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Pyrano(3,2-c)quinoline-6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds

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.

Dimeric and hybrid anti-alzheimer drug candidates

In the last decade much attention has been paid to the development of metabolically non-reversible dimeric or hybrid compounds, which combine two structural units of one or two lead compounds of interest for the treatment of Alzheimers disease. As a consequence of their capability to simultaneously interact with two binding sites of the same biological target (the enzyme acetylcholinesterase in most cases), to expand their interaction in the main binding site of the target molecule, or to interact with two different biological targets of interest in the pathogenesis of the disease, these dimeric or hybrid compounds exhibit an improved pharmacological profile including high affinity interactions, additional non conventional actions or complementary actions, what makes them potential drug candidates for the treatment of Alzheimers disease. Herein, we review from a structural point of view the main classes of dimeric or hybrid compounds developed for the treatment of Alzheimers disease, along with the pharmacological profile of the most active compounds.

Synthesis and evaluation of tacrine–Huperzine a hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of alzheimer’s disease

Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7jy, 2.5 times less active than tacrine as AChE inhibitor, but much more active than its (Z)-stereoisomer (7iy). Derivatives 7dy and 7ey, lacking the ethylidene substituent, showed to be more active than tacrine. Many other structural modifications of 7jy led to less active compounds. Compounds 7dy and 7ey also showed to be much more active than tacrine in reversing the partial neuromuscular blockade induced by d-tubocurarine.

Exploring the Size Limit of Templates for Inhibitors of the M2 Ion Channel of Influenza A Virus

Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.

Huprine–Tacrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer’s and Prion Diseases

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 β-amyloid peptide (Aβ) 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 Aβ aggregation, and β-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 Alzheimers and prion diseases.

Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates.

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 Alzheimers disease progression.

Novel huprine derivatives with inhibitory activity toward β-amyloid aggregation and formation as disease-modifying anti-Alzheimer drug candidates.

A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE‐induced and self‐induced β‐amyloid (Aβ) aggregation and β‐secretase (BACE‐1), and to cross the blood–brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil‐related 5,6‐dimethoxy‐2‐[(4‐piperidinyl)methyl]indane moiety as the active site and peripheral site to mid‐gorge‐interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE‐induced and self‐induced Aβ aggregation, and BACE‐1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti‐Alzheimer drug candidates with the potential to modify the natural course of this disease.

Cholinergic Drugs in Pharmacotherapy of Alzheimers Disease

The cholinergic hypothesis of Alzheimers disease has spurred the development of numerous structural classes of compounds with different pharmacological profiles aimed at increasing central cholinergic neurotransmission, thus providing a symptomatic treatment for this disease. Indeed, the only drugs currently approved for the treatment of Alzheimers disease are cholinomimetics with the pharmacological profile of acetylcholinesterase inhibitors. Recent evidence of a potential disease modifying role of acetylcholinesterase inhibitors and M(1) muscarinic agonists have led to a revival of this approach, which might be considered as more than a symptomatic treatment.

Enantioselective synthesis of tacrine–huperzine A hybrids. Preparative chiral MPLC separation of their racemic mixtures and absolute configuration assignments by X-ray diffraction analysis

A new synthesis of racemic 7-substituted bicyclo[3.3.1]non-6-en-3-ones, rac-4, whose key-step involves the reaction of a vinyl triflate, rac-7, with an organometallic reagent, has been developed. This procedure has been applied to the enantioselective synthesis of (+)- and (−)-7-ethylbicyclo[3.3.1]non-6-en-3-one, (+)- and (−)-4b, from which both enantiomers of the cholinesterase inhibitor, tacrine–huperzine A hybrid, 9b, have been obtained. Rac-9b and its related compounds rac-9a and rac-10a were separated into their enantiomers on a preparative scale by medium pressure liquid chromatography (MPLC) using microcrystalline cellulose triacetate as the chiral stationary phase. X-ray diffraction analysis of (−)-10a as the o-iodobenzoic acid salt, allowed us to establish its absolute configuration and deduce those of other enantiopure tacrine–huperzine A hybrids.

(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in the enantioselective preparation of α-aryloxypropanoic acid herbicides and α-chlorocarboxylic acids

Abstract rac -α-Chlorocarboxylic acids, rac - 9a – e , were formally deracemized by reaction of the corresponding acyl chlorides with the chiral auxiliaries ( R )- and ( S )-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, ( R )- and ( S )- 4 , followed by mild alkaline hydrolysis. The highest o.p. (99%) was obtained in the case of ( S )-α-chloropropanoic acid, a known precursor for the synthesis of ( R )-α-aryloxypropanoic acid herbicides such as dichlorprop-P, ( R )- 3a , or mecoprop-P, ( R )- 3b , which, together with their enantiomers, were also obtained in moderate e.e.s by dynamic kinetic resolution from (α RS ,3 S )-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-bromopropanoate, (α RS ,3 S )- 6 , by reaction with the corresponding phenoxide followed by mild acid hydrolysis.