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.     

Design,synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors

A novel series of chalcone derivatives (4a–8d) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The log P values of the compounds were shown to range from 1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC₅₀: 4.68 μmol/L) was 2-fold more potent than Rivastigmine against AChE (IC₅₀: 10.54 μmol/L) and showed a high selectivity for AChE over BuChE (ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE.     

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.     

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.     

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.     

Acetylcholinesterase and carbonic anhydrase inhibitory properties of novel urea and sulfamide derivatives incorporating dopaminergic 2-aminotetralin scaffolds

In the present study a series of urea and sulfamide compounds incorporating the tetralin scaffolds were synthesized and evaluated for their acetylcholinesterase (AChE), human carbonic anhydrase (CA, EC 4.2.1.1) isoenzyme I, and II (hCA I and hCA II) inhibitory properties. The urea and their sulfamide analogs were synthesized from the reactions of 2-aminotetralins with N,N-dimethylcarbamoyl chloride and N,N-dimethylsulfamoyl chloride, followed by conversion to the corresponding phenols via O-demethylation with BBr₃. The novel urea and sulfamide derivatives were tested for inhibition of hCA I, II and AChE enzymes. These derivatives exhibited excellent inhibitory effects, in the low nanomolar range, with K_i values of 2.61–3.69 nM against hCA I, 1.64–2.80 nM against hCA II, and in the range of 0.45–1.74 nM against AChE. In silico techniques such as, atomistic molecular dynamics (MD) and molecular docking simulations, were used to understand the scenario of the inhibition mechanism upon approaching of the ligands into the active site of the target enzymes. In light of the experimental and computational results, crucial amino acids playing a role in the stabilization of the enzyme–inhibitor adducts were identified.     

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 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 K_i 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 K_i values between 63.27–132.34 and of 29.63–127.31 nM, respectively.     

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.     

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.     

Synthesis and biological evaluation of novel tris-chalcones as potent carbonic anhydrase,acetylcholinesterase, butyrylcholinesterase and α-glycosidase inhibitors

A novel class of fluoro-substituted tris-chalcones derivatives (5a-5i) was synthesized from phloroglucinol and corresponding benzaldehydes. A three step synthesis method was followed for the production of these tris-chalcone compounds. The structures of the newly synthesized compounds (5a-5i) were confirmed on the basis of IR, ¹H NMR, ¹³C NMR, and elemental analysis. The compounds’ inhibitory activities were tested against human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly). These chalcone derivatives had K_i values in the range of 19.58–78.73 nM for hCA I, 12.23–41.70 nM for hCA II, 1.09–6.84 nM for AChE, 8.30–32.30 nM for BChE and 0.93 ± 0.20–18.53 ± 5.06 nM against α-glycosidase. These results strongly support the promising nature of the tris-chalcone scaffold as selective carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase inhibitor. Overall, due to these derivatives’ inhibitory potential on the tested enzymes, they are promising drug candidates for the treatment of diseases like glaucoma, leukemia, epilepsy; Alzheimer’s disease; type-2 diabetes mellitus that are associated with high enzymatic activity of carbonic anhydrase, acetylcholine esterase, butyrylcholinesterase, and α-glycosidase.     

Sulfonamide chalcone as a new class of alpha-glucosidase inhibitors

Chalcones 1-20, a new class of glycosidase inhibitors, were synthesized, and their glycosidase inhibitory activities were investigated. Non-aminochalcones 1-12 had no inhibitory activity, however, aminochalcones 13-20 had strong glycosidase (alpha-glucosidase, alpha-amylase, and beta-amylase) inhibitory activities. In particular, sulfonamide chalcones 17-20 had more potent alpha-glucosidase inhibitory activity than aminated chalcone 13-16. 4'-(p-Toluenesulfonamide)-3,4-dihydroxy chalcone 20 (IC(50)=0.4microM) was the best inhibitor against alpha-glucosidase, and these sulfonamide chalcones showed non-competitive inhibition.     

(3,4-Dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives as carbonic anhydrase isoenzymes inhibitors

In this study, we have synthesised (3,4-dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and a series of its derivatives (5, 13–16) and tested the ability of these compounds to inhibit two metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I and hCA II. The synthesised compounds showed inhibitory effect on hCA I and hCA II isozymes. The results showed that synthesised compounds (5, 13–16) demonstrated the best inhibition activity against hCA I (IC₅₀: 3.22–54.28 μM) and hCA II (IC₅₀: 18.52–142.01 μM). The compound 14 showed the highest inhibiton effect against hCA I (IC₅₀: 3.22 μM; K_i: 1.19?±?1.4 μM). On the other hand, the compound 13 showed the highest inhibiton effect against hCA II (IC₅₀: 18.52 μM; K_i: 3.25?±?1.13 μM).     

Design,synthesis and preliminary structure–activity relationship investigation of nitrogen-containing chalcone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors: a further study based on Flavokawain B Mannich base derivatives

In order to study the structure–activity relationship of Flavokawain B Mannich-based derivatives as acetylcholinesterase (AChE) inhibitors in our recent investigation, 20 new nitrogen-containing chalcone derivatives (4?a–8d) were designed, synthesized, and evaluated for AChE inhibitory activity in vitro. The results suggested that amino alkyl side chain of chalcone dramatically influenced the inhibitory activity against AChE. Among them, compound 6c revealed the strongest AChE inhibitory activity (IC₅₀ value: 0.85?μmol/L) and the highest selectivity against AChE over BuChE (ratio: 35.79). Enzyme kinetic study showed that the inhibition mechanism of compound 6c against AChE was a mixed-type inhibition. The molecular docking assay showed that this compound can both bind with the catalytic site and the peripheral site of AChE.     

Evaluation of acetylcholinesterase and carbonic anhydrase inhibition profiles of 1,2,3,4,6‐pentasubstituted‐4‐hydroxy‐cyclohexanes

Carbonic anhydrase (CA; EC 4.2.1.1) is used for remedial purposes for several years, as there is significant focus on expanding more new activators (CAAs) and high affinity inhibitors. Alzheimer′s disease and other similar ailments such as dementia and vascular dementia with Lewy bodies reduce cholinergic activity in the important areas involved in cognition and memory. Prevalent drugs for the symptomatic therapy of dementia are significant in increasing the associated cholinergic deficiency by inhibiting acetylcholinesterase (AChE). These six‐membered carbocycles showed nice inhibitory action against AChE and human carbonic anhydrase (hCA) II and I isoforms. The hCA I, II, and AChE were efficiently inhibited by these molecules, with K_i values in the range of 6.70–35.85 nM for hCA I, 18.77–60.84 nM for hCA II, and 0.74–4.60 for AChE, respectively.     

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,biological evaluation and in silico studies of novel N-substituted phthalazine sulfonamide compounds as potent carbonic anhydrase and acetylcholinesterase inhibitors

The synthesis, characterization and biological evaluation of a series of novel N-substituted phthalazine sulfonamide (5a-l) are disclosed. Phthalazines which are nitrogen-containing heterocyclic compounds are biologically preferential scaffolds, endowed with versatile pharmacological activity, such as anti-inflammatory, cardiotonic vasorelaxant, anticonvulsant, antihypertensive, antibacterial, anti-cancer action. The compounds were investigated for the inhibition against the cytosolic hCA I, II and AChE. Most screened sulfonamides showed high potency in inhibiting hCA II, widely involved in glaucoma, epilepsy, edema, and other pathologies (K_is in the ranging from 6.32 ± 0.06 to 128.93 ± 23.11 nM). hCA I was inhibited with K_is in the range of 6.80 ± 0.10–85.91 ± 7.57 nM, whereas AChE in the range of 60.79 ± 3.51–249.55 ± 7.89 nM. ADME prediction study of the designed N-substituted phthalazine sulfonamides showed that they are not only with carbonic anhydrase and acetylcholinesterase inhibitory activities but also with appropriate pharmacokinetic, physicochemical parameters and drug-likeness properties. Also, in silico docking studies were investigated the binding modes of selected compounds, to hCA I, II, and AChE.     

Comprehensive Phytochemical Content by LC/MS/MS and Anticholinergic,Antiglaucoma, Antiepilepsy,and Antioxidant Activity of Apilarnil (Drone Larvae)

Apilarnil is 3–7 days old drone larvae. It is an organic bee product known to be rich in protein. In this study, the biological activities of Apilarnil were determined by its antioxidant and enzyme inhibition effects. Antioxidant activities were determined by Fe³⁺, Cu²⁺, Fe³⁺-TPTZ ((2,4,6-tris(2-pyridyl)-s-triazine), reducing ability and 1,1-diphenyl-2-picrylhydrazyl (DPPH⋅) scavenging assays. Also, its enzyme inhibition effects were tested against carbonic anhydrase I and II isoenzymes (hCA I, hCA II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Antioxidant activity of Apilarnil was generally lower than the standard molecules in the applied methods. In DPPH⋅ radical scavenging assay, Apilarnil exhibited higher radical scavenging than some standards. Enzyme inhibition results towards hCA I (IC₅₀: 14.2 μg/mL), hCA II: (IC₅₀: 11.5 μg/mL), AChE (IC₅₀: 22.1 μg/mL), BChE (IC₅₀: 16.1 μg/mL) were calculated. In addition, the quantity of 53 different phytochemical compounds of Apilarnil was determined by a validated method by LC/MS/MS. Compounds with the highest concentrations (mg analyte/g dry extract) were determined as quinic acid (1091.045), fumaric acid (48.714), aconitic acid (47.218), kaempferol (39.946), and quercetin (27.508). As a result, it was determined that Apilarnil had effective antioxidant profile when compared to standard antioxidants.     

Vinyl functionalized 5,6-dimethylbenzimidazolium salts: Synthesis and biological activities

A series of vinyl functionalized 5,6-dimethylbenzimidazolium salts are synthesized. All compounds were fully characterized by elemental analyses, MS, ¹H-NMR, ¹³C-NMR, and IR spectroscopy techniques. Enzyme inhibition is a very active area of research in drug design and development. In this study, the synthesized novel benzimidazolium salts were evaluated toward the human erythrocyte carbonic anhydrase I (hCA I), and II (hCA II) isoenzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. They demonstrated highly potent inhibition ability against hCA I with K_i values of 484.8 ± 62.6–1389.7 ± 243.2 nM, hCA II with K_i values of 298.9 ± 55.7–926.1 ± 330.0 nM, α-glycosidase with K_i values of 170.3 ± 27–760.1 ± 269 μM, AChE with K_i values of 27.1 ± 3–77.6 ± 1.7 nM, and BChE with K_i values of 21.0 ± 5–61.3 ± 15 nM. As a result, novel vinyl functionalized 5,6-dimethylbenzimidazolium salts (1a–g) exhibited effective inhibition profiles toward studied metabolic enzymes. Therefore, we believe that these results may contribute to the development of new drugs particularly to treat some global disorders including glaucoma, Alzheimer's disease, and diabetes.     

The impact of some natural phenolic compounds on carbonic anhydrase,acetylcholinesterase, butyrylcholinesterase,and α‐glycosidase enzymes: An antidiabetic,anticholinergic, and antiepileptic study

Natural products from food and plant sources have been used for medicinal usage for ages. Also, natural products with therapeutic significance are compounds derived from animals, plants, or any microorganism. In this study, chrysin, carvacrol, hesperidin, zingerone, and naringin as natural phenols showed excellent inhibitory effects against human (h) carbonic anhydrase (CA) isoforms I and II (hCA I and II), α‐glucosidase (α‐Gly), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). These phenolic compounds were tested for the inhibition of α‐glycosidase, hCA I, hCA II, AChE, and BChE enzymes and demonstrated efficient inhibition profiles with K_i values in the range of 3.70 ± 0.92–79.66 ± 20.81 nM against hCA I, 2.98 ± 0.33–84.88 ± 40.32 nM against hCA II, 4.93 ± 2.01–593.60 ± 134.74 nM against α‐Gly, 0.52 ± 0.18–46.80 ± 17.15 nM against AChE, and 1.25 ± 0.22–32.08 ± 2.68 against BChE.