Human Carbonic Anhydrase Isoenzymes Research Articles

A multifunctional natural treasure based on a “one stone, many birds” strategy for designing health-promoting applications: Tordyliumapulum

Wild plants provide important bioactive compounds, and their analysis relies heavily on selecting the right extraction techniques and solvents. This study was conducted to determine the phenolic content and biopharmaceutical potential of four different extracts (ethyl acetate, ethanol, 70% ethanol, and water) from the aerial parts of wild plant Tordylium apulum L. The biochemical profile of the extract was screened using high performance liquid chromatography -mass spectrometry (HPLC-MS) analysis. The total phenolic and flavonoid content was examined using the Folin-Ciocalteu assay and the aluminium trichloride assay, respectively. The antioxidant activity was evaluated through several tests, including 2,2-Diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), phosphomolybdenum (PBD), and metal chelating activity (MCA). Five types of enzyme inhibition activity were tested against acetylcholinesterase (AChE), butrylcholinesterase (BChE), tyrosinase, α-amylase, and α-glucosidase. Additionally, For the first time, the inhibitory activity of T. apulum extract against human carbonic anhydrase isoenzymes I and II (hCA-I and hCA-II) was evaluated. Fifty-five compounds for negative ionization mode, and twenty-eight compounds for positive ionization mode were recorded in HPLC-MS analysis and they were polyphenolic, flavonoids, carbohydrates, sugar alcohol and amino acids. These results indicate that different solvents extract varying levels of antioxidants from T. apulum, with ethanol and water extracts generally exhibiting superior antioxidant activities. The ethanol extract of T. apulum exhibited the maximum contents of total phenolics measuring 33.71 mg gallic acid equivalent (GAE)/g. The ethanol extract exhibited the highest inhibition of AChE with 2.28 mg galanthamine equivalent (GALAE)/g. The ethyl acetate and ethanol extracts also showed the highest hCA-I and hCA-II inhibition potential, respectively. The ethanol-water and water extracts acted on the biofilm of E. coli (49.93% and 45.22%, respectively), and the biofilm of P. aeruginosa (50.68% and 44.46%, respectively). The extracts were tested on different cell lines for cytotoxic potentials and in particular the water extract induced the apoptotic pathways in cervical cancer (HELA) cell lines. In conclusion, T. apulum exhibit multidirectional biological properties and it could be considered as a versatile agent for the development of health-promoting applications.

Investigation of Some Metabolic Enzyme Inhibition Properties of Novel Chalcone‐Cu Complexes

AbstractFourteen novel Chalcone‐Cu complexes were effectively synthesized in this work. The newly synthesized Chalcone‐Cu complexes were assessed for their effects on human carbonic anhydrase isoenzymes I and II, acetylcholinesterase enzymes, and antioxidant activity. The intricate compounds exhibited Ki values ranging from 41.65–190.42 nM against hCA I, 15.79–259.07 nM against hCA II, and 14.36–175.73 nM against AChE enzymes. These complexes demonstrated potent inhibitory profiles against the specified metabolic enzymes, surpassing the inhibitory effects of acetazolamide (for hCA I and II) and tacrine (for AChE). The antioxidant properties of the compounds were assessed using DPPH and ABTS radical scavenging assays, revealing that the complexes had moderate to high efficacy in neutralizing free radicals. All complexes underwent molecular docking experiments. Compounds 14, 22, and 23 yielded the highest docking scores. Compound 14 demonstrated a docking score of −6.414 kcal/mol against hCAI, whereas compound 23 attained a docking score of −6.697 kcal/mol against hCA II. Compound 22 exhibited the most favorable docking score of −9.645 kcal/mol against AChE. The acquired results have the potential to help towards the development of new drugs containing Cu complex structures for the treatment of prevalent ailments such as glaucoma and Alzheimer's diseases.

Synthesis of new sulfonamide derivatives: Investigation of their interactions with carbonic anhydrase and cholinesterase enzymes by in vitro and in silico evaluations

In this study, a series of novel sulfonamide derivatives (6–10) bearing an aryl sulfonate moiety was designed, and synthesized for the first time, and their inhibitory activities against human carbonic anhydrase isoenzymes (hCA II and I), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) were investigated by in vitro and silico studies. The chemical structures of the derivatives were elucidated by elemental analysis and spectral techniques. All tested hybrids showed remarkably low nanomolar inhibition with Kı values of in the range of 8.98 ± 0.10 to 14.56 ± 0.41 nM against hCA I, 7.73 ± 0.10 to 13.85 ± 0.32 nM against hCA II, 12.90 ± 0.29 to 16.38 ± 0.41 nM against AChE, and 6.21 ± 0.09 to 14.52 ± 0.38 nM against BChE. Overall, the majority of these molecules inhibited these metabolic enzymes significantly more than acetazolamide (AZA) and neostigmine. Moreover, the biological effects of the compounds produced were assessed through computational studies of target enzymes. In this regard, in silico ADMET properties were evaluated to determine the physicochemical properties of target compounds. The calculated results support the biological activity results.

Evaluation of antioxidant activities and inhibition effects of Tribulus terrestris L. extracts on some metabolic enzymes

This research aimed to determine the antioxidant capacity of Tribulus terrestris extracts made using various solvents and their effects on some metabolic enzymes. Five different antioxidant methods were used to assess the antioxidant capacities of the water, ethanol, acetone, chloroform, and hexane extracts of T. terrestris. The inhibitory effects of the extracts on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glycosidase enzymes and human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were investigated. The study showed that acetone extract had the strongest inhibition effects in DPPH (IC50:25.86 ± 0.010 µg/mL) and ABTS (IC50:10.13 ± 0.023 µg/mL) radical scavenging activities. In CUPRAC/Fe3+-Fe2+/FRAP reduction tests, ethanol extract showed the highest reducing power. The ethanol extract exhibited the highest level of inhibition for the AChE/BChE and α-glycosidase enzymes (IC50:12.13 ± 0.37 µg/mL, IC50:22.33 ± 0.27 µg/mL and IC50:25.98 ± 0.75 µg/mL), respectively. Chloroform extract showed the strongest inhibition effect on hCA-I/hCA-II isoenzymes (IC50:21.82 ± 0.55 µg/mL, IC50:20.97 ± 0.63 µg/mL), respectively.

Synthesis of Novel Hydrazide-Hydrazone Compounds and In Vitro and In Silico Investigation of Their Biological Activities against AChE, BChE, and hCA I and II.

The abnormal levels of the human carbonic anhydrase isoenzymes I and II (hCA I and II) and cholinesterase enzymes, namely, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are linked with various disorders including Alzheimer's disease. In this study, six new nicotinic hydrazide derivatives (7-12) were designed and synthesized for the first time, and their inhibitory profiles against hCA I, hCA II, AChE, and BChE were investigated by in vitro assays and in silico studies. The structures of novel molecules were elucidated by using spectroscopic techniques and elemental analysis. These molecules showed inhibitory activities against hCA I and II with IC50 values ranging from 7.12 to 45.12 nM. Compared to reference drug acetazolamide (AZA), compound 8 was the most active inhibitor against hCA I and II. On the other hand, it was determined that IC50 values of the tested molecules ranged between 21.45 and 61.37 nM for AChE and between 18.42 and 54.74 nM for BChE. Among them, compound 12 was the most potent inhibitor of AChE and BChE, with IC50 values of 21.45 and 18.42 nM, respectively. In order to better understand the mode of action of these new compounds, state-of-the-art molecular modeling techniques were also conducted.

Phytochemical analysis and molecular docking studies of two endemic varieties of Salvia sericeotomentosa.

The use of medicinal plants for treating various diseases dates back thousands of years and has been a part of many cultures around the world. Various parts of plants, including roots, leaves, and flowers, and their extracts have been used to develop remedies to cure different ailments like fever, pain, inflammation, infections, among others. In this research, the aerial parts of both Salvia varieties were extracted with ethanol and water to obtain infusion and decoction, separately. S. sericeotomentosa var. hatayica Celep & Doğan (SH) and Salvia sericeotomentosa Rech. f. var. sericeotomentosa (ST) plants were chemically analyzed for polar compounds using LC-HRMS for the first time. All SH and ST extracts were found to be very rich in rosmarinic acid, salvianolic acid B, hispidulin-7-O-glucoside, and caffeic acid. The study also investigated the antiinflammatory and carbonic anhydrase inhibition properties of the most abundant secondary metabolites extracted from SH and ST. In silico studies were conducted for the first time to explore the effects of these metabolites on TNF-α, iNOS, and human carbonic anhydrase isoenzymes (hCAI and hCAII). Salvianolic acid B should be considered a strong antiinflammatory agent and a carbonic anhydrase I and II inhibitors due to low binding energy scores with the tested enzymes (TNF-α: -12.391 kcal/mol), (iNOS: -7.547 kcal/mol), (hCAI: -7.877 kcal/mol), and (hCAII: -4.312 kcal/mol).

The synthesis, biological evaluation and in silico studies of asymmetric 3,5-diaryl-rhodanines as novel inhibitors of human carbonic anhydrase isoenzymes

The synthesis of rhodanine core, which forms the main skeleton of organics used as a large number of drugs, is obtained with more green approaches is very significant. Additionally, asymmetrical functionalization from C5 and N(3) positions of 3-NH2-Rh (1) via a green approach is representing a challenge. In this connect, the primary goal of this study is to obtain novel asymmetric 3,5-diarylRhs by an effective green synthetic approach. For this, initially, the reactions of the variety of aromatic aldehydes with 5-Ar-Rhs 2a and 2b were investigated by changing parameters such as catalyst, solvent, and temperature. As a result of the studies, novel asymmetric 3,5-diarylRhs were obtained as the main product of acetic acid catalyst reactions carried out at reflux temperatures of ethanol. Moreover, the site-selective reduction of the imine group in the structure of the asymmetric 3,5-diarylRhs was also carried out within the scope of this study. Following synthesis, we also carried out inhibition studies of novel 3,5-diarylRhs against cytosolic human carbonic anhydrase I, and II (hCA I and II) isoforms. As a result of these inhibition studies, inhibition constants (Ki) for hCA I and hCA II were found in the range of 107.26 ± 31.18 to 601.97 ± 46.44 nM, and 127.72 ± 15.75 to 480.13 ± 47.24 nM, respectively. In order to support the results obtained as a result of the inhibition studies, molecular docking studies of the asymmetrical 3,5-diarylRhs 4i and 4l showing the best activity for hCA I and hCA II were also carried out, and the morphology of the binding was examined. Furthermore, the organics comply with Lipinski's and Jorgensen's rules of all compounds were determined by calculated ADME and drug-likeness parameters. That is, the ADME and drug-likeness parameters of the new 3,5-diarylRhs showed that they are not only with hCA I and hCA II inhibitory activities but also with appropriate drug-likeness properties and physicochemical parameters.

Synthesis and In Vitro Human Carbonic Anhydrase I and II Inhibition Properties of Some Novel Hydrazone Compounds Containing an Aryl Sulfonate Moiety

The aim of this research was to evaluate the enzyme inhibitory potential of some new hydrazone derivatives bearing an aryl sulfonate moiety against the human carbonic anhydrase isoenzymes I and II (hCA I and II), which were attained from commercial suppliers. In the current study, the structures of targeted molecules (5-8) were characterized by some spectroscopic techniques. The inhibition capacities of the compounds on hCA I and II activities were examined by employing the esterase activity method under in vitro conditions. The IC50 values of the tested molecules were determined in the range of 15.7-135.2 µM against hCA I and in the range of 13.5-76.3 µM against hCA II. Among them, compound 7 exhibited the highest activity against both hCA I and II. The inhibitory activity results of all tested compounds were also compared to the standard drug Acetazolamide (AAZ). It was established that some of the tested molecules showed the inhibitory activities close to AAZ.

Synthesis, characterization, and biological evaluation of some novel Schiff bases as potential metabolic enzyme inhibitors.

In this study, a series of novel Schiff base derivatives containing a pyrazolone ring (2a-e) were designed, successfully synthesized for the first time, and characterized by elemental analysis and some spectroscopic methods. These compounds were tested for their inhibitory activities on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and the human carbonic anhydrase isoenzymes I and II (hCA I and II). All synthesized molecules indicated significant inhibition effects with IC50 values ranging from 14.15 to 107.62 nM against these enzymes. Compound 2d showed the most potent inhibitory activity among the tested molecules towardAChE and BChE (IC50 = 15.07 and 14.15 nM) compared to the standard drug neostigmine. We determined that the IC50 values of the tested molecules ranged between 16.86 and 57.96 nM for hCA I and 15.24-46.21 nM for hCA II. As a consequence, we may say that some of the Schiff base derivatives may be used as potential drug candidates in later studies.

Synthesis, molecular docking and some metabolic enzyme inhibition properties of biphenyl-substituted chalcone derivatives

The new synthesized biphenyl-substituted chalcone derivatives were evaluated against the human carbonic anhydrase isoenzymes I and II (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes. The synthesized biphenyl-substituted chalcone derivatives showed Ki values in range of 14.71–62.95 nM against hCA I, 31.69–47.20 nM against hCA II, 4.33–16.97 nM against AChE, and 3.72–6.74 nM against BChE enzymes. The synthesized biphenyl-substituted chalcone derivatives exhibited effective inhibition profiles against indicated metabolic enzymes when compared to acetazolamide (for hCA I and II) and tacrine (for AChE and BChE). Molecular docking, MD simulation, and MM/PB(GB)SA calculations were applied for nine compounds. The best dock scores were obtained from compounds 21, 22 and 24, and the lowest △GMM/PBSA energy were determined as 19, 21 and 22. All results may contribute to the development of new drugs particularly to treat some disorders, which widespread display in the world including glaucoma and Alzheimer's diseases.

New sulfonylhydrazones containing methane sulfonic acid hydrazıde havıng human anticarbonic anhydrase and antimicrobıal activıty: synthesis, spectroscopic characterization, electrochemical properties, and biological activıties

In this work, new sulfonylhydrazones nomenclatured as 3,5-ditertbutylsalicylaldehyde methane­sulfonylhydrazone (II), 3-tertbutylsalicylaldehyde methanesulfonylhydrazone (III), and 5-bromosalicyl­aldehyde methanesulfonylhydrazone (IV) were synthesized by the reaction of methanesulfo­nicacidhydrazide (I) with 3,5-ditertbutylsalicylaldehyde, 3-tertbutylsalicyl aldehyde, and 5-bromosalicylaldehyde. The structures of the aromatic sulfonylhydrazones were determined by using elemental analysis, UV-Vis, FT-IR, 1H-NMR, and 13C-NMR methods. The structure of IV was also supported with the X-ray diffraction method. Sulfonamides were generally investigated for their inhibitory effects on human carbonic anhydrase isoenzymes (hCAs). Synthesized alkyl­sulfonylhydrazones have a sulfonamide group, which is the most important pharmacophore for the carbonic anhydrase (CA) inhibition efficiency like the reference agent acetazolamide (AAZ). The enzyme inhibition trends of alkylsulfonylhydrazones on the hCA I isoenzyme were qualitatively investigated by cyclic voltammetry (CV) and differantial pulse voltammetry (DPV). Also, the inhibition activities of sulfonylhydrazones were determined by using UV-Vis spectrophotometry, and their inhibition parameters, such as Km, IC50, and Ki, were calculated. Among the tested compounds, IV was found to be the most active compound on the hCA I isoenzyme with an IC50 value of 4.86×10–6 M, whereas II and III were found to be the least potent compounds on hCA I with an IC50 value of 3.96×10–4 M and 5.58×10–5 M, respectively.All of the compounds showed excellent inhibition activity against gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia) and gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidi), with minimum inhibitory concentration (MIC) values less than that of standard drugs (sulfamethoxazole and sulfisoxazole). In addition, all of the compounds exhibited excellent antifungal inhibition against C. albicans and A. fumigatus, with MIC values of 8–16 μg/ml, which were 2–4 fold higher than the standard drug fluconazole (32 μg/ml).

Synthesis and some enzyme inhibition effects of isoxazoline and pyrazoline derivatives including benzonorbornene unit

Four new and four known isoxazoline derivatives were synthesized from the reactions of benzonorbornadiene with nitrile oxides formed from the corresponding benzaldehydes. Three new and one known pyrazoline derivatives were also synthesized from the reactions of the benzonorbornadiene with nitrile imines formed from the corresponding compounds. The synthesized nitrogen-based novel heterocyclic compounds were evaluated against the human carbonic anhydrase isoenzymes I and II (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes. The synthesized nitrogen-based novel heterocyclic compounds showed IC50 values in the range of 2.69-7.01 against hCA I, 2.40-4.59 against hCA II, 0.81-1.32 µM against AChE, and 20.83-1.70 µM against BChE enzymes. On the contrary, nitrogen-based novel heterocyclic compounds demonstrated Ki values between 2.93 ± 0.59-8.61 ± 1.39 against hCA I, 2.05 ± 0.62-4.97 ± 0.95 against hCA II, 0.34 ± 0.02-0.92 ± 0.17 nM against AChE, and 0.50 ± 0.04-1.20 ± 0.16 µM against BChE enzymes. The synthesized nitrogen-based novel heterocyclic compounds exhibited effective inhibition profiles against both indicated metabolic enzymes. These results may contribute to the development of new drugs particularly to treat some disorders, which are widespreadin the world including glaucoma and Alzheimer's diseases.

Silver N‐heterocyclic carbene complexes bearing fluorinated benzyl group: Synthesis, characterization, crystal structure, computational studies, and inhibitory properties against some metabolic enzymes

A series of the silver N‐heterocyclic carbene (NHC) complexes have been synthesized from the reactions between benzimidazolium salts bearing fluorinated benzyl group and Ag2O via the deprotonation method. All Ag(I)NHC complexes were characterized by known spectroscopic techniques (1H nuclear magnetic resonance [NMR], 13C NMR, and Fourier transform infrared [FT‐IR]) and elemental analysis. The molecular structures of the two complexes were unambiguously elucidated through single‐crystal X‐ray diffraction analysis. Namely, X‐ray studies show that the coordination geometry around the Ag(I) atom in the case of complex 2c is revealed to be almost linear with C–Ag–Cl angle, whereas in complex 2e, it appears as a nonlinear structure. The inhibitory profiles of these new complexes are investigated on some metabolic enzymes. Representatively, the most potent complex against human carbonic anhydrase isoenzymes I and II (hCAs I and II), 2d, was 1.8 times more potent than standard inhibitor acetazolamide against hCAs I and II. On the other hand, complexes 2c and 2b as most potent compounds against both cholinesterase enzymes was around 5 and 1.6 times more potent than tacrine against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively. The most active α‐glucosidase inhibitor 2d had similar activity to acarbose as a standard inhibitor. Furthermore, it confirms its in vitro studies as a result of molecular docking studies for each enzyme with (i) binding energy and inhibition constant values and (ii) the definition of the best conformation and nonbonding interactions of the related complexes (2b, 2c, and 2d) against the different target proteins.

Investigation of in vitro and in silico effects of some novel carbazole Schiff bases on human carbonic anhydrase isoforms I and II

Carbonic anhydrases (CAs, EC4.2.1.1) are metalloenzymes that catalyse reversible hydration reaction of carbon dioxide to bicarbonate and protons. In recent years, there has been a great interest in inhibitors/activators of carbonic anhydrase isoenzymes. Therefore, we investigated the effects of four different carbazole Schiff base derivatives, which are believed to have a potential to be used as a drug, on human carbonic anhydrase (hCA) isoenzymes I and II under in vitro conditions. The IC50 values of carbazole Schiff base derivatives were found to be in the range of 32.09–151.2 μM for hCA isoenzyme I and 21.82–40.54 μM for hCA isoenzyme II. Among all compounds, (E)-3-(((9-Octyl-9H-carbazole-3-yl)imino)methyl)benzene-1,2-diol (C3) had the strongest inhibitory effect on hCA isoenzyme II. It was determined that 2,3,4-trimethoxy and 4-hydroxy phenyl containing carbazole compounds have selective inhibition against hCA II isoenzyme. Docking studies were performed against hCA I and II receptors using induced-fit docking method. The compounds had affinity scores varying from −7.74 ± 0.27 to −6.27 ± 0.07 kcal/mol for hCA I and from −8.04 ± 0.17 to −7.27 ± 0.18 kcal/mol for hCA II. Communicated by Ramaswamy H. Sarma

Computer-aided identification of human carbonic anhydrase isoenzyme VII inhibitors as potential antiepileptic agents

Human carbonic anhydrase (hCA) belongs to a superfamily of metalloenzymes that reversibly catalyse the hydration of carbon dioxide to give bicarbonate (HCO3 −) and proton (H+). As HCO3 − ions play an important role in neuronal signalling hence, hCA enzymes are an attractive target for antiepileptic drugs. Out of all the isoforms, hCA VII is predominantly expressed in the brain cortex and hippocampus region, which are the most affected area during seizure activity. Hence, we have identified some hCA VII inhibitors employing computational tools like atom-based 3D quantitative structure–activity relationship (QSAR), auto-QSAR, pharmacophore-based virtual screening, molecular docking, and molecular dynamics (MD) simulations. Atom-based 3D QSAR modelling outperformed auto-QSAR with an R 2 and Q 2 value of 0.9634 and 0.9646, respectively. A four-feature pharmacophore model (AADR_1) was developed and a focussed library of around 3,00,000 compounds was screened. Compounds with a phase screen score >2.40 were selected for docking studies. The activity of the selected hits was predicted employing the developed 3D QSAR model. Finally, three compounds were taken up for the MD simulation studies which also suggest that the identified hits might form a stable complex with hCA VII enzyme. A comparative docking study was also done with other hCA isoforms like I, II, IV, IX, and XII to examine the selectivity of the identified hits towards hCA VII. Based on these studies, three hits have been identified as potential hCA VII inhibitor which is drug-like molecules. Further, in vitro studies are required to develop leads from these identified hits. Communicated by Ramaswamy H. Sarma

Concise syntheses and some biological activities of dl-2,5-di-O-methyl-chiro-inositol, dl-1,4-di-O-methyl-scyllo-inositol, and dl-1,6-dibromo-1,6-dideoxy-2,5-di-O-methyl-chiro-inositol.

The regio- and stereospecific synthesis of O-methyl-chiro-inositols and O-methyl-scyllo-inositol was achieved, starting from p-benzoquinone. After preparing dimethoxy conduritol-B as a key compound, regiospecific bromination of the alkene moiety of dimethoxy conduritol-B and acid-catalyzed ring opening of dimethoxydiacetate conduritol-B epoxide with Ac2 O afforded the desired new chiro-inositol derivatives and scyllo-inositol derivative, respectively. Spectroscopic methods were employed for the characterization of all synthesized compounds. The novel inositols (11-17) had effective inhibition profiles against human carbonic anhydrase isoenzymes I and II (hCA I and II) and acetylcholinesterase (AChE). The novel inositols 11-17 were found to be effective inhibitors against AChE, hCA I, and hCA II enzymes. Ki values were calculated in the range of 87.59 ± 7.011 to 237.95 ± 17.75 μM for hCA I, 65.08 ± 12.39 to 538.98 ± 61.26 μM for hCA II, and 193.28 ± 43.13 to 765.08 ± 209.77 μM for AChE, respectively. Also, due to the inhibitory effects of the novel inositols 11-17 against the tested enzymes, these novel inositols are potential drug candidates to treat some diseases such as glaucoma, epilepsy, leukemia, and Alzheimer's disease.

β-D-Glukan, Lektin, Linoleik Asit ve β-Karoten Bileşiklerinin Karbonik Anhidraz Enzimleri Üzerindeki Etkilerinin Araştırılması

β-D-glukan, lektin, linoleik asit ve β-karoten; hayvansal, bitkisel ve bakteriyel kaynaklarda bulunan, biyolojik olarak aktif bileşiklerdir. Glokom, dünya genelinde körlüğe neden olma bakımından katarakttan sonra ikinci sırada gelen bir hastalıktır. Karbonik anhidraz (CA) inhibitörleri uzun yıllardır glokom tedavisinde kullanılmaktadır. Ancak, inhibitör ajanların yan etkileri azımsanmayacak derecede çoktur. Yeni CA inhibitörlerinin geliştirilmesi üzerine çeşitli araştırma grupları çalışmalar yapmaktadırlar. Doğal kaynaklı bileşiklerin CA inhibitörü olarak kullanımının araştırılması da son yıllarda popülerlik kazanmıştır. Bu çalışmada, β-D-glukan, lektin, linoleik asit ve β-karoten bileşiklerinin, insan eritrosit CA izoenzimleri olan hCA I ve hCA II üzerine etkileri in vitro koşullarda araştırılmıştır. Bileşiklerin Ki değerleri hCA I için 0.45±0.09 µM − 37.02±17.85 µM aralığında, hCA II için 3.12±1.38 µM − 61.23±25.46 µM aralığındadır.

Synthesis, spectroscopic characterizations, carbonic anhydrase II inhibitory activity, anticancer activity and docking studies of new Schiff bases of sulfa drugs

Herein we present the synthesis, and biological evaluation of new Schiff bases incorporating (2‑hydroxy-5-methylbenzaldehyde sulfisoxazole (S2M-S1) and 2‑hydroxy-5-methylbenzaldehyde sulfamethoxazole (S1M-S1) derived from sulfisoxazole (S2)/sulfamethoxazole (S1) and substituted salicylaldehyde and their Pd (II), Cu(II) complexes. The synthesized compounds were characterized by FT-IR, 1H–13C NMR, LC-MS, magnetic susceptibility and conductivity measurements. The molecular structure of S2M-S1 was also determined by the single crystal X-ray diffraction technique and was found to crystallize in the monoclinic, space group P1 21/n 1. We investigated the effects of molecules on human carbonic anhydrase isoenzyme II (hCAII). Cu(S2M-S1)2, Pb(S2M-S1)2, Pb(S1M-S1)2, and Cu(S1M-S1)2, exhibited inhibitory effects with 10, 20, 42 and 67 µM IC50 value, respectively. Also, molecular Docking studies performed and anticancer activities of newly synthesized compounds were evaluated against three human cancer cell lines with the sulfonamide B test. S2M-S1, S1M-S1 compounds and their Cu (II) complexes exhibited promising cytotoxic activity against all cell lines. IC50 values for breast (MCF7) cells are 40 µM for S2M-S1, S1M-S1 compounds and their Cu (II) complexes.

Novel propanolamine derivatives attached to 2-metoxifenol moiety: Synthesis, characterization, biological properties, and molecular docking studies

The synthesis of seven new ß-amino alcohols was designed and performed by starting from eugenol, a natural phenolic compound known to be biologically active. The synthesized compounds were obtained in yields ranging from 54 to 81%. Molecule structures were determined with FT-IR, 1H NMR and 13C NMR spectroscopies. In addition, the inhibitory effects of these substances on acetylcholinesterase (AChE), α-glycosidase (α-Gly), human carbonic anhydrase I (hCA I), and human carbonic anhydrase II (hCA II) enzymes have been investigated. It has been seen that all compounds have a better ability to inhibit compared to existing tried inhibitors. Among these, the best inhibitor against AChE enzyme is 2b (Ki 62.08 ± 11.67 µM and IC50 90.33), and against α-Gly, 2c showed the highest effect (Ki 0.33 ± 0.08 µM and IC50 0.28). The best inhibitor against hCA I, and hCA II enzymes is compound 2f. For hCA I and hCA II, Ki value was measured as 9.68 ± 1.32 and 11.46 ± 2.64 µM and IC50 values as 7.37 and 8.26 µM respectively. The interactions of the studied new propanolamine derivatives with the enzymes were done by molecular docking calculations and their biological activities were compared to the experimental tests. Studied enzymes in molecular docking calculations are acetylcholinesterase (AChE) is PDB ID: 4M0E, α-glycosidase (α-Gly) is PDB ID: 1R47, human carbonic anhydrase isoenzyme I (hCA I) PDB ID: 3LXE is human carbonic anhydrase isoenzyme II (hCA II) is PDB ID: 5 AML.

5-Arylisothiazol-3(2H)-one-1,(1)-(di)oxides: A new class of selective tumor-associated carbonic anhydrases (hCA IX and XII) inhibitors

Sixteen 5-aryl-substituted isothiazol-3(2H)-one-1,(1)-(di)oxide analogs have been prepared from the corresponding 5-chloroisothiazol-3(2H)-one-1-oxide or −1,1-dioxide by a Suzuki-Miyaura cross-coupling reaction and screened for their inhibition potency against four human carbonic anhydrase isoenzymes: the transmembrane tumor-associated hCA IX and XII and the cytosolic off-target hCA I and II. Most of the synthesized derivatives inhibited hCA IX and XII isoforms in nanomolar range, whereas remained inactive or modestly active against both hCA I and II isoenzymes. In the N-tert-butylisothiazolone series, the 5-phenyl-substituted analog (1a) excelled in the inhibition of tumor-associated hCA IX and XII (Ki = 4.5 and Ki = 4.3 nM, respectively) with excellent selectivity against off target hCA I and II isoenzymes (S > 2222 and S > 2325, respectively). Since the highest inhibition activities were observed with N-tert-butyl derivatives, lacking a zinc-binding group, we suppose to have a new binding mode situated out of the active site. Additionally, three free-NH containing analogs (3a, 4a, 3i) have also been prepared in order to study the impact of free-NH containing N-acyl-sulfinamide- (-SO-NH-CO-) or N-acyl-sulfonamide-type (-SO2-NH-CO-) derivatives on the inhibitory potency and selectivity. Screening experiments evidenced 5-phenylisothiazol-3(2H)-one-1,1-dioxide (4a), the closest saccharin analog, to be the most active derivative with inhibition constants of Ki = 40.3 nM and Ki = 9.6 nM against hCA IX and hCA XII, respectively. The promising biological results support the high potential of 5-arylisothiazolinone-1,(1)-(di)oxides to be exploited for the design of potent and cancer-selective carbonic anhydrase inhibitors.