Inhibition profiles of Voriconazole against acetylcholinesterase, α‐glycosidase,and human carbonic anhydrase I and II isoenzymes

In this work, the inhibitory activity of Voriconazole was measured against some metabolic enzymes, including human carbonic anhydrase (hCA) I and II isoenzymes, acetylcholinesterase (AChE), and α‐glycosidase; the results were compared with standard compounds including acetazolamide, tacrine, and acarbose. Half maximal inhibition concentration (IC₅₀) values were obtained from the enzyme activity (%)‐[Voriconazole] graphs, whereas K_i values were calculated from the Lineweaver‐Burk graphs. According to the results, the IC₅₀ value of Voriconazole was 40.77 nM for α‐glycosidase, while the mean inhibition constant (K_i) value was 17.47 ± 1.51 nM for α‐glycosidase. The results make an important contribution to drug design and have pharmacological applications. In addition, the Voriconazole compound demonstrated excellent inhibitory effects against AChE and hCA isoforms I and II. Voriconazole had K_i values of 29.13 ± 3.57 nM against hCA I, 15.92 ± 1.90 nM against hCA II, and 10.50 ± 2.46 nM against AChE.     

The human carbonic anhydrase isoenzymes I and II inhibitory effects of some hydroperoxides,alcohols, and acetates

The carbonic anhydrases (CAs, EC 4.2.1.1) represent a superfamily of widespread enzymes, which catalyze a crucial biochemical reaction, the reversible hydration of carbon dioxide to bicarbonate and protons. Human CA isoenzymes I and II (hCA I and hCA II) are ubiquitous cytosolic isoforms. In this study, a series of hydroperoxides, alcohols, and acetates were tested for the inhibition of the cytosolic hCA I and II isoenzymes. These compounds inhibited both hCA isozymes in the low nanomolar ranges. These compounds were good hCA I inhibitors (K_is in the range of 24.93–97.99?nM) and hCA II inhibitors (K_is in the range of 26.04–68.56?nM) compared to acetazolamide as CA inhibitor (K_i: 34.50?nM for hCA I and K_i: 28.93?nM for hCA II).     

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Benzothiazepine compounds have a wide range of applications such as antibacterial, antidepressants, anticonvulsants, antihypertensives, antibiotics, antifungal, hypnotic, enzyme inhibitors, antitumor, anticancer and anti‐HIV agents. In this study, the synthesis of novel tetralone‐based benzothiazepine derivatives ( 1–16 ) and their in vitro antibacterial activity and human carbonic anhydrase isoenzymes I and II (hCA I and II) inhibitory effects were investigated. Both isoenzymes were purified by sepharose‐4B‐l ‐tyrosine‐sulfanilamide affinity chromatography from fresh human red blood cells. All compounds demonstrated the low nanomolar inhibitory effects on both isoenzymes using esterase activity. Benzothiazepine derivative 2 demonstrated the best hCA I inhibitory effect with K_i value of 18.19 nM. Also, benzothiazepine derivative 7 showed the best hCA II inhibitory effect with K_i value of 11.31 nM. On the other hand, acetazolamide clinically used as CA inhibitor, showed K_i value of 19.92 nM against hCA I and 33.60 nM against hCA II, respectively.     

Synthesis and Characterization of Novel 1,3-Diaryltriazene-Substituted Sulfaguanidine Derivatives as Selective Carbonic Anhydrase Inhibitors: Biological Evaluation,in Silico ADME/T and Molecular Docking Study

Sulfonamide compounds known as human carbonic anhydrase (hCA) inhibitors are used in the treatment of many diseases such as epilepsy, antibacterial, glaucoma, various diseases. 1,3-diaryl-substituted triazenes and sulfaguanidine are used for therapeutic purposes in many drug structures. Based on these two groups, the synthesis of new compounds is important. In the present study, the novel 1,3-diaryltriazene-substituted sulfaguanidine derivatives ( SG1-13 ) were synthesized and fully characterized by spectroscopic and analytic methods. Inhibitory effect of these compounds on the hCA I and hCA II was screened as in vitro. All the series of synthesized compounds have been identified as potential hCA isoenzymes inhibitory with K_I values in the range of 6.44±0.74-86.85±7.01 nM for hCA I and with K_I values in the range of 8.16±0.40-77.29±9.56 nM for hCA II. Moreover, the new series of compounds showed a more effective inhibition effect than the acetazolamide used as a reference. The possible binding positions of the compounds with a binding affinity to the hCA I and hCA II was demonstrated by in silico studies. In conclusion, compounds with varying degrees of affinity for hCA isoenzymes have been designed and as selective hCA inhibitors. These compounds may be potential alternative agents that can be used to treat or prevent diseases associated with glaucoma and hCA inhibition.     

Synthesis and inhibitory properties of some carbamates on carbonic anhydrase and acetylcholine esterase

A series of carbamate derivatives were synthesized and their carbonic anhydrase I and II isoenzymes and acetylcholinesterase enzyme (AChE) inhibitory effects were investigated. All carbamates were synthesized from the corresponding carboxylic acids via the Curtius reactions of the acids with diphenyl phosphoryl azide followed by addition of benzyl alcohol. The carbamates were determined to be very good inhibitors against for AChE and hCA I, and II isoenzymes. AChE inhibition was determined in the range 0.209–0.291?nM. On the other hand, tacrine, which is used in the treatment of Alzheimer’s disease possessed lower inhibition effect (K_i: 0.398?nM). Also, hCA I and II isoenzymes were effectively inhibited by the carbamates, with inhibition constants (K_i) in the range of 4.49–5.61?nM for hCA I, and 4.94–7.66?nM for hCA II, respectively. Acetazolamide, which was clinically used carbonic anhydrase (CA) inhibitor demonstrated K_i values of 281.33?nM for hCA I and 9.07?nM for hCA II. The results clearly showed that AChE and both CA isoenzymes were effectively inhibited by carbamates at the low nanomolar levels.     

Synthesis of novel benzenesulfonamide bearing 1,2,3-triazole linked hydroxy-trifluoromethylpyrazolines and hydrazones as selective carbonic anhydrase isoforms IX and XII inhibitors

A series of twenty four hydroxy-trifluoromethylpyrazoline-carbonyl-1,2,3-triazoles and four hydrazones bearing benzenesulfonamide moieties was obtained by condensation of carboxyhydrazides with substituted 1,3-diketones. All the newly synthesized compounds were investigated as inhibitors of physiologically and pharmacologically relevant human (h) carbonic anhydrsae (CA, EC 4.2.1.1) cytosolic isoforms hCA I and II, as well as transmembrane tumor-assosciated isoforms hCA IX and XII. These compounds exhibited excellent CA inhibitory potency against the four CA isoenzymes as compared to clinically used reference drug acetazolamide (AAZ). Some compounds bearing bulkier group at C-5′ position of 1,2,3-triazoles ring were weaker inhibitors of hCA I. Inhibition assay against hCA II indicates, that several derivatives exhibited upto 27-fold more effective inhibitory activity compared to AAZ. Five of the assayed compounds displayed low nanomolar potency (K_i ≤ 10 nM) against hCA IX, whereas five compounds were found to be endowed with excellent inhibitory potencies (K_i ≤ 5 nM) against hCA XII. The biological activity profile presented herein will be useful for designing new leads and provide candidates for preclinical investigations.     

Evaluation of antimicrobial,antibiofilm and carbonic anhydrase inhibition profiles of 1,3‐bis‐chalcone derivatives

A series of 1,3‐bis‐chalcone derivatives ( 3a‐i, 6a‐i and 8 ) were synthesized and evaluated antimicrobial, antibiofilm and carbonic anhydrase inhibition activities. In this evaluation, 6f was found to be the most active compound showing the same effect as the positive control against Bacillus subtilis and Streptococcus pyogenes in terms of antimicrobial activity. Biofilm structures formed by microorganisms were damaged by compounds at the minimum inhibitory concentration value between 0.5% and 97%.1,3‐bis‐chalcones ( 3a‐i, 6a‐i and 8 ) showed good inhibitory action against human (h) carbonic anhydrase (CA) isoforms I and II. hCA I and II were effectively inhibited by these compounds, with K _i values in the range of 94.33 ± 13.26 to 787.38 ± 82.64 nM for hCA I, and of 100.37 ± 11.41 to 801.76 ± 91.11 nM for hCA II, respectively. In contrast, acetazolamide clinically used as CA inhibitor showed K _i value of 1054.38 ± 207.33 nM against hCA I, and 983.78 ± 251.08 nM against hCA II, respectively.     

Investigation of the effects of some sulfonamides on acetylcholinesterase and carbonic anhydrase enzymes

Human carbonic anhydrase I and II isoenzymes (hCA I and II) and acetylcholinesterase (AChE) are important metabolic enzymes that are closely associated with various physiological and pathological processes. In this study, we investigated the inhibition effects of some sulfonamides on hCA I, hCA II, and AChE enzymes. Both hCA isoenzymes were purified by Sepharose‐4B‐L‐Tyrosine‐5‐amino‐2‐methylbenzenesulfonamide affinity column chromatography with 1393.44 and 1223.09‐folds, respectively. Also, some inhibition parameters including IC₅₀ and K_i values were determined. Sulfonamide compounds showed IC ₅₀ values of in the range of 55.14 to 562.62 nM against hCA I, 55.99 to 261.96 nM against hCA II, and 98.65 to 283.31 nM against AChE. K_i values were in the range of 23.40 ± 9.10 to 365.35 ± 24.42 nM against hCA I, 45.87 ± 5.04 to 230.08 ± 92.23 nM against hCA II, and 16.00 ± 45.53 to 157.00 ± 4.02 nM against AChE. As a result, sulfonamides had potent inhibition effects on these enzymes. Therefore, we believe that these results may contribute to the development of new drugs particularly in the treatment of some disorders.     

1,2,4-Trisubstituted imidazolinones with dual carbonic anhydrase and p38 mitogen-activated protein kinase inhibitory activity

Various 1,2,4 trisubstituted imidazolin-5-one derivatives were synthesized and evaluated for their inhibitory activity against p38 mitogen-activated protein kinase (p38MAPK) and carbonic anhydrase (CA) enzymes aiming to explore potential dual inhibitors. Results revealed that compounds 3c, 3g, 3h, 4a, 6c and 6d were the most effective derivatives against p38αMAPK (IC₅₀ = 0.14, 0.14, 0.056, 0.14, 0.13 and 0.14 μM, respectively) compared to sorafenib (IC₅₀ = 1.58 μM) as standard drug. On the other hand, compound 4a revealed the best inhibitory activity against all the tested carbonic anhydrase isoforms CA I, II, IV and IX with K_i values of 95.0, 0.83, 6.90 and 12.4 nM, respectively compared to acetazolamide with K_i values 250, 12.1, 74 and 12.8 nM, respectively. Therefore, compound 4a can be considered as a potent dual p38αMAPK/CA inhibitor.     

The synthesis of novel sulfamides derived from β-benzylphenethylamines as acetylcholinesterase,butyrylcholinesterase and carbonic anhydrase enzymes inhibitors

In this study, a series of novel β-benzylphenethylamines and their sulfamide derivatives were synthesized starting from (Z)-2,3-diphenylacrylonitriles. Pd-C catalysed hydrogenation of diphenylacrylonitriles, reduction of propanenitriles with LiAlH₄ in the presence of AlCl₃ followed by addition of conc. HCl afforded β-benzylphenethylamine hydrochloride salts. The reactions of these amine hydrochloride salts with chlorosulfonyl isocyanate (CSI) in the presence of tert-BuOH and excess Et₃N gave sulfamoylcarbamates. Removing of Boc group from the synthesized sulfamoylcarbamates with trifluoroacetic acid (TFA) yielded novel sulfamides in good yields. These novel sulfamides derived from β-benzylphenethylamines were effective inhibitors of the cytosolic carbonic anhydrase I and II isoenzymes (hCA I and II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with K_i values in the range of 0.278–2.260 nM for hCA I, 0.187–1.478 nM for hCA II, 0.127–2.452 nM for AChE and 0.494–1.790 nM for BChE. The inhibitory effects of the synthesized novel sulfamides derived from β-benzylphenethylamines were compared to those of acetazolamide and dorzolamide as clinical hCA I and II isoenzymes inhibitors and tacrine as a clinical AChE and BChE enzymes inhibitors. In addition to in vitro tests, molecular modeling approaches are implemented not only for prediction of the binding affinities of the compounds but also to study their inhibition mechanisms in atomic level at the catalytic domains.     

Inhibition pattern of sulfamide-related compounds in binding to carbonic anhydrase isoforms I,II, VII,XII and XIV

A set of sulfamides and sulfamates were synthesized and tested against several isoforms of carbonic anhydrase: CA I, CA II, CA VII, CA XII and CA XIV. The biological assays showed a broad range of inhibitory activity, and interesting results were found for several compounds in terms of activity (K_i <1 μm) and selectivity: some aromatic sulfamides are active against CA I, CA II and/or CA VII; while they are less active in CA XII and CA XIV. On the other hand, bulky sulfamides are selective to CA VII. To understand the origin of the different inhibitory activity against each isozyme we used molecular modeling techniques such as docking and molecular dynamic simulations.     

1H‐indazole molecules reduced the activity of human erythrocytes carbonic anhydrase I and II isoenzymes

Carbonic anhydrase (CA) is an important metabolic enzyme family closely related to many physiological and pathological processes. Currently, carbonic anhydrase inhibitors are the target molecules in the treatment and diagnosis of many diseases. In present study, we investigated the inhibitory effects of some indazole molecules on the CA‐I and CA‐II isoenzymes isolated from human erythrocytes. We showed that human CA‐I and CA‐II activities were reduced by of some indazoles at low concentrations. IC₅₀ values, K_i constants, and inhibition types for each indazole molecule were determined. The indazoles showed K_i constants in a range of 0.383 ± 0.021 to 2.317 ± 0.644 mM, 0.409 ± 0.083 to 3.030 ± 0.711 mM against CA‐I and CA‐II, respectively. Each indazole molecule exhibited a noncompetitive inhibition effect. Bromine‐ and chlorine‐bonded indazoles were found to be more potent inhibitory effects on carbonic anhydrase isoenzymes. In conclusion, we conclude that these results may be useful in the synthesis of carbonic anhydrase inhibitors.     

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 K_i 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 K_i 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.     

Novel N‐propylphthalimide‐ and 4‐vinylbenzyl‐substituted benzimidazole salts: Synthesis,characterization, and determination of their metal chelating effects and inhibition profiles against acetylcholinesterase and carbonic anhydrase enzymes

The novel N‐propylphthalimide‐substituted and 4‐vinylbenzyl‐substituted N‐heterocyclic carbene (NHC) precursors were synthesized by N‐substituted benzimidazolium with aryl halides. The novel N‐propylphthalimide‐substituted and 4‐vinylbenzyl‐substituted NHC precursors have been characterized by using ¹H NMR, ¹³C NMR, FTIR spectroscopy, and elemental analysis techniques. They were tested for the inhibition of AChE and hCA enzymes and demonstrated efficient inhibition profiles with K_i values in the range of 351.0–1269.9 nM against hCA I, 346.6–1193.1 nM against hCA II, and 19.0–76.3 nM against AChE. On the other hand, acetazolamide, a clinically used molecule, utilized as CA inhibitor, obtained a K_i value of 1246.7 nM against hCA I and 1407.6 nM against hCA II. Additionally, tacrine inhibited AChE and obtained a K_i value of 174.6 nM.     

Synthesis,molecular modelling and QSAR study of new N-phenylacetamide-2-oxoindole benzensulfonamide conjugates as carbonic anhydrase inhibitors with antiproliferative activity

In continuation of our previous studies to optimise potent carbonic anhydrase inhibitors, two new series of isatin N-phenylacetamide based sulphonamides were synthesised and screened for their human (h) carbonic anhydrase (EC 4.2.1.1) inhibitory activities against four isoforms hCA I, hCA II, hCA IX and hCA XII. The indole-2,3-dione derivative 2h showed the most effective inhibition profile against hCAI and hCA II (K_I = 45.10, 5.87 nM) compared to acetazolamide (AAZ) as standard inhibitor. Moreover, 2h showed appreciable inhibition activity against the tumour-associated hCA XII, similar to AAZ showing K_I of 7.91 and 5.70 nM, respectively. The analogs 3c and 3d showed good cytotoxicity effects, and 3c revealed promising selectivity towards lung cell line A549. Molecular docking was carried out for 2h and 3c to predict their binding conformations and affinities towards the hCA I, II, IX and XII isoforms.     

Intermolecular amination of allylic and benzylic alcohols leads to effective inhibitions of acetylcholinesterase enzyme and carbonic anhydrase I and II isoenzymes

In this study, we aimed to determine the inhibition effects of novel synthesized sulfamates ( 2a–g ), sulfonamides ( 3b–f ), carbonyl sulfonamides ( 3h and i ), and carbonyl sulfamates ( 4h and 4i ), which were tested against two human cytosolic carbonic anhydrase I and II isozymes (hCA I and II) and acetylcholinesterase (AChE) enzyme. For inhibition properties of allylic sulfamates, the half maximal inhibitory concentration (IC₅₀) and inhibition constant (K_i) were calculated for each novel compounds. The allylic sulfamates showed that K_i values are in the range of 187.33–510.31 pM for hCA I, 104.22–290.09 pM against hCA II, and 12.73–103.63 pM against AChE. The results demonstrated that all newly synthesized compounds had shown effective inhibition against hCA I and II isoenzymes and AChE enzyme.     

Sulfamide derivatives with selective carbonic anhydrase VII inhibitory action

A set of N,N′-disubstituted sulfamides and sodium cyclamate have been tested for their inhibitory action against six isoforms of carbonic anhydrase (CA, EC 4.2.1.1) found in the brain, that is, CA I, CA II, CA VII, CA IX, CA XII and CA XIV, some of which are involved in epileptogenesis. The biological data showed interesting results for CA VII inhibition, the isozyme thought to be a novel antiepileptic target. Strong CA VII inhibitors, with K_i values in the low nanomolar–subnanomolar range were identified. Some of these derivatives showed selectivity for inhibition of CA VII versus the ubiquitous isoform CA II, for which the K_i values were in the micromolar range. Molecular modeling approaches were employed to understand the binding interactions between these compounds and the two CA isoforms, since the mechanism of action of such disubstituted sulfamides was not yet investigated by means of X-ray crystallography.     

Carbonic anhydrase inhibitory properties of novel benzylsulfamides using molecular modeling and experimental studies

In this study, a series of sulfamoyl carbamates and sulfamide derivatives were synthesized. Six commercially available benzyl amines and BnOH were reacted with chlorosulfonyl isocyanate (CSI) to give sulfamoyl carbamates. Pd–C catalyzed hydrogenolysis reactions of carbamates afforded sulfamides. The inhibition effects of novel benzylsulfamides on the carbonic anhydrase I, and II isoenzymes (CA I, and CA II) purified from fresh human blood red cells were determined by Sepharose-4B-L-Tyrosine-sulfanilamide affinity chromatography. In vitro studies were shown that all of novel synthesized benzylsulfamide analogs inhibited, concentration dependently, both hCA isoenzyme activities. The novel benzylsulfamide compounds investigated here exhibited nanomolar inhibition constants against the two isoenzymes. K_i values were in the range of 28.48 ± 0.01–837.09 ± 0.19 nM and 112.01 ± 0.01–268.01 ± 0.22 nM for hCAI and hCA II isoenzymes, respectively. Molecular modeling approaches were also applied for studied compounds.     

Spirobisnaphthalenes effectively inhibit carbonic anhydrase

This study explores the correlation between human carbonic anhydrase (CA, EC 4.2.1.1) isoforms I and II (hCA I, II) and the inhibitory features of some spirobisnaphthalene derivatives. A group of spirobisnaphthalenes was synthesized and their hCA I and II inhibitory effects was investigated. The K_i values were similar for both CA isoenzymes, the compounds showing good inhibitory activity. K_i values ranged between 1.60 and 460.42?µM for hCA I and between 0.39 and 419.42?µM for hCA II, respectively. The spirobisnaphthalenes derivatives might be useful for designing CA inhibitors belonging to novel chemotypes compared to the highly investigated sulfonamides, sulfamates or coumarins.     

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 K_i 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 K_i 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 K_i values of 397.03 ± 31.66 and 210.21 ± 15.98 nM, respectively.