Salicylanilide diethyl phosphates as cholinesterases inhibitors

Based on the presence of dialkyl phosphate moiety, we evaluated twenty-seven salicylanilide diethyl phosphates (diethyl [2-(phenylcarbamoyl)phenyl] phosphates) for the inhibition of acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.) and butyrylcholinesterase (BChE) from equine serum. Ellman’s spectrophotometric method was used. The inhibitory activity (expressed as IC₅₀ values) was compared with that of the established drugs galantamine and rivastigmine. Salicylanilide diethyl phosphates showed significant activity against both cholinesterases with IC₅₀ values from 0.903 to 86.3 μM. IC₅₀s for BChE were comparatively lower than those obtained for AChE. All of the investigated compounds showed higher inhibition of AChE than rivastigmine, and six of them inhibited BChE more effectively than both rivastigmine and galantamine. In general, derivatives of 4-chlorosalicylic acid showed enhanced activity when compared to derivatives of 5-halogenated salicylic acids, especially against BChE. The most effective inhibitor of AChE was O-{5-chloro-2-[(3-bromophenyl)carbamoyl]phenyl} O,O-diethyl phosphate with IC₅₀ of 35.4 μM, which is also one of the most potent inhibitors of BChE. O-{5-Chloro-2-[(3,4-dichlorophenyl)carbamoyl]phenyl} O,O-diethyl phosphate exhibited in vitro the strongest inhibition of BChE (0.90 μM). Salicylanilide diethyl phosphates act as pseudo-irreversible cholinesterases inhibitors.     

Tetramethonium derivatives as reversible inhibitors of various cholinesterases

To study the effect of the onium atom nature on anticholinesterase efficiency, we tested elementorganic derivatives of tetramethylenbisonium compounds as reversible inhibitors of the following cholinesterases (ChE): acetyl-ChE from human erythrocytes, butyryl-ChE from horse serum, ChE from the brain of the grass frog Rana temporaria, ChEs from visual ganglia of the Pacific squid Todarodes pacificus, and ChE from visual ganglia of the commander squid Berryteuthis magister from different habitats in the Northwestern Pacific Ocean. Bisphosphonium inhibitors were found to be much stronger effectors than bisammonum compounds, although this may be due to a significantly increased size and hydrophobicity of their onium groups. Bisammonium organosilicon compound and its monoammonium analog were equally active as reversible ChE inhibitors in mammals. The first studied bis(phenyliodonium) derivative, which is characterized by a significantly increased hydrophobicity due to the introduction of fluorine atoms to the interonium tetramethylene chain, also exhibited a pronounced anticholinesterase effect on mammalian ChE.     

Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases

The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30 μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE.     

Acetylenic amines as inhibitors of microsomal monooxygenases

A new class of compounds: acetylenic amines, possessing structural similarity with the known inhibitor SKF-525A, and their saturated analogues, has been studied for its effect on the microsomal cytochrome P-450-dependent monooxygenases (MM). Significant differences in sensitivity of different substrate oxidation reactions in experiments with the mouse liver MM were observed. It was shown that the acetylenic amines investigated 13-30 times exceeded their saturated analogues as to the ability to inhibit aminopyrine and benzo[a]pyrene oxidation, and differed but slightly from their analogues with respect to p-nitroanisole and paraoxon oxidation. Benzo[a]pyrene hydroxylase of the house-fly abdomens was less sensitive to the compound investigated than that of the mouse liver, however, in contrast to it exhibited selectively to the diphenyl derivatives and not to the monophenyl ones.     

Indole alkaloids of Psychotria as multifunctional cholinesterases and monoamine oxidases inhibitors

Thirteen Psychotria alkaloids were evaluated regarding their interactions with acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A and MAO-B), which are enzymatic targets related with neurodegenerative diseases. Two quaternary β-carboline alkaloids, prunifoleine and 14-oxoprunifoleine, inhibited AChE, BChE and MAO-A with IC₅₀ values corresponding to 10 and 3.39 μM for AChE, 100 and 11 μM for BChE, and 7.41 and 6.92 μM for MAO-A, respectively. Both compounds seem to behave as noncompetitive AChE inhibitors and time-dependent MAO-A inhibitors. In addition, the monoterpene indole alkaloids (MIAs) angustine, vallesiachotamine lactone, E-vallesiachotamine and Z-vallesiachotamine inhibited BChE and MAO-A with IC₅₀ values ranging from 3.47 to 14 μM for BChE inhibition and from 0.85 to 2.14 μM for MAO-A inhibition. Among the tested MIAs, angustine is able to inhibit MAO-A in a reversible and competitive way while the three vallesiachotamine-like alkaloids display a time-dependent inhibition on this target. Docking calculations were performed in order to understand the binding mode between the most active ligands and the selected targets. Taken together, our findings established molecular details of AChE, BChE and MAO-A inhibition by quaternary β-carboline alkaloids and MIAs from Psychotria, suggesting these secondary metabolites are scaffolds for the development of multifunctional compounds against neurodegeneration.     

Anabasine derivatives as reversible and irreversible inhibitors of cholinesterases from different animals

A comparative study was carried out of action of 18 specifically synthesized anabasine derivatives and their analogs, including diiodomethylates of anabasine acylates and bis-anabasine derivatives of dicarboxylic glutaric, adipic, azelaic, and sebacic acids, on activity of cholinesterase of brain of frog Rana temporaria and visual ganglia of the Pacific squid Todarodes pacificus and Commander squid Berryteuthis magister from different zones of habitations in the northwest part of the Pacific Ocean as well as of erythrocyte acetylcholinesterase and serum butyrylcholinesterase. These compounds were not submitted to cholinesterase hydrolysis and turned out to be efficient reversible inhibitors that have to certain degree specificity toward the studied enzymes both by their potency and by the type of their inhibitory action. Specificity of effects of the key structural fragments of the anabasine grouping on anticholinesterase efficacy was checked. Also performed was analysis of action of 24 reversible and irreversible organophosphorus inhibitors, anabasine derivatives, toward erythrocyte acetylcholinesterase and serum butyrylcholinesterase. The anticholinesterase effects of anabasine-containing inhibitors differing in structure and action mechanism was compared.     

Lipophilic amines as potent inhibitors of N-acylethanolamine-hydrolyzing acid amidase

N-Acylethanolamines (NAEs) including N-arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine are endogenous lipid mediators. These molecules are degraded to the corresponding fatty acids and ethanolamine by fatty acid amide hydrolase (FAAH) or NAE-hydrolyzing acid amidase (NAAA). Lipophilic amines, especially pentadecylamine (2c) and tridecyl 2-aminoacetate (11b), were found to exhibit potent NAAA inhibitory activities (IC(50)=5.7 and 11.8μM), with much weaker effects on FAAH. These simple structures would provide a scaffold for further improvement in NAAA inhibitory activity.     

Organosilicon reversible inhibitors of cholinesterases of different animals

The review presents data on cholinesterase effects of 28 specially synthesized organosilicon compounds (monoonium, organoelement, and bisonium derivatives) studied as reversible inhibitors of acetylcholinesterase (acetyl-ChE) of human erythrocytes, butyryl-ChE of horse blood serum, ChE of brain of common frog Rana temporaria, ChE of the optical ganglia tissue of Pacific squid Todarodes pacificus and of individuals of Commandor squid Berryteuthis magister from various habitats in the Northwestern aquatoria of the Pacific ocean. Among the tested compounds, there are revealed highly specific inhibitors of mammalian ChE as well as of ChE of the B. magister individuals from various habitats.     

Siliconorganic reversible inhibitors of cholinesterases of various animals

The review present data on cholinesterase effects of 28 specially synthesized siliconorganic compounds (monoonium, clementorganic, and bisonium derivatives) studied as reversible inhibitors of acetylcholinesterase (acetyl-ChE) of human erythrocytes, butyryl-ChE of horse blood serum, ChE of brain of common frog Rana temporaria, ChE of the optical ganglia tissue of Pacific squid Todarodes pacificus and of individuals of Commandor squid Berryteuthis magister from various habitats in the Northwestern aquatoria of the Pacific ocean. Among the tested compounds, there are revealed highly specific inhibitors of mammalian ChE as well as of ChE of the B. magister individuals from various habitats.     

Synthesis and evaluation of d-gluco-pyranocyclopropyl amines as potential glucosidase inhibitors

In the recent past sugar-derived cyclopropylamines were proposed as structurally new glycosidase inhibitors. In this Letter we report our efforts in the synthesis of a set of α-glucose configured oxabicyclo[4.1.0] heptanes, based on this hypothesis, bearing an amine substituent on the propyl ring and reveal that their inhibitory potential towards a range of mammalian glucosidases is modest.     

Quaternary phosphonium reversible inhibitors of cholinesterases of different animals

The quaternary phosphonium compounds were found to be reversible inhibitors of cholinesterases of different animals and showed species-specificity of action depending on their inhibitor structure. We have revealed difference in the inhibitory specificity of various acetylcholinesterase preparations. A difference has been shown in inhibitory parameters of optic ganglia of individuals of the squid Berryteuthis magister from different habitat areas. For the first time in comparing phosphonium and ammonium isologues-tetrabutyl- and tributylhexyl derivatives, it has been shown that they are agents practically similar by the character of the anticholinesterase action.     

Effect of reversible inhibitors on the thermal denaturation of cholinesterases]

The capacity of reversible inhibitors--galanthamine and tacrine--to protect the cholinesterase of rat and mouse brain from the thermal denaturation with the action of the temperature of 56 and 58 degrees C was revealed. The protective action was also noted when the reversible inhibitors decreased the activity of the enzyme. It appeared that with galanthamine the cholinesterase resistance to the thermal action was greater than with the action of tacrine.     

Schiffs bases and derived secondary amines as plant growth inhibitors

Seventy-two Schiffs bases, 44 corresponding secondary amines, and 12 N-acetylated compounds were tested on their growth activity. Eighty-one compounds were active as growth inhibitors in at least one of three bioassays.     

Schiffs bases and derived secondary amines as plant growth inhibitors

Seventy-two Schiffs bases, 44 corresponding secondary amines, and 12 N-acetylated compounds were tested on their growth activity. Eighty-one compounds were active as growth inhibitors in at least one of three bioassays.     

Isomeric derivatives of lupinine and epilupinine--organophosphorus inhibitors of cholinesterases

The isomeric-structure analysis data of anticholinesterase action of organophosphorous inhibitors with similar structure help in the search of specific effectors and detection of differences in reactivity of various animals' enzymes. This study compared the data of efficacy in respect of 4 mammal and 5 arthropoda cholinesterase preparations for 26 quinolizidine inhibitors, which molecules contain both the isomeric unbranched and branched alkoxyl radicals in the phosphoryl group, and the epimeric lupinine and epilupinine derivatives in the leaving group. The changes in the alkoxyl radical structure of inhibitor molecules act on their efficacy only with respect to the mammal enzymes ("group" inhibitor specificity). The differences between lupinine and epilupinine derivatives were revealed. Highly specific inhibitors of different enzymes were detected among the tested compounds.     

Quaternary phosphonium reversibile inhibitors of cholinesterases of different animals

Quaternary phosphonium compounds were found to be reversible inhibitors of cholinesterases of various animals and showed species-specificity of action depending on the inhibitor structure. It became possible to reveal difference in inhibitory specificity of various preparations of acetylcholinesterases. A difference has been shown in inhibitory parameters of the series of phosphonium toward cholinesterase of visual ganglia of individuals of the squid Berryteuthis magister from different zones of the habitat areal. For the first time, when comparing phosphonium and ammonium isologues - tetrabutyl- and tributylhe-xyl derivatives, it has been shown that they are agents practically similar by the character of anticholinesterase action.     

Insect cholinesterases and irreversible inhibitors. Statistical treatment of the data

The data on sensitivity of cholinesterases (ChE) of different insects to reversible inhibitors, as well as the data on physico-chemical parameters of amino acids constituting their active centers, were treated by factor analysis and juxtaposed. It is shown that both these characteristics are related to taxonomical belonging of insects. It is revealed the "material substrate" of the factors determining inhibitor action specificity, which are specific sites in ChE active center.     

Use of ethopropazine and BW 284C51 as selective inhibitors for cholinesterases from various species

Both inhibitors tested were still able to depress the cholinesterase (ChE) for which it is not selective (BW 284C51 for pseudo ChE, ethopropazine for the true ChE) provided the concentration was high (greater than 10(-2) M). BW 284C51 totally depressed the true ChE activity from bovine erythrocytes at a concentration of 10(-6) M. This inhibitor concentration gave no depression of pseudo ChE activity from horse serum. Ethopropazine totally depressed the pseudo ChE activity from horse serum at a concentration of 5 X 10(-5) M. The true ChE was not inhibited at this concentration. For true ChE from bovine erythrocytes and pseudo ChE from horse serum BW 284C51 and ethopropazine therefore certainly have a potential as selective ChE inhibitors. Ethopropazine at a concentration of 5 X 10(-6) M completely inhibited the pseudo ChE activity in rat plasma and cortex without affecting true ChE activity. BW 284C51 at a concentration of 10(-6) M gave a total depression of the true ChE activity in these preparations. In rat plasma, however, a considerable part of the pseudo ChE activity was depressed at this concentration.