BACKGROUND: Multifactorial diseases such as Alzheimer's disease (AD) should be more efficiently tackled by drugs which hit multiple biological targets involved in their pathogenesis. We have recently developed a new family of huprine-tacrine heterodimers, rationally designed to hit multiple targets involved upstream and downstream in the neurotoxic cascade of AD, namely ß-amyloid aggregation and formation as well as acetylcholinesterase catalytic activity. OBJECTIVE: In this study, the aim was to expand the pharmacological profiling of huprine-tacrine heterodimers investigating their effect on muscarinic M(1) receptors as well as their neuroprotective effects against an oxidative insult. METHODS: Sprague-Dawley rat hippocampus homogenates were used to assess the specific binding of two selected compounds in competition with 1 nM [(3)H]pirenzepine (for M(1) receptors) or 0.8 nM [(3)H]quinuclidinyl benzilate (for M(2) receptors). For neuroprotection studies, SHSY5Y cell cultures were subjected to 250 µM hydrogen peroxide insult with or without preincubation with some huprine-tacrine heterodimers. RESULTS: A low nanomolar affinity and M(1)/M(2) selectivity has been found for the selected compounds. Huprine-tacrine heterodimers are not neurotoxic to SHSY5Y cells at a range of concentrations from 1 to 0.001 µM, and some of them can protect cells from the oxidative damage produced by hydrogen peroxide at concentrations as low as 0.001 µM. CONCLUSION: Even though it remains to be determined if these compounds act as agonists at M(1) receptors, as it is the case of the parent huprine Y, their low nanomolar M(1) affinity and neuroprotective effects expand their multitarget profile and increase their interest as disease-modifying anti-Alzheimer agents.


Subject(s)
Aminoquinolines/metabolism , Heterocyclic Compounds, 4 or More Rings/metabolism , Protein Multimerization/physiology , Tacrine/metabolism , Analysis of Variance , Animals , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Hydrogen Peroxide/pharmacology , Muscarinic Antagonists/pharmacokinetics , Neuroblastoma/pathology , Oxidative Stress/drug effects , Oxidative Stress/physiology , Pirenzepine/pharmacokinetics , Protein Binding/drug effects , Protein Multimerization/drug effects , Quinuclidinyl Benzilate/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tritium/metabolism
2.
J Med Chem ; 55(2): 661-9, 2012 Jan 26.
Article in English | MEDLINE | ID: mdl-22185619

ABSTRACT

A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the ß-amyloid peptide (Aß) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Aß aggregation, and ß-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases.


Subject(s)
Alzheimer Disease/drug therapy , Aminoquinolines/chemical synthesis , Amyloid beta-Peptides/antagonists & inhibitors , Cholinesterase Inhibitors/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Prion Diseases/drug therapy , Prions/antagonists & inhibitors , Tacrine/analogs & derivatives , Tacrine/chemical synthesis , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Aminoquinolines/pharmacokinetics , Aminoquinolines/pharmacology , Amyloid beta-Peptides/chemistry , Animals , Brain/metabolism , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/pharmacokinetics , Cholinesterase Inhibitors/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Membranes, Artificial , Mice , Models, Molecular , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/chemistry , Permeability , Prions/chemistry , Recombinant Proteins/chemistry , Stereoisomerism , Structure-Activity Relationship , Tacrine/pharmacokinetics , Tacrine/pharmacology
3.
Bioorg Med Chem ; 19(5): 1702-7, 2011 Mar 01.
Article in English | MEDLINE | ID: mdl-21315611

ABSTRACT

A series of 19 huprines has been evaluated for their activity against cultured bloodstream forms of Trypanosoma brucei and Plasmodium falciparum. Moreover, cytotoxicity against rat myoblast L6 cells was assessed for selected huprines. All the tested huprines are moderately potent and selective trypanocidal agents, exhibiting IC(50) values against T. brucei in the submicromolar to low micromolar range and selectivity indices for T. brucei over L6 cells of approximately 15, thus constituting interesting trypanocidal lead compounds. Two of these huprines were also found to be active against a chloroquine-resistant strain of P. falciparum, thus emerging as interesting trypanocidal-antiplasmodial dual acting compounds, but they exhibited little selectivity for P. falciparum over L6 cells.


Subject(s)
Aminoquinolines/chemical synthesis , Antimalarials/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Plasmodium falciparum/drug effects , Trypanocidal Agents/chemical synthesis , Trypanosoma brucei brucei/drug effects , Aminoquinolines/chemistry , Aminoquinolines/classification , Aminoquinolines/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Cells, Cultured , Heterocyclic Compounds, 4 or More Rings/classification , Heterocyclic Compounds, 4 or More Rings/pharmacology , Molecular Structure , Rats , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology
4.
Chem Biol Interact ; 187(1-3): 411-5, 2010 Sep 06.
Article in English | MEDLINE | ID: mdl-20167211

ABSTRACT

Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimer's disease progression.


Subject(s)
Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Catalytic Domain , Tacrine/chemistry , Tacrine/pharmacology , Alzheimer Disease/epidemiology , Amino Acid Motifs , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Donepezil , Drug Discovery , Humans , Indans/chemistry , Indans/pharmacology , Indans/therapeutic use , Models, Molecular , Piperidines/chemistry , Piperidines/pharmacology , Piperidines/therapeutic use , Protein Multimerization/drug effects , Protein Structure, Quaternary , Quinolines/chemistry , Quinolines/pharmacology , Quinolines/therapeutic use , Tacrine/therapeutic use
5.
J Med Chem ; 52(17): 5365-79, 2009 Sep 10.
Article in English | MEDLINE | ID: mdl-19663388

ABSTRACT

Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.


Subject(s)
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Cholinesterase Inhibitors/pharmacology , Tacrine/analogs & derivatives , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Animals , Binding Sites , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Butyrylcholinesterase/metabolism , Cattle , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/therapeutic use , Drug Design , Humans , Isomerism , Membranes, Artificial , Mice , Models, Molecular , Molecular Conformation , Permeability , Protein Binding/drug effects , Tacrine/chemistry , Tacrine/metabolism , Tacrine/pharmacology , Tacrine/therapeutic use
6.
J Med Chem ; 51(12): 3588-98, 2008 Jun 26.
Article in English | MEDLINE | ID: mdl-18517184

ABSTRACT

A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.


Subject(s)
Acetylcholinesterase/chemistry , Amyloid beta-Peptides/chemistry , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemical synthesis , Indans/chemical synthesis , Piperidines/chemical synthesis , Animals , Binding Sites , Cattle , Cholinesterase Inhibitors/chemistry , Donepezil , Humans , Indans/chemistry , Models, Molecular , Piperidines/chemistry , Structure-Activity Relationship , Tacrine/analogs & derivatives , Tacrine/chemical synthesis , Tacrine/chemistry
7.
J Org Chem ; 71(9): 3464-71, 2006 Apr 28.
Article in English | MEDLINE | ID: mdl-16626127

ABSTRACT

Treatment of 1-indanones with aromatic aldehydes and NaOEt in THF affords complex spiropolycyclic compounds through a four-component reaction in which two molecules of each starting compound are combined with formation of four new carbon-carbon bonds, leading to the elaboration of a new five-membered ring that bears five contiguous stereogenic centers with a well-defined relative configuration. Different amounts of a minor epimer of the main product are also formed. The presence of methoxy substituents in the indanone component and the use of aldehydes derived from pi-excedent heterocycles make the dimerization step a slower transformation. In these cases, better yields of spirodimers are obtained starting from the preformed enones. The reaction seems to take place by cross-aldol condensation, dehydration, and dimerization of the thus formed enones. The molecular mechanism of the dimerization reaction of enone 5g has been studied using DFT methods at the B3LYP/6-31G level. The dimerization takes place through a process involving a Michael addition of a carbanion, obtained by deprotonation of 5g at the 3-position, to a second molecule of 5g, followed by an intramolecular Michael addition in the corresponding intermediate. The final protonation of the resulting anion accounts for the formation of the cis-fused pentacyclic system.


Subject(s)
Indenes/chemical synthesis , Spiro Compounds/chemical synthesis , Aldehydes/chemistry , Dimerization , Indans/chemistry , Stereoisomerism
8.
Org Biomol Chem ; 3(18): 3273-83, 2005 Sep 21.
Article in English | MEDLINE | ID: mdl-16132089

ABSTRACT

Structural studies of peri-interactions with dimethylamino groups in naphthalene systems indicate that the N-phenylcarboxamide group has a through-space electron attracting power closer to that of a carboxylic ester than a N,N-dialkylcarboxamide, while 2-nitroalkenyl groups have a lower through-space electron attracting power. However, addition of a benzoyl group to the 2-position of the nitroethenyl group leads to cyclisation to give a zwitterion, in which the carbanion is stabilised by full conjugation with the nitro group and partial conjugation with the carbonyl group. An interesting case where a steric interaction overrides an electrophile/nucleophile attraction is also described. The limitations to the interpretation of short contact distances from crystallographic measurements are discussed.

9.
J Med Chem ; 48(6): 1701-4, 2005 Mar 24.
Article in English | MEDLINE | ID: mdl-15771413

ABSTRACT

A series of huprine-tacrine heterodimers has been developed by connection of huprine Y, a compound with one of the highest affinities for the active site of acetylcholinesterase yet reported, with tacrine, a compound with known affinity for the peripheral site of the enzyme, through a linker of appropriate length to allow simultaneous interaction with both binding sites. These compounds exhibit human acetylcholinesterase and butyrylcholinesterase inhibitory activities with IC(50) values in the subnanomolar and low nanomolar range, respectively.


Subject(s)
Acetylcholinesterase/chemistry , Aminoquinolines/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Tacrine/analogs & derivatives , Tacrine/chemical synthesis , Aminoquinolines/chemistry , Animals , Binding Sites , Butyrylcholinesterase/chemistry , Cattle , Cholinesterase Inhibitors/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Structure-Activity Relationship , Tacrine/chemistry
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