Novel silver(I)N-heterocyclic carbene complexes bearing 2-(4-hydroxyphenyl)ethyl group: Synthesis,characterization, and enzyme inhibition properties

Herein, novel silver-based N-heterocyclic carbene (NHC) complexes bearing 2-(4-hydroxyphenyl)ethyl group were synthesized. Novel Ag(I)NHC complexes were synthesized from the 2-(4-hydroxyphenyl)ethyl-substituted benzimidazolium salts and silver oxide via in situ deprotonation method. The successful formation of all Ag(I)NHC complexes was proved by using ¹H NMR, ¹³C NMR, FTIR spectroscopy, and elemental analysis techniques. In addition, their inhibitory effects have been investigated of these substances on acetylcholinesterase (AChE), α-glycosidase (α-Gly), human carbonic anhydrase I (hCA I), and human carbonic anhydrase II (hCA II) enzymes. It has been seen that all compounds have a better ability to inhibit compared with existing tried inhibitors. Among these, the best inhibitor against AChE enzyme is 1g (K_i : 9.54 ± 0.98 μM and IC₅₀ : 17.40), and against α-Gly, 1c showed the highest effect (K_i 3.09 ± 0.36 μM and IC₅₀ 7.91). The best inhibitor against hCA I and hCA II enzymes are 1c and 1g compounds. For hCA I and hCA II, IC₅₀ values were calculated as 17.85 and 9.06 μM and K_i values were measured as 5.45 ± 2.02 and 8.99 ± 2.02 μM, respectively.     

Cholinesterases,carbonic anhydrase inhibitory properties and in silico studies of novel substituted benzylamines derived from dihydrochalcones

A series of novel urea, sulfamide and N,N-dipropargyl substituted benzylamines were synthesized from dihydrochalcones. The synthesized compounds were evaluated for their cholinesterases and carbonic anhydrase inhibitory actions. The known dihydrochalcones were converted into four new benzylamines via reductive amination. N,N-Dipropargylamines, ureas and sulfamides were synthesized following the reactions of benzylamines with propargyl bromide, N,N-dimethyl sulfamoyl chloride and N,N-dimethyl carbamoyl chloride. The novel substituted benzylamines derived from dihydrochalcones were evaluated against some enzymes such as human erythrocyte carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The novel substituted benzylamines derived from dihydrochalcones exhibited K_i values in the range of 0.121–1.007 nM on hCA I, and 0.077–0.487 nM on hCA II closely related to several pathological processes. On the other hand, K_i values were found in the range of 0.112–0.558 nM on AChE, 0.061–0.388 nM on BChE. As a result, novel substituted benzylamines derived from dihydrochalcones showed potent inhibitory profiles against indicated metabolic enzymes. In addition, Induced-Fit Docking (IFD) simulations and ADME prediction studies have also been carried out to elucidate the inhibition mechanisms and drug-likeness of the synthesized compounds. Therefore, these results can make significant contributions to the treatment of some global diseases, especially Alzheimer's diseases and glaucoma, and the development of new drugs.     

Novel Mannich bases with strong carbonic anhydrases and acetylcholinesterase inhibition effects: 3-(aminomethyl)-6-{3-[4-(trifluoromethyl)phenyl]acryloyl}-2(3H)-benzoxazolones

In this study, a new series of Mannich bases, 3-(aminomethyl)-6-{3-[4-(trifluoromethyl)phenyl]acryloyl}-2( 3H )-benzoxazolones ( 1a–g ), were synthesized by the Mannich reaction. Inhibitory effects of the newly synthesized compounds towards carbonic anhydrases (CAs) and acetylcholinesterase (AChE) enzymes were evaluated to find out new potential drug candidate compounds. According to the inhibitory activity results, K_i values of the compounds 1 and 1a–g were in the range of 12.3 ± 1.2 to 154.0 ± 9.3 nM against hCA I, and they were in the range of 8.6 ± 1.9 to 41.0 ± 5.5 nM against hCA II. Ki values of acetazolamide (AZA) that was used as a reference compound were 84.4 ± 8.4 nM towards hCA I and 59.2 ± 4.8 nM towards hCA II. K_i values of the compounds 1 and 1a–g were in the range of 35.2 ± 2.0 to 158.9 ± 33.5 nM towards AChE. K_i value of Tacrine (TAC), the reference compound, was 68.6 ± 3.8 nM towards AChE. Furthermore, docking studies were done with the most potent compounds 1d , 1g , and 1f (in terms of hCA I, hCA II, and AChE inhibition effects, respectively) to determine the binding profiles of the series with these enzymes. Additionally, the prediction of ADME profiles of the compounds pointed out that the newly synthesized compounds had desirable physicochemical properties as lead compounds for further studies.     

Synthesis and investigation of antibacterial activities and carbonic anhydrase and acetyl cholinesterase inhibition profiles of novel 4,5-dihydropyrazol and pyrazolyl-thiazole derivatives containing methanoisoindol-1,3-dion unit

Novel 4,5-dihydropyrazole derivatives (3a–i), 3-(4-((3aR,4S,7R,7aS)-1,3-dioxo-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindol-2(3H)-yl)phenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbothio amide, were obtained by the addition of thiosemicarbazide (2) to the chalcones (1a–i). The addition–cyclization of 2,4′-dibromoacetophenone (4) to pyrazole derivatives (3a–i) gave the new pyrazolyl-thiazole derivatives (5a–i), (3aR,4S,7R,7aS)-2-(4-(1-(4-(4-bromophenyl)thiazol-2-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione. Antibacterial and acetylcholinesterase (AChE) enzyme and human carbonic anhydrase (hCA) I, and II isoform inhibitory activities of the compounds 3a–i and 5a–i were investigated. Some of the compounds showed promising antibacterial activity. In addition, the hCA II and I were effectively inhibited by the lately synthesized derivatives, with K_i values in the range of 18.90?±?2.37 ?58.25?±?13.62?nM for hCA II and 5.72?±?0.98 ?37.67?±?5.54?nM for hCA I. Also, the K_i parameters of these compounds for AChE were obtained in the range of 25.47?±?11.11???255.74?±?82.20?nM. Also, acetazolamide, clinical molecule, was used as a CA standard inhibitor that showed K_i value of 70.55?±?12.30?nM against hCA II, and 67.17?±?9.1?nM against hCA I, and tacrine inhibited AChE showed K_i value of 263.67?±?91.95.     

Synthesis and inhibition profiles of N-benzyl- and N-allyl aniline derivatives against carbonic anhydrase and acetylcholinesterase – A molecular docking study

The alkyl and aryl derivatives of aniline are important starting materials in fine organic synthesis. Allyl bromide and benzyl chloride were taken as substrates for the alkylation reaction and as a halide ion scavenger. Triethylamine was utilized at reflux condition of N,N-dimethylacetamide (DMA). Novel synthesized N-benzyl and N-allyl aniline derivatives (1a-f) were evaluated to be highly potent inhibitors for acetylcholinesterase (AChE) and carbonic anhydrases (hCAs). The half maximal inhibitory concentration (IC₅₀) of N-benzyl- and N-allyl aniline derivatives were calculated between 243.11 and 633.54 nM for hCA I, 296.32–518.37 nM for hCA II and 182.45–520.21 nM for AChE enzymes. On the other hand, K_i values are in the range of 149.24 ± 15.59 to 519.59 ± 102.27 nM for AChE, 202.12 ± 16.21 to 635.31 ± 45.33 nM for hCA I and 298.57 ± 94.13 to 511.18 ± 115.98 nM for hCA II isoenzyme. Additionally, in silico molecular docking computations were performed with Autodock Vina program to support the experimental in vitro studies for both hCAs and AChE inhibitors. The in silico molecular docking results demonstrated that the scores are in good agreement with the experimental results.     

Synthesis,characterization and biological evaluation of N-substituted triazinane-2-thiones and theoretical–experimental mechanism of condensation reaction

The synthesis of triazinthions and their reactions with some nucleophilic reagents have been investigated during this scientific study. Thus, thiourea with a single component has been synthesized as a result of concomitant reactions of aldehyde and amines trials. The structure of the synthesized compounds was confirmed by ¹H, ¹³C NMR spectroscopy methods. The inhibitory effects of novel N-substituted triazinane-2-thione derivatives on acetylcholinesterase (AChE) activity were performed according to the spectrophotometric method of Ellman et al. These novel N-substituted triazinane-2-thiones derivatives were effective inhibitors of the α-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and Acetylcholinesterase (AChE) enzymes with K_i values in the range of 1.01 ± 0.28 to 2.12 ± 0.37 nm for α-glycosidase, 13.44 ± 4.39 to 74.98 ± 6.25 nm for hCA I, 10.41 ± 4.8 to 72.6 ± 17.66 nm for hCA II, 36.82 ± 9.95 to 108.48 ± 1.17 nm for AChE, and 624.62 ± 100.34 to 1124.16 ± 205.14 nm for α-glycosidase, respectively.     

Synthesis and pharmacological effects of novel benzenesulfonamides carrying benzamide moiety as carbonic anhydrase and acetylcholinesterase inhibitors

N -(1-(4-Methoxyphenyl)-3-oxo-3-((4-( N -(substituted)sulfamoyl)phenyl)amino)prop-1-en-1-yl)benzamides 3a – g were designed since sulfonamide and benzamide pharmacophores draw great attention in novel drug design due to their wide range of bioactivities including acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and hCA II) inhibitory potencies. Structure elucidation of the compounds was carried out by 1H NMR, 13C NMR, and HRMS spectra. In vitro enzyme assays showed that the compounds had significant inhibitory potential against hCA I, hCA II, and AChE enzymes at nanomolar levels. Ki values were in the range of 4.07 ± 0.38 – 29.70 ± 3.18 nM for hCA I and 10.68 ± 0.98 – 37.16 ± 7.55 nM for hCA II while Ki values for AChE were in the range of 8.91 ± 1.65 – 34.02 ± 5.90 nM. The most potent inhibitors 3g (Ki = 4.07 ± 0.38 nM, hCA I), 3c (Ki = 10.68 ± 0.98 nM, hCA II ) , and 3f (Ki = 8.91 ± 1.65 nM, AChE) can be considered as lead compounds of this study with their promising bioactivity results. Secondary sulfonamides showed promising enzyme inhibitory effects on AChE while primary sulfonamide derivative was generally effective on hCA I and hCA II isoenzymes.     

Synthesis,antioxidant, and anticholinesterase activities of novel N-arylsulfonyl hydrazones bearing sulfonate ester scaffold

In this research, two new series of N-arylsulfonyl hydrazone compounds ( 14 – 25 ) possessing a sulfonate moiety were synthesized and characterized by elemental analysis and various spectroscopic techniques including fourier transform infrared (FT-IR), ¹H-, and ¹³C nuclear magnetic resonance (NMR). These compounds synthesized as target molecules ( 14 – 25 ) were tested for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition activities and antioxidant potential. The antioxidant capacities of the tested molecules were determined by four different assays. The IC₅₀ values of the screened molecules were determined in the range of 60.14 ± 0.25–84.81 ± 1.09 μM against AChE and in the range of 70.11 ± 0.67–93.60 ± 0.47 μM against BChE. In the AChE assay, 4-hydroxybenzaldehyde-based compound 25 (60.14 ± 0.25 μM) showed the highest activity in comparison to rivastigmine (501 ± 3.08 μM). This compound (71.42 ± 0.19 μM) is also one of the compounds with the highest activity against BChE. In the BChE assay, 2-hydroxybenzaldehyde-based compound 19 (70.11 ± 0.67 μM) indicated the highest activity in comparison to rivastigmine (19.95 ± 0.20 μM). In antioxidant activity studies, the tested molecules showed lower activities than the standard compounds (butylated hydroxytoluene and α-tocopherol). Consequently, some novel compounds can be used as potential inhibitor candidates in future studies.     

Fluorescent Silica Nanoparticles with Multivalent Inhibitory Effects towards Carbonic Anhydrases

Multifunctional silica nanoparticles decorated with fluorescent and sulfonamide carbonic anhydrase (CA) inhibitors were prepared and investigated as multivalent enzyme inhibitors against the cytosolic isoforms hCA I and II and the transmembrane tumor‐associated ones hCA IX and XII. Excellent inhibitory effects were observed with these nanoparticles, with K_I values in the low nanomolar range (6.2–0.67 nM ) against all tested isozymes. A significant multivalency effect was seen for the inhibition of the monomeric enzymes hCA I and II compared to the dimeric hCA IX and hCA XII isoforms, where no multivalent effect was observed, suggesting that the multivalent binding is occurring through enzyme clustering.     

2-methylindole analogs as cholinesterases and glutathione S-transferase inhibitors: Synthesis,biological evaluation,molecular docking,and pharmacokinetic studies

In this study, we aimed to (i) synthesize new 2-methylindole analogs containing various amino structures, pyrrolidine, piperidine, morpholine, and substituted phenyl groups through structural and molecular modifications, (ii) evaluate the pharmaceutical potential of 2-methylindole analogs via assessing enzyme inhibitory activity against glutathione S-transferase (GST), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), (iii) predict ADMET and pharmacokinetic properties of the synthesized 2-methylindole analogs, (iv) reveal the possible interactions between the synthesized 2-methylindole analogs with GST, AChE, and BChE enzymes using several molecular docking software. In vitro enzyme inhibition assays showed that the synthesized indole analogs exhibited moderate to good inhibitory activities against GST, AChE, and BChE enzymes. Briefly, the inhibitory activities of the analogs 4b and 4i against AChE, 4a and 4b against BChE, and analogs 1 and 4i against GST were detected to be higher or close to the standard inhibitor compounds. The analog 4b was detected to have the best inhibitory activity against both AChE and BChE enzymes with the lowest IC₅₀ values as 0.648 µM for AChE and 0.745 µM for BChE. The analyses of enzyme inhibition relationship with the synthesized analogs could help to design new analogs for the inhibitors of cholinergic and glutathione pathways based on the indole derivatives.     

Synthesis,cytotoxic, and carbonic anhydrase inhibitory effects of new 2-(3-(4-methoxyphenyl)-5-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)benzo[d]thiazole derivatives

2-(3-[4-Methoxyphenyl]-5-aryl-4,5-dihydro-1H-pyrazol-1-yl)benzo[d]thiazoles ( 1b-7b ) were synthesized for the first time except 1b , and spectral methods such as ¹H NMR, ¹³C NMR and HRMS were utilized to illuminate the chemical structures of the synthesized compounds. Phenyl ( 1b ), 2-methoxyphenyl ( 2b ), 4-methoxyphenyl ( 3b ), 4-methoxy-3-hydroxyphenyl ( 4b ), 2,5-dimethoxyphenyl ( 5b ), 3,4,5-trimethoxyphenyl ( 6b ), or thiophene-2-yl ( 7b ) was used as a aryl part. The inhibitory effects of the compounds were evaluated toward human carbonic anhydrase I and II enzymes (hCA I and hCA II). In vitro cytotoxic effects of the compounds against human oral squamous carcinomas and human normal oral cells were carried out via MTT. The compounds ( 1b-7b ) had Ki values of 36.87 ± 11.62-66.24 ± 2.99 μM (hCA I) and 22.66 ± 1.41-89.95 ± 6.25 μM (hCA II). Compounds 1b (Ki = 36.87 ± 11.62 μM) toward hCA I, 6b (Ki = 22.66 ± 1.41 μM) toward hCA II had significant enzyme inhibitory potency. Compound 6b had the highest tumor selectivity (TS = 29.3) and potency selectivity expression (PSE = 272.3) values. Therefore, compounds 1b and 6b with CAs inhibition effect and compound 6b with the cytotoxicity may be forwarded to further studies as potent compounds.     

Synthesis,Characterization, and Investigation of Cholinesterase Inhibitory Properties of Novel Phthalocyanines

In this study, 4‐{2‐(2‐thienyl)ethoxy}phthalonitrile ( 3 ) and its tetra substituted peripherally metal‐free ( 4 ), lead (II) ( 5 ), magnesium (II) ( 6 ), and cobalt (II) ( 7 ) phthalocyanines were synthesized. The structural characterization of the obtained compounds was performed by a combination of FTIR, ¹H‐NMR, UV–vis, and MALDI‐TOF techniques. The inhibitory properties of these compounds were determined using Ingkaninan's methods against cholinesterase enzymes. Compound ( 7 ) had the highest enzyme inhibitory effect toward AChE and BuChE enzymes with IC₅₀ values of 23.71 ± 0.39 and 27.29 ± 0.22 μM, respectively. The enzyme kinetic study of compound ( 7 ) demonstrated noncompetitive AChE inhibition and uncompetitive BuChE inhibition. The K_i values of compound ( 7 ) against AChE and BuChE were found to 39.15 and 7.25 μM, respectively. In the tested compounds, ( 7 ) deserves further investigation for potential therapeutic candidates of Alzheimer's disease.     

First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease

Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer’s disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a K_i value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental K_i values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.     

Synthesis and bioactivities of 1-(4-hydroxyphenyl)-2-((heteroaryl)thio)ethanones as carbonic anhydrase I,II and acetylcholinesterase inhibitors

The discovery of enzyme targeting inhibitors is a popular area of drug research. Biological activities of the compounds bearing phenol and heteroaryl groups make them popular groups in drug design targeting important enzymes such as acetylcholinesterase (AChE, E.C.3.1.1.7) and carbonic anhydrases (CAs, EC 4.2.1.1). 1-(4-hydroxyphenyl)- 2-((aryl)thio)ethanones as possible AChE and CAs inhibitors were synthesized, and their chemical structures were confirmed by IR, ¹H NMR, ¹³C NMR, and HRMS. The compounds 2 and 4 were found potent AChE inhibitors with the Ki values of 22.13 ±1.96 nM and 23.71 ±2.95 nM, respectively, while the compounds 2 (Ki = 8.61 ±0.90 nM, on hCA I) and 1 (Ki = 8.76 ±0.84 nM, on hCA II) had considerable CAs inhibitory potency. The lead compounds may help the scientists for the rational designing of an innovative class of drug candidates targeting enzyme-based diseases.     

Synthesis and biological evaluation of new pyrazolebenzene-sulphonamides as potential anticancer agents and hCA I and II inhibitors

Cancer is a disease characterized by the continuous growth of cells without adherence to the rules that healthy normal cells obey. Carbonic anhydrase I and II (CA I and CA II) inhibitors are used for the treatment of some diseases. The available drugs in the market have limitations or side effects, which bring about the need to develop new drug candidate compound(s) to overcome the problems at issue. In this study, new pyrazole-sulphonamide hybrid compounds 4-[5-(1,3-benzodioxol-5-yl)-3-aryl-4,5-dihydro-1 H -pyrazol-1-yl]benzenesulphonamides (4a - 4j) were designed to discover new drug candidate compounds. The compounds 4a - 4j were synthesized and their chemical structures were confirmed using spectral techniques. The hypothesis tested was whether an introduction of methoxy and polymethoxy group(s) lead to an increased potency selectivity expression (PSE) value of the compound, which reflects cytotoxicity and selectivity of the compounds. The cytotoxicity of the compounds towards tumor cell lines were in the range of 6.7 – 400 µM. The compounds 4i (PSE₂ = 461.5) and 4g (PSE₁ = 193.2) had the highest PSE values in cytotoxicity assays. Ki values of the compounds were in the range of 59.8 ± 3.0 - 12.7 ± 1.7 nM towards hCA I and in the range of 24.1 ± 7.1 - 6.9 ± 1.5 nM towards hCA II. While the compounds 4b, 4f, 4g, and 4i showed promising cytotoxic effects, the compounds 4c and 4g had the inhibitory potency towards hCA I and hCA II, respectively. These compounds can be considered as lead compounds for further research.     

Synthesis,spectroscopic characterization,crystal structure,density functional theory studies and biological properties of coordination complex Ni(II) 2-fluorobenzoate with 3-hydroxypyridine

A novel Ni(II) complex containing 2-fluorobenzoate and 3-hydroxypyridine ligands was synthesized and characterized using elemental analysis, Fourier transform infrared (FT-IR) spectroscopy and single-crystal X-ray diffraction. FT-IR peaks show that the carboxylate group from 2-fluorobenzoate has a monodentate coordination mode. The coordination environment around the Ni²⁺ ion is of distorted octahedral geometry. The octahedral geometry consists of a total of four oxygen atoms from two carboxylate groups of two fluorobenzoate anions, two water molecules and two nitrogen atoms from two 3-hydroxypyridine ligands. The complex shows excellent inhibitory effects against some metabolic enzymes. K_i values for the complex were found as 108.17 ± 25.63, 124.88 ± 36.20, 28.11 ± 2.87, 20.95 ± 5.65 and 32.63 ± 9.67 μM against human carbonic anhydrase I, human carbonic anhydrase II, α-glycosidase, acetylcholinesterase and butyrylcholinesterase, respectively. In addition, geometry optimization and vibration frequencies were calculated, and single point energy was studied based on optimization. Experimental and theoretical data were compared. The B3LYP/6-31G(d,p) basis set was used for all calculations.     

New naphthalene derivative for cost-effective AChE inhibitors for Alzheimer’s treatment: In silico identification,in vitro and in vivo validation

Neurodegenerative diseases have complex etiology and pose a challenge to scientists to develop simple and cost-effective synthetic compounds as potential drug candidates for such diseases. Here, we report an extension of our previously published in silico screening, where we selected four new compounds as AChE inhibitors. Further, based on favorable binding possess, MD simulation and MMGBSA, two most promising compounds (3a and 3b) were selected, keeping in view the ease of synthesis and cost-effectiveness. Due to the critical role of BChE, LOX and α-glucosidase in neurodegeneration, the selected compounds were also screened against these enzymes.The IC₅₀ values of 3a against AChE and BChE found to be 12.53 and 352.42 μM, respectively. Moderate to slight inhibitions of 45.26 % and 28.68 % were presented by 3a against LOX and α-glucosidase, respectively, at 0.5 mM. Insignificant inhibitions were observed with 3b against the four selected enzymes. Further, in vivo trial demonstrated that 3a could significantly diminish AChE levels in the mice brain as compared to the control. These findings were in agreement with the histopathological analysis of the brain tissues. The results corroborate that selected compounds could serve as a potential lead for further development and optimization as AChE inhibitors to achieve cost-effective anti-Alzheimer’s drugs.     

Epoxy Type Inhibitors of Cholesterol Esterase,Acetylcholinesterase, and Butyrylcholinesterase

Epoxy type inhibitors, 3‐t‐butylphenyl 3‐1,2‐epoxybutyl ether ( 1 ), 3‐t‐butylphenyl 3‐1,2‐epoxyhexyl ether ( 2 ), and 2‐naphthyl 3‐1,2‐epoxyhexyl ether ( 3 ) are synthesized as the active site‐directed inhibitors of cholesterol esterase, acetylcholinesterase, and butyrylcholinesterase. All epoxy compounds are characterized as the time‐independent inhibitors for all three enzymes from the stopped‐time assay. Further, all epoxy compounds are characterized as the competitive inhibitors for all three enzymes from the Lineweaver‐Burk plots. The inhibition constants (K_i) of cholesterol esterase for compounds 1‐3 are 320 ± 40, 190 ± 20, 130 ± 20 μM, respectively. The K_i values of acetylcholinesterase for compounds 1‐3 are 490 ± 20, 141 ± 5, 200 ± 30 μM, respectively. Values of K_i of butyrylcholinesterase for compounds 1‐3 are 250 ± 30, 26 ± 4, 120 ± 20 μM, respectively. Compound 2 is the most potent inhibitor for butyrylcholinesterase probably because the compound mimics most the natural substrate, butyrylcholine.     

Peripheral or nonperipheral tetra‐[4‐(9H‐carbazol‐9‐yl)phenoxy] substituted cobalt(II), manganese(III) phthalocyanines: Synthesis,acetylcholinesterase, butyrylcholinesterase,and α‐glucosidase inhibitory effects and anticancer activities

In this work, peripheral or nonperipheral tetra‐[4‐(9H‐carbazol‐9‐yl)phenoxy] substituted cobalt(II), manganese (III) phthalocyanines were synthesized for the first time. Their acetylcholinesterase from Electrophorus electricus (AChE), butyrylcholinesterase equine serum (BuChE), and α‐glucosidase Saccharomyces cerevisiae inhibition were investigated spectrophotometrically. Finally, in vitro cytotoxicities of the compounds were investigated on human neuroblastoma (SH‐SY5Y) cell line using MTT cell viability assay. The compounds inhibited to enzymes in the range of 7.39 ± 0.25–35.29 ± 2.49 μM with IC₅₀ values for AChE and 14.38 ± 0.66–58.02 ± 4.94 μM for BuChE as compared with galantamine, which used as a positive control. For α‐glucosidase, all compounds had stronger inhibition action than acarbose according to the IC₅₀ values. The IC₅₀ values of N? Co and N? Mn were found to be 3.05 ± 0.10 and 15.82 ± 1.85 μM, respectively. The results of cytotoxicity showed that the IC₅₀ values were above 100 μM showing the compounds had low cytotoxic action against SH‐SY5Y cell line for 24 h. Overall, carbazole substituted nonperipheral compounds can be considered as a potential agent for the treatment of Alzheimer's diseases and diabetes mellitus.     

New Histamine-Related Five-Membered N-Heterocycle Derivatives as Carbonic Anhydrase I Activators

A series of histamine (HST)-related compounds were synthesized and tested for their activating properties on five physiologically relevant human Carbonic Anhydrase (hCA) isoforms (I, II, Va, VII and XIII). The imidazole ring of HST was replaced with different 5-membered heterocycles and the length of the aliphatic chain was varied. For the most interesting compounds some modifications on the terminal amino group were also performed. The most sensitive isoform to activation was hCA I (K_A values in the low micromolar range), but surprisingly none of the new compounds displayed activity on hCA II. Some derivatives (1, 3a and 22) displayed an interesting selectivity for activating hCA I over hCA II, Va, VII and XIII.