Synthesis and Inhibitor Effect Novel Alkoxymethyl Derivatives of Dihetero Cycloalkanes on Carbonic Anhydrase and Acetylcholinesterase.

1,3-Diheterocycloalkanes derivatives are important starting materials in fine organic synthesis. These compounds can be widely used in various fields such as industry, medicine, biotechnology and chemical technology. The paper is focused on synthesis and study of alkoxymethyl derivatives of diheterocycloalkanes (M1-M15) and inhibition effect on carbonic anhydrase and acetylcholinesterase. The structures of compounds were confirmed by 1H and 13C NMR spectroscopy. Also, in this study alkoxymethyl derivatives of diheterocycloalkanes were assessed for their influence on various metabolic enzymes, including acetylcholinesterase (AChE) and human carbonic anhydrase isoenzymes (hCA I and hCA II). The results demonstrated that all these compounds exhibited potent inhibitory effects on all the target enzymes, surpassing the standard inhibitors, as evidenced by their IC50 and Ki values. The Ki values for the compounds concerning AChE, hCA I, and hCA II enzymes were in the ranges of 1.02±0.17-8.38±1.02, 15.30±3.15-58.14±5.17 and 24.05±3.70-312.94±27.24 nM, respectively.

Design, synthesis, characterization, biological evaluation, and molecular docking studies of novel 1,2-aminopropanthiols substituted derivatives as selective carbonic anhydrase, acetylcholinesterase and α-glycosidase enzymes inhibitors.

In the article, various substituted derivatives of 1,2-aminopropanthiol (1a-g) have been prepared by a general and efficient method, in one-steps, starting from available thiirane and aromatic amines (aniline, o-toluidine) as a convenient source of sulfur and nitrogen. The synthesized compounds were fully characterized by spectral and analytical data. Seven novel compounds are synthesized. The biochemical properties indicating their potential for constituting an anti-Alzheimer's disease substance were also recorded revealing strong carbonic anhydrase I, and II, α-glycosidase, and acetylcholinesterase inhibitory effects. These synthesized novel 1,2-aminopropanthiols substituted derivatives (1a-g) were found to be effective inhibitors for the α-glycosidase, human carbonic anhydrase I and II, and acetylcholinesterase enzymes, with Ki values in the range of 11.47 ± 0.87-24.09 ± 6.37 µM for α-glycosidase, 29.30 ± 4.67-79.01 ± 4.49 µM for hCA I, 14.27 ± 2.82-30.85 ± 12.24 µM for hCA II and 5.76 ± 1.55-55.39 ± 2.27 µM for AChE, respectively. In the last step of this study, molecular docking calculations were obtained in order to compare the biological activities of indicated molecules against the enzymes of acetylcholinesterase, butyrylcholinesterase and α-glycosidase. Communicated by Ramaswamy H. Sarma.

Synthesis of nitrogen, phosphorus, selenium and sulfur-containing heterocyclic compounds - Determination of their carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase and α-glycosidase inhibition properties.

Sulfur-containing pyrroles (1-3), tris(2-pyridyl)phosphine(selenide) sulfide (4-5) and 4-benzyl-6-(thiophen-2-yl)pyrimidin-2-amine (6) were synthesized and characterized by elemental analysis, IR and NMR spectra. In this study, the synthesized compounds of nitrogen, phosphorus, selenium and sulfur-containing heterocyclic compounds (1-6) were evaluated against the human erythrocyte carbonic anhydrase I, and II isoenzymes, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase enzymes. The synthesized heterocyclic compounds showed IC50 values in range of 33.32-60.79 nM against hCA I, and 37.05-66.64 nM against hCA II closely associated with various physiological and pathological processes. On the other hand, IC50 values were found in range of 13.13-22.21 nM against AChE, 0.54-31.22 nM against BChE, and 13.51-26.55 nM against α-glycosidase as a hydrolytic enzyme. As a result, nitrogen, phosphorus, selenium and sulfur-containing heterocyclic compounds (1-6) demonstrated potent inhibition profiles against indicated metabolic enzymes. Therefore, we believe that these results may contribute to the development of new drugs particularly in the treatment of some global disorders including glaucoma, Alzheimer's disease and diabetes.

Novel functionally substituted esters based on sodium diethyldithiocarbamate derivatives: Synthesis, characterization, biological activity and molecular docking studies.

Alkylation of sodium diethyldithiocarbamate with allyl-2-chloroacetate, allyl-3-chloropropionate, chloromethyl-2-(tetrahydrofuran-2-yl)acetate, and 4-(chloromethyl)-1,3-dioxolane in the aqueous medium synthesized functionally substituted esters of N, N-dietyleditiocarbamic acid (M1-M4). Most active compounds were docked into the catalytic active site of the enzyme. We identified that acetate moiety for inhibition of hCA I, hCA II, and α-glycosidase and dioxolane and thiocarbamic acid moieties for inhibition of AChE and BChE enzymes are very important. The hCA I isoform was inhibited by these novel functionally substituted esters based on sodium diethyldithiocarbamate derivatives (M1-M4) in low micromolar levels, the Ki of which differed between 48.03 ± 9.77 and 188.42 ± 46.08 µM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 57.33 ± 6.21 to 174.34 ± 40.72 µM. Also, these novel derivatives (M1-M4) effectively inhibited AChE, with Ki values in the range of 115.42 ± 12.44 to 243.22 ± 43.65 µM. For BChE Ki values were found in the range of 94.33 ± 9.14 to 189.45 ± 35.88 µM. For α-glycosidase the most effective Ki values of M4 and M3 were with Ki values of 32.86 ± 7.88 and 37.63 ± 4.08 µM, respectively.

Novel tribenzylaminobenzolsulphonylimine based on their pyrazine and pyridazines: Synthesis, characterization, antidiabetic, anticancer, anticholinergic, and molecular docking studies.

A new method of obtaining multifunctional pyrazoles by the reaction of 1,3-dipolar addition of tribenzylsulfonyliminochloride to polarophiles has been developed. This imine is obtained by reacting tribenzylamine with N-chlorobenzene sulfamide (chloramine-B). Regardless of the structure and composition of polarophiles, the cyclization reaction takes place in the presence of alkali in 6-8 h of boiling, which proves the activation of the methylene groups of tribenzylamine using the electron-withdrawing sulfonamide group. These novel derivatives were effective inhibitors of the α-glycosidase, butyrylcholinesterase (BChE), and acetylcholinesterase enzymes (AChE) with Ki values in the range of 0.45 ±â€¯0.08-1.24 ±â€¯0.27 µM for α-glycosidase, 6.04 ±â€¯0.95-11.61 ±â€¯2.84 µM for BChE, and 2.04 ±â€¯0.24-4.23 ±â€¯1.02 µM for AChE, respectively. The biological activities of the studied molecules against enzyme molecules were investigated by molecular docking calculations. The enzymes studied were AChE for ID 4M0E, BChE for ID 5NN0 BChE, and α-Glycosidase for ID 1XSI (α-Gly) respectively.

Synthesis, crystal structure, and biological evaluation of optically active 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-3-carbonitriles: Antiepileptic, antidiabetic, and anticholinergics potentials.

In the presence of chiral organic catalysts, the optically active 4H-chromine was synthesized from the multicomponent condensation of 5,5-dimethylcyclohexane-1,3-dione with malononitrile and methylene-active compound, and the specific angle of rotation of the compounds was determined in the AUTOPOL-III polarimeter and their structures were confirmed by the X-ray spectroscopic analysis method. These optically active 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-3-carbonitriles were effective inhibitors of α-glycosidase, the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) enzymes with Ki values in the range of 21.33 ± 1.11 to 40.24 ± 10.78 µM for hCA I, 28.91 ± 6.51 to 59.97 ± 15.62 µM for hCA II, 18.16 ± 3.18 to 66.57 ± 1.36 µM for α-glycosidase, and 8.68 ± 0.93 to 102.61 ± 24.96 µM for AChE.

Synthesis, characterization, antioxidant, antidiabetic, anticholinergic, and antiepileptic properties of novel N-substituted tetrahydropyrimidines based on phenylthiourea.

In the presence of trifluoroacetic acid, on the basis of three-component condensation of phenylthiourea with its salicylaldehyde and methyl-3-oxobutanoate, an efficient method for the synthesis of 1-(4-(2-hydroxyphenyl)-6-methyl-1-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)ethanone (I) has been worked out. These novel N-substituted tetrahydropyrimidines based on phenylthiourea showed good inhibitory action against acetylcholinesterase (AChE), α-glycosidase, and human carbonic anhydrase (hCA) isoforms I and II. K i values of AChE enzyme were in the range of 0.48 to 7.46 nM. The hCA I and II were effectively inhibited by the compounds, with K i values in the range of 502.44 to 923.11 nM for hCA I and 400.32 to 801.57 nM for hCA II, respectively. The antioxidant activity of the novel N-substituted tetrahydropyrimidines based on phenylthiourea was investigated by using different in vitro antioxidant assays; including 1,1-diphenyl-2-picrylhydrazyl (DPPH·) radical scavenging, Cu 2+  and Fe 3+ reducing activities.

Synthesis, crystal structure and biological evaluation of spectroscopic characterization of Ni(II) and Co(II) complexes with N-salicyloil-N'-maleoil-hydrazine as anticholinergic and antidiabetic agents.

[Ni(C11 H9 N2 O5 )2 (H2 O)2 ]•3(C3 H7 NO) (1) and [Co(C11 H9 N2 O5 )2 (H2 O)2 ]•3(C3 H7 NO) (2) are synthesized and characterized by elemental analysis, FT-IR spectra, magnetic susceptibility, and thermal analysis. In addition, the crystal structure of Ni(II) complex is presented. Both complexes show distorted octahedral geometry. In 1 and 2, metal ions are coordinated by two oxygen atoms of salicylic residue and two nitrogen atoms of maleic amide residue from two ligands, and two oxygen atoms from two water molecules. In this paper, both compounds showed excellent inhibitory effects against human carbonic anhydrase (hCA) isoforms I, and II, α-glycosidase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compounds 1 and 2 had Ki values of 18.36 ± 4.38 and 26.61 ± 7.54 nM against hCA I and 13.81 ± 3.02 and 29.56 ± 6.52 nM against hCA II, respectively. On the other hand, their Ki values were found to be 487.45 ± 54.18 and 453.81 ± 118.61 nM against AChE and 199.21 ± 50.35 and 409.41 ± 6.86 nM against BChE, respectively.

Novel amides of 1,1-bis-(carboxymethylthio)-1-arylethanes: Synthesis, characterization, acetylcholinesterase, butyrylcholinesterase, and carbonic anhydrase inhibitory properties.

The thiolation reaction was carried out in a benzene solution at 80°C and p-substituted ketones and mercaptoacetic acid in a molar ratio (1:4) of in the presence of a catalytic amount of toluene sulfonic acids. The enzyme inhibition activities of the novel amides of 1,1-bis-(carboxymethylthio)-1-arylethanes derivatives were investigated. These novel amides of 1,1-bis-(carboxymethylthio)-1-arylethanes derivatives showed good inhibitory action against acetylcholinesterase (AChE) butyrylcholinesterase (BChE), and human carbonic anhydrase I and II isoforms (hCA I and II). AChE inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. Many clinically established drugs are carbonic anhydrase inhibitors, and it is highly anticipated that many more will eventually find their way into the market. The novel synthesized compounds inhibited AChE and BChE with Ki values in the range of 0.64-1.47 nM and 9.11-48.12 nM, respectively. On the other hand, hCA I and II were effectively inhibited by these compounds, with Ki values between 63.27-132.34 and of 29.63-127.31 nM, respectively.

Synthesis and discovery of potent carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase enzymes inhibitors: The novel N,N'-bis-cyanomethylamine and alkoxymethylamine derivatives.

During this investigation, N,N'-bis-azidomethylamines, N,N'-bis-cyanomethylamine, new alkoxymethylamine and chiral derivatives, which are considered to be a new generation of multifunctional compounds, were synthesized, functional properties were investigated, and anticholinergic and antidiabetic properties of those compounds were studied through the laboratory tests, and it was approved that they contain physiologically active compounds rather than analogues. Novel N-bis-cyanomethylamine and alkoxymethylamine derivatives were effective inhibitors of the α-glycosidase, cytosolic carbonic anhydrase I and II isoforms, butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) with Ki values in the range of 0.15-13.31 nM for α-glycosidase, 2.77-15.30 nM for human carbonic anhydrase isoenzymes I (hCA I), 3.12-21.90 nM for human carbonic anhydrase isoenzymes II (hCA II), 23.33-73.23 nM for AChE, and 3.84-48.41 nM for BChE, respectively. Indeed, the inhibition of these metabolic enzymes has been considered as a promising factor for pharmacologic intervention in a diversity of disturbances.

Synthesis and investigation of the conversion reactions of pyrimidine-thiones with nucleophilic reagent and evaluation of their acetylcholinesterase, carbonic anhydrase inhibition, and antioxidant activities.

The conversion reactions of pyrimidine-thiones with nucleophilic reagent were studied during this scientific research. For this purpose, new compounds were synthesized by the interaction between 1,2-epoxy propane, 1,2-epoxy butane, and 4-chlor-1-butanol and pyrimidine-thiones. These pyrimidine-thiones derivatives (A-K) showed good inhibitory action against acetylcholinesterase (AChE), and human carbonic anhydrase (hCA) isoforms I and II. AChE inhibition was in the range of 93.1 ± 33.7-467.5 ± 126.9 nM. The hCA I and II were effectively inhibited by these compounds, with Ki values in the range of 4.3 ± 1.1-9.1 ± 2.7 nM for hCA I and 4.2 ± 1.1-14.1 ± 4.4 nM for hCA II. On the other hand, acetazolamide clinically used as CA inhibitor showed Ki value of 13.9 ± 5.1 nM against hCA I and 18.1 ± 8.5 nM against hCA II. The antioxidant activity of the pyrimidine-thiones derivatives (A-K) was investigated by using different in vitro antioxidant assays, including Cu2+ and Fe3+ reducing, 1,1-diphenyl-2-picrylhydrazyl (DPPH• ) radical scavenging, and Fe2+ chelating activities.

Synthesis and biological evaluation of aminomethyl and alkoxymethyl derivatives as carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitors.

Compounds containing nitrogen and sulfur atoms can be widely used in various fields such as industry, medicine, biotechnology and chemical technology. Therefore, the reactions of aminomethylation and alkoxymethylation of mercaptobenzothiazole, mercaptobenzoxazole and 2-aminothiazole were developed. Additionally, the alkoxymethyl derivatives of mercaptobenzoxazole and 2-aminothiazole were synthesized by a reaction with hemiformals, which are prepared by the reaction of alcohols and formaldehyde. In this study, the inhibitory effects of these molecules were investigated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) enzymes and carbonic anhydrase I, and II isoenzymes (hCA I and II). Both hCA isoenzymes were significantly inhibited by the recently synthesized molecules, with Ki values in the range of 58-157 nM for hCA I, and 81-215 nM for hCA II. Additionally, the Ki parameters of these molecules for BChE and AChE were calculated in the ranges 23-88 and 18-78 nM, respectively.

Discovery of potent carbonic anhydrase, acetylcholinesterase, and butyrylcholinesterase enzymes inhibitors: The new amides and thiazolidine-4-ones synthesized on an acetophenone base.

Compounds containing nitrogen and sulfur atoms can be widely used in various fields, including industry, medicine, biotechnology, and chemical technology. Among them, amides of acids and heterocyclic compounds have an important place. These amides and thiazolidine-4-ones showed good inhibitory action against butyrylcholinesterase (BChE), acetylcholinesterase (AChE), and human carbonic anhydrase isoforms. AChE exists at high concentrations in the brain and red blood cells. BChE is an important enzyme that is plentiful in the liver, and it is released into the blood in a soluble form. They were demonstrated to have effective inhibition profiles with Ki values of 23.76-102.75 nM against hCA I, 58.92-136.64 nM against hCA II, 1.40-12.86 nM against AChE, and 9.82-52.77 nM against BChE. On the other hand, acetazolamide showed Ki value of 482.63 ± 56.20 nM against hCA I, and 1019.60 ± 163.70 nM against hCA II. Additionally, Tacrine inhibited AChE and BChE, showing Ki values of 397.03 ± 31.66 and 210.21 ± 15.98 nM, respectively.

Synthesis and bioactivity of several new hetaryl sulfonamides.

1-(4-Methylsulfonyl)-2-thione-4-aryl-5-Z-6-methyl and oxyalkyl-imidazoles were synthesized from different tetrahydropyrimidinethiones and aryl sulfonyl chloride. These compunds were tested for metal chelating effects and to determine the phrase in which inhibition occured between two physiologically pertinent compunds and carbonic anhydrase (CA) isozymes I and II (hCA I and II), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE). AChE was detected in high concentrations in the brain and red blood cells. BChE is another enzymes that is abundant available in the liver and released into the blood in a soluble form. Newly synthesized hetaryl sulfonamides exhibited impressive inhibition profiles with Ki values in the range of 1.42-6.58 nM against hCA I, 1.72-7.41 nM against hCA II, 0.20-1.14 nM against AChE and 1.55-5.92 nM against BChE. Moreover, acetazolamide showed Ki values of 43.69 ± 6.44 nM against hCA I and 31.67 ± 8.39 nM against hCA II. Additionally, tacrine showed Ki values of 25.75 ± 3.39 nM and 37.82 ± 2.08 against AChE and BChE, respectively.

Synthesis of 4,5-disubstituted-2-thioxo-1,2,3,4-tetrahydropyrimidines and investigation of their acetylcholinesterase, butyrylcholinesterase, carbonic anhydrase I/II inhibitory and antioxidant activities.

A series of tetrahydropyrimidinethiones were synthesized from thiourea, ß-diketones and aromatic aldehydes, such as p-tolualdehyde, p-anisaldehyde, o-tolualdehyde, salicylaldehyde and benzaldehyde. These cyclic thioureas showed good inhibitory action against acetylcholine esterase (AChE), butyrylcholine esterase (BChE), and human (h) carbonic anhydrase (CA) isoforms I and II. AChE and BChE inhibitions were in the range of 6.11-16.13 and 6.76-15.68 nM, respectively. hCA I and II were effectively inhibited by these compounds, with Ki values in the range of 47.40-76.06 nM for hCA I, and of 30.63-76.06 nM for hCA II, respectively. The antioxidant activity of the cyclic thioureas was investigated by using different in vitro antioxidant assays, including 1,1-diphenyl-2-picrylhydrazyl (DPPH·) radical scavenging, Cu2+ and Fe3+ reducing, and Fe2+ chelating activities.

Synthesis of some tetrahydropyrimidine-5-carboxylates, determination of their metal chelating effects and inhibition profiles against acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase.

2-(Methacryloyloxy)ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate, is a cyclic urea derivative synthesized from urea, 2-(methacryloyloxy) ethyl acetoacetate and substituted benzaldehyde, and tested in terms of the inhibition of two physiologically relevant carbonic anhydrase (CA) isozymes I and II. Acetylcholinesterase (AChE) is found in high concentrations in the red blood cells and brain. Butyrylcholinesterase (BChE) is another enzyme abundantly present in the liver and released into blood in a soluble form. Also, they were tested for the inhibition of AChE and BChE enzymes and demonstrated effective inhibition profiles with Ki values in the range of 429.24-530.80 nM against hCA I, 391.86-530.80 nM against hCA II, 68.48-97.19 nM against AChE and 104.70-214.15 nM against BChE. On the other hand, acetazolamide clinically used as CA inhibitor, showed Ki value of 281.33 nM against hCA I, and 202.70 nM against hCA II. Also, Tacrine inhibited AChE and BChE showed Ki values of 396.03 and 209.21 nM, respectively.