Evaluation of hydrazone and -acylhydrazone derivatives of vitamin B6 and pyridine-4-carbaldehyde as potential drugs against Alzheimer's disease.

The growing prevalence of Alzheimer's disease calls for a drug that can simultaneously act towards several targets involved in the pathophysiology of the disease. In our study, we evaluated the potential of hydrazone and -acylhydrazone derivatives of vitamin B6 and pyridine-4-carbaldehyde to be used as multi-target directed ligands targeting cholinergic system by inhibiting acetyl- and butyrylcholinesterase, lowering the accumulation of β-amyloid plaques by inhibiting both the β-secretase activity and amyloid self-aggregation, and maintaining the biometal balance by chelating certain biometals. Our results showed that all of the tested hydrazones were potent inhibitors of human cholinesterases with inhibition constants (i) in micromolar range able to lower the activity of β-secretase, inhibit amyloid aggregation, chelate biometals and act as antioxidants.

Derivatives of Amodiaquine as Potent Human Cholinesterases Inhibitors: Implication for Treatment of Alzheimer's Disease.

As some previously reported studies have proven that amodiaquine, in addition to its primary antimalarial activity, also has potential for new applications such as the inhibition of cholinesterases, in our study we focused on the evaluation of the influence of different substituents in the aminoquinoline part of the amodiaquine structure on the inhibition of human acetylcholinesterase and butyrylcholinesterase to investigate the possibility for their use as drugs for the treatment of AD. We synthesized a series of amodiaquine derivatives bearing H-, F-, CF-, NO-, CN-, COH- or CHO- groups on the aminoquinoline ring, and determined that all of the tested derivatives were very potent inhibitors of both cholinesterases, with inhibition constants () in the nM and low μM range and with prominent selectivity (up to 300 times) for the inhibition of acetylcholinesterase. All compounds displayed an ability to chelate biometal ions Fe, Zn and Cu and an antioxidant power comparable to that of standard antioxidants.

Synthesis and biological evaluation of novel aminoquinolines with an n-octyl linker: Impact of halogen substituents on C(7) or a terminal amino group on anticholinesterase and BACE1 activity.

Alzheimer's disease is age-related multifactorial neurodegenerative disease manifested by gradual loss of memory, cognitive decline and changes in personality. Due to rapid and continuous growth of its prevalence, the treatment of Alzheimer's disease calls for development of new and efficacies drugs, especially those that could be able to simultaneously act on more than one of possible targets of action. Aminoquinolines have proven to be a highly promising structural scaffold in the design of such a drug as cholinesterases and β-secretase 1 inhibitors.

Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease.

The most successful therapeutic strategy in the treatment of Alzheimer's disease (AD) is directed toward increasing levels of the neurotransmitter acetylcholine (ACh) by inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes responsible for its hydrolysis. In this paper, we extended our study on 4-aminoquinolines as human cholinesterase inhibitors on twenty-six new 4-aminoquinolines containing an n-octylamino spacer on C(4) and different substituents on the terminal amino group. We evaluated the potency of new derivatives to act as multi-targeted ligands by determining their inhibition potency towards human AChE and BChE, ability to chelate biometals Fe, Cu and Zn, ability to inhibit the action of β-secretase 1 (BACE1) and their antioxidant capacity.

Design, Synthesis and Biological Evaluation of Biscarbamates as Potential Selective Butyrylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

As butyrylcholinesterase (BChE) plays a role in the progression of symptoms and pathophysiology of Alzheimer's disease (AD), selective inhibition of BChE over acetylcholinesterase (AChE) can represent a promising pathway in treating AD. The carbamate group was chosen as a pharmacophore because the carbamates currently or previously in use for the treatment of AD displayed significant positive effects on cognitive symptoms. Eighteen biscarbamates with different substituents at the carbamoyl and hydroxyaminoethyl chain were synthesized, and their inhibitory potential toward both cholinesterases and inhibition selectivity were determined.

Synthesis, Biological Evaluation and Machine Learning Prediction Model for Fluorinated Alkaloid-Based Derivatives as Cholinesterase Inhibitors.

A series of 46 alkaloid derivatives that differ in positions of fluorine atom(s) in the molecule were synthesized and tested as human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. All tested compounds reversibly inhibited AChE and BChE in the nanomolar to micromolar range; for AChE, the determined enzyme-inhibitor dissociation constants () ranged from 3.9-80 µM, and 0.

4-Aminoquinoline-Based Adamantanes as Potential Anticholinesterase Agents in Symptomatic Treatment of Alzheimer's Disease.

Considering that acetylcholinesterase (AChE) inhibition is the most important mode of action expected of a potential drug used for the treatment of symptoms of Alzheimer's disease (AD), our previous pilot study of 4-aminoquinolines as potential human cholinesterase inhibitors was extended to twenty-two new structurally distinct 4-aminoquinolines bearing an adamantane moiety. Inhibition studies revealed that all of the compounds were very potent inhibitors of AChE and butyrylcholinesterase (BChE), with inhibition constants () ranging between 0.075 and 25 µM.

Quinuclidine-Based Carbamates as Potential CNS Active Compounds.

The treatment of central nervous system (CNS) diseases related to the decrease of neurotransmitter acetylcholine in neurons is based on compounds that prevent or disrupt the action of acetylcholinesterase and butyrylcholinesterase. A series of thirteen quinuclidine carbamates were designed using quinuclidine as the structural base and a carbamate group to ensure the covalent binding to the cholinesterase, which were synthesized and tested as potential human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The synthesized compounds differed in the substituents on the amino and carbamoyl parts of the molecule.

Carbamate group as structural motif in drugs: a review of carbamate derivatives used as therapeutic agents.

Due to their very good chemical and proteolytic stability, ability to penetrate cell membranes, and resemblance to a peptide bond, carbamate derivatives have received much attention in recent years and got an important role in modern drug discovery and medicinal chemistry. Today, carbamates make structural and/or functional part of many drugs and prodrugs approved and marketed for the treatment of various diseases such as cancer, epilepsy, hepatitis C, HIV infection, and Alzheimer's disease. In drugs they can play a role in drug-target interaction or improve the biological activity of parent molecules.

Structural isomers of saligenin-based β2-agonists: synthesis and insight into the reaction mechanism.

Salmeterol and albuterol are well-known β2-adenoreceptor agonists widely used in the treatment of inflammatory respiratory diseases, such as bronchial asthma and chronic obstructive pulmonary disease. Here we report the preparation of structural isomers of salmeterol and albuterol, which can be obtained from the same starting material as the corresponding β2-agonists, depending on the synthetic approach employed. Using 1D and various 2D NMR measurements, we determined that the structure of prepared isomers holds the β-aryl-β-aminoethanol moiety, in contrast to the α-aryl-β-aminoethanol moiety found in salmeterol and albuterol.

Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates.

Mammalian paraoxonase-1 hydrolyses a very broad spectrum of esters such as certain drugs and xenobiotics. The aim of this study was to determine whether carbamates influence the activity of recombinant PON1 (rePON1). Carbamates were selected having a variety of applications: bambuterol and physostigmine are drugs, carbofuran is used as a pesticide, while Ro 02-0683 is diagnostic reagent.

Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase.

Eight derivatives of 4-aminoquinolines differing in the substituents attached to the C(4)-amino group and C(7) were synthesised and tested as inhibitors of human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Both enzymes were inhibited by all of the compounds with inhibition constants (K) ranging from 0.50 to 50 μM exhibiting slight selectivity toward AChE over BChE.

Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold.

This paper describes the synthesis and anticholinesterase potency of Cinchona-based alkaloids; ten quaternary derivatives of cinchonines and their corresponding pseudo-enantiomeric cinchonidines. The quaternization of quinuclidine moiety of each compound was carried out with groups diverse in their size: methyl, benzyl and differently meta- and para-substituted benzyl groups. All of the prepared compounds reversibly inhibited human butyrylcholinesterase and acetylcholinesterase with Ki constants within nanomolar to micromolar range.

Oxime-assisted reactivation of tabun-inhibited acetylcholinesterase analysed by active site mutations.

The antidotal property of oximes is attributed to their ability to reactivate acetylcholinesterase (AChE) inhibited by organophosphorus compounds (OP) such as pesticides and nerve warfare agents. Understanding their interactions within the active site of phosphylated AChE is of great significance for the search for more efficient reactivators, especially in the case of the most resistant OP to reactivation, tabun. Therefore, herein we studied the interactions and reactivation of tabun-inhibited AChE by site-directed mutagenesis and a series of bispyridinium oximes.

Resorcinol-, catechol- and saligenin-based bronchodilating β2-agonists as inhibitors of human cholinesterase activity.

We investigated the influence of bronchodilating β2-agonists on the activity of human acetylcholinesterase (AChE) and usual, atypical and fluoride-resistant butyrylcholinesterase (BChE). We determined the inhibition potency of racemate and enantiomers of fenoterol as a resorcinol derivative, isoetharine and epinephrine as catechol derivatives and salbutamol and salmeterol as saligenin derivatives. All of the tested compounds reversibly inhibited cholinesterases with K constants ranging from 9.

Peripheral site and acyl pocket define selective inhibition of mouse butyrylcholinesterase by two biscarbamates.

In this study we related metacarb (N-(2-(3,5-bis(dimethylcarbamoyloxy)phenyl)-2-hydroxyethyl)propan-2-aminium chloride) and isocarb (N-(2-(3,4-bis(dimethylcarbamoyloxy)phenyl)-2-hydroxyethyl)propan-2-aminium chloride) inhibition selectivity, as well as stereoselectivity of mouse acetylcholinesterase (AChE; 3.1.1.

Metaproterenol, isoproterenol, and their bisdimethylcarbamate derivatives as human cholinesterase inhibitors.

Metaproterenol and isoproterenol are bronchodilators that provide a structural basis for many other bronchodilators currently in use. One of these structurally related bronchodilators is terbutaline; it is administered as a prodrug, bambuterol, and is metabolized (bioconverted) into terbutaline by butyrylcholinesterase (BChE). The metabolism rate can be affected by BChE gene polymorphism in the human population and BChE stereoselectivity.

[Cholinesterases: structure, role, and inhibition].

Enzymes acetylcholinesterase (AChE; E.C. 3.

Differentiation of EDTA-sensitive from EDTA-insensitive human serum esterases hydrolysing phenylacetate.

The aim of this study was to differentiate the EDTA-sensitive from the EDTA-insensitive human serum esterases by evaluating their catalytic constants, K(M) and V(m), for the hydrolysis of phenylacetate (PA). Measurements were done at 37 degrees C in 0.1 M Tris/HCl buffer pH 7.

Stereoselective inhibition of human, mouse, and horse cholinesterases by bambuterol enantiomers.

Bambuterol is a chiral carbamate and a selective inhibitor of butyrylcholinesterase (BChE, EC 3.1.1.

Interactions of butane, but-2-ene or xylene-like linked bispyridinium para-aldoximes with native and tabun-inhibited human cholinesterases.

Kinetic parameters were evaluated for inhibition of native and reactivation of tabun-inhibited human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.

Oximes: Reactivators of phosphorylated acetylcholinesterase and antidotes in therapy against tabun poisoning.

One of the therapeutic approaches to organophosphate poisoning is to reactivate AChE with site-directed nucleophiles such as oximes. However, pyridinium oximes 2-PAM, HI-6, TMB-4 and obidoxime, found as the most effective reactivators, have limiting reactivating potency in tabun poisoning. We tested oximes varying in the type of ring (pyridinium and/or imidazolium), the length and type of the linker between rings, and in the position of the oxime group on the ring to find more effective oximes to reactivate tabun-inhibited human erythrocyte AChE.

Amino acid residues involved in stereoselective inhibition of cholinesterases with bambuterol.

Bambuterol is a chiral carbamate known as selective inhibitor of butyrylcholinesterase (BChE). In order to relate bambuterol selectivity and stereoselectivity of cholinesterases to the active site residues, we studied the inhibition of recombinant mouse BChE, acetylcholinesterase (AChE) and six AChE mutants, employed to mimic BChE active site residues, by bambuterol enantiomers. Both enantiomers selectively inhibited BChE about 8000 times faster than AChE.

Limitation of the Ellman method: cholinesterase activity measurement in the presence of oximes.

The Ellman method for assaying thiols is widely used for cholinesterase activity measurement. Cholinesterase activity is measured indirectly by quantifying the concentration of 5-thio-2-nitrobenzoic acid (TNB) ion formed in the reaction between the thiol reagent 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) and thiocholine, a product of substrate (i.e.

Structure-activity approach in the reactivation of tabun-phosphorylated human acetylcholinesterase with bispyridinium para-aldoximes.

We investigated interactions of bispyridinium para-aldoximes N,N'-(propano)bis(4-hydroxyiminomethyl) pyridinium bromide (TMB-4), N,N'-(ethano)bis(4-hydroxyiminomethyl)pyridinium methanosulphonate (DMB-4), and N,N'-(methano)bis(4-hydroxyiminomethyl)pyridinium chloride (MMB-4) with human erythrocyte acetylcholinesterase phosphorylated by tabun. We analysed aldoxime conformations to determine the flexibility of aldoxime as an important feature for binding to the acetylcholinesterase active site. Tabun-inhibited human erythrocyte acetylcholinesterase was completely reactivated only by the most flexible bispyridinium aldoxime - TMB-4 with a propylene chain between two rings.