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Twenty novel 1,2,3-triazole benzenesulfonamides featuring nitrile 8a-g, carbothioamide 9a-f, and N'-hydroxycarboximidamide 10a-g functionalities were designed and synthesized to improve potency and selectivity as carbonic anhydrase inhibitors (CAIs). The synthesized 1,2,3-triazole compounds were tested in vitro as CAIs against four physiologically and pharmacologically relevant isoforms of human carbonic anhydrase (hCA I, II, IV, and IX). Compounds 8a-g, 9a-f, and 10a-g displayed variable inhibition constants ranging from 8.1 nM to 3.22 μM for hCA I, 4.7 nM to 0.50 μM for hCA II, 15.0 nM to 3.7 μM for hCA IV, and 29.6 nM to 0.27 μM for hCA IX. As per the inhibition data profile, compounds 9a-e exhibited strong efficacy for hCA IV, whereas the inhibition was found to be somewhat diminished in the case of hCA IX by nearly all the compounds. A computational protocol based on docking and MM-GBSA was conducted to reveal the plausible interactions of the targeted sulfonamides within the hCA II and IX binding sites. The outcomes of appending various functionalities at the C-4 position of the 1,2,3-triazole motif over the inhibition potential and selectivity of the designed sulfonamides were examined with a potential for the discovery of new isoform selective CAIs. The CAI and SAR data established the significance of the synthesized 1,2,3-triazoles as building blocks for developing CAI drugs.

A series of some naphthol derivatives 4a-f, 5a,f, 6a, and 7a,b (six novel ones: 4c,d, 5a, 6a, 7a,b) bearing F, Cl, Br, OMe, and dioxole substituents at different positions of the aromatic rings was designed, synthesized, and characterized. The naphthol derivatives were synthesized in three steps, namely the addition reaction of furan via Diels-Alder cycloaddition reaction, copper(II) trifluoromethanesulfonate (Cu(OTf)2 )-catalyzed aromatization reaction, and the bromination reaction, respectively. The structures of the newly obtained compounds (4c,d, 5a, 6a, 7a,b) were characterized by spectroscopic techniques. In addition, some biological activity studies were investigated under in vitro conditions. Inhibition studies of these compounds were performed on human carbonic anhydrase (hCA) I and II isoenzymes purified from human erythrocytes as a biological evaluation. Moreover, their potential antioxidant and antiradical activities were studied by analytical methods like ABTS•+ and DPPH• scavenging, and it was determined that some molecules showed good activity. Also, inhibition of acetylcholinesterase (AChE), which is a marker of many degenerative neurological diseases, was tested and the results were discussed. Excellent enzyme inhibition results were recorded for most of the molecules. These 1-naphthol derivatives were found as effective inhibitors for hCA I, hCA II, and AChE with K i values ranging from 0.034 ± 0.54 to 0.724 ± 0.18 µM for hCA I, 0.172 ± 0.02 to 0.562 ± 0.21 µM for hCA II, and 0.096 ± 0.01 to 0.177 ± 0.02 µM for AChE.

Carbonic anhydrase (CA) enzymes are involved in many physiological events. These enzymes, which contain Zn

This paper presents experimental and molecular docking studies on the inhibitory effects of tyrosol, hydroxytyrosol, luteolin, diosmetin, caffeic acid, luteolin 7-O-glycoside, and apigenin 7-O-glycoside from olive (Olea europaea L.) leaf against human carbonic anhydrase (hCA, E.C.4.2.1.1) isozymes I and II. After these isozymes were separately purified, their activities were determined using the esterase activity. IC50 values for hCA I and II were calculated as 2.02-11.38 mu M and 2.23-9.05 mu M, respectively. The compounds were identified as CA inhibitors, with K-i values in the ranges of 1.66-9.17 mu M for the hCA I isozyme and 1.49-14.21 mu M for hCA II. The inhibitory effects of these natural compounds were also compared to acetazolamide, which is a potent inhibitor of both CA isozymes. Our results may contribute to the synthesis of new CA inhibitors and pave the way for new drug design in the treatment of a number of diseases including cancer, obesity, diabetes, and glaucoma.

Six new monopeptides, seven new dipeptides, and two deprotected monopeptide dihydroquinolinone conjugates were prepared by the benzothiazole-mediated method and their structures were confirmed by nuclear magnetic resonance, mass, infrared spectroscopy, and elemental analysis methods. The human carbonic anhydrase (hCA) I and hCA II enzyme inhibition activities of the compounds were determined using the stopped-flow instrument. The synthesized peptide-dihydroquinolinone conjugates 2, 3, 6, 10, 13, and 15 showed inhibition against the hCA II enzyme in the range of 15.7-65.7 µM. However, none of the compounds showed inhibition of hCA I at a concentration of 100 µM. The antioxidant activities of the compounds were also examined using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging method at concentrations of 12.5-125 µg/ml, but when compared with the standard antioxidant compounds α-tocopherol and butylated hydroxyanisole (BHA), weak antioxidant activities were detected. The cytotoxic effects of four compounds against the A549 and BEAS-2B cell lines were also investigated. Among the compounds studied, compound 7 was found to be most effective, with the IC50 values on the A549 cells for 48 and 72 h being 26.87 and 9.979 µg/ml, respectively, and the IC50 values on the BEAS-2B cells being >100 µg/ml. None of the tested compounds showed antimicrobial activity in the concentration range (800-1.56 µg/ml) studied.

In this study, 23 different imidazole derivatives were synthesized, and the inhibitory properties of these derivatives against carbonic anhydrase I and II isoenzymes were investigated for the first time. The inhibition concentrations of the imidazole derivatives were found to be in the range of 2.89-115.5 nM. Docking studies examined the binding properties of the imidazole derivatives, and the structure-activity relationship is discussed. Theoretical calculations showed that the binding mode of the imidazole ring was non-zinc binding.

A novel series of sulfonamides, 4-(3-phenyltriaz-1-en-1-yl)-N-(4-methyl-2-pyrimidinyl)benzenesulfonamides (1-9), was designed and synthesized by the diazo reaction between sulfamerazine and substituted aromatic amines for the first time. Their chemical structures were characterized by 1 H nuclear magnetic resonance (NMR), 13 C NMR, and high-resolution mass spectra. The newly synthesized compounds were evaluated in terms of acetylcholineasterase (AChE) and human carbonic anhydrases (hCA) I and II isoenzymes inhibitory activities. According to the AChE inhibition results, the Ki values of the compounds 1-9 were in the range of 19.9 ± 1.5 to 96.5 ± 20.7 nM against AChE. Tacrine was used as the reference drug and its Ki value was 49.2 ± 2.7 nM against AChE. The Ki values of the compounds 1-9 were in the range of 10.2 ± 2.6 to 101.4 ± 27.8 nM against hCA I, whereas they were 18.3 ± 4.4 to 48.1 ± 4.5 nM against hCA II. Acetazolamide was used as a reference drug and its Ki values were 72.2 ± 5.4 and 52.2 ± 5.7 nM against hCA I and hCA II, respectively. The most active compounds, 1 (nonsubstituted) against AChE, 5 (4-ethoxy-substituted) against hCA I, and 8 (4-bromo-substituted) against hCA II, were chosen and docked at the binding sites of these enzymes to explain the inhibitory activities of the series. The newly synthesized compounds presented satisfactory pharmacokinetic properties via the estimation of ADME properties.

Coumarins and their derivatives are receiving increasing attention due to numerous biochemical and pharmacological applications. In this study, a series of novel coumarin–1,2,3-triazole-acetamide hybrids was tested against some metabolic enzymes including α-glycosidase (α-Gly), α-amylase (α-Amy), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), human carbonic anhydrase I (hCA I), and hCA II. The new coumarin–1,2,3-triazole-acetamide hybrids showed Ki values in the range of 483.50–1,243.04 nM against hCA I, 508.55–1,284.36 nM against hCA II, 24.85–132.85 nM against AChE, 27.17–1,104.36 nM against BChE, 590.42–1,104.36 nM against α-Gly, and 55.38–128.63 nM against α-Amy. The novel coumarin–1,2,3-triazole-acetamide hybrids had effective inhibition profiles against all tested metabolic enzymes. Also, due to the enzyme inhibitory effects of the new hybrids, they are potential drug candidates to treat diseases such as epilepsy, glaucoma, type-2 diabetes mellitus (T2DM), Alzheimer's disease (AD), and leukemia. Additionally, these inhibition effects were compared with standard enzyme inhibitors like acetazolamide (for hCA I and II), tacrine (for AChE and BChE), and acarbose (for α-Gly and α-Amy). Also, those coumarin–1,2,3-triazole-acetamide hybrids with the best inhibition score were docked into the active site of the indicated metabolic enzymes. © 2020 Deutsche Pharmazeutische Gesellschaft

The antioxidant and radical scavenging activities of the synthesized compounds 3, 5, and 6 were determined by various in vitro assays such as 2,2-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid radical (ABTS(·+) ) scavenging, ferric ion (Fe(3+) ) reducing power and ferrous ion (Fe(2+) ) chelating activities. Moreover, these activities were compared to those of standard antioxidants such as butylated hydroxyanisole, butylated hydroxytoluene, and trolox. The results showed that the new compounds (3, 5, and 6) had potential antioxidant activity. Besides, inhibition of the two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II with some nitrobenzene compounds was investigated. Compounds 1-6 showed Ki values in the range of 4.88-193.4 µM and 5.295-54.75 µM for hCA I and hCA II, respectively.

In the present study, human carbonic anhydrase (hCA) enzyme was purified and characterized from fresh blood human red cells by Sepharose-4B-l-tyrosine-sulfanilamide affinity gel chromatography. Secondly, a series of new tetrabromo chalcone derivatives containing 4,7-methanoisoindol-1,3-dione (2a-i) were synthesized from the addition of Br

Known and novel derivatives including CO, Br, and OH (benzylic and phenolic), and the corresponding benzylic alcohols of (3,4-dimethoxyphenyl)(2,3,4-dimethoxyphenyl)methanone were synthesized, and their inhibitory effects on the carbonic anhydrase (CA) isoenzymes I and II were investigated. CAs are the metalloenzymes catalyzing the reversible hydration of carbon dioxide (CO2 ) to bicarbonate (HCO3 (-) ). The inhibitory effects of diphenylmethanone derivatives 5-18 were tested on human CA (hCA, EC 4.2.1.1) isoenzymes (hCA I and hCA II) and they inhibited both isoenzymes at micromolar levels. Compounds 5 and 10 were found to be the best inhibitors against both CA isoenzymes. According to our data, compound 10 was the best inhibitor for isoenzyme hCA I (IC50 = 3.48 µM, Ki = 2.19 µM) whereas compound 5 was found to be the best inhibitor for isoenzyme hCA II (IC50 = 1.33 µM, Ki = 2.09 µM). Probably, stable conformations of 5 and 10 are more convenient for interaction with CA isoenzymes than those of the other compounds.

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

GULCIN, Ilhami/0000-0001-5993-1668; AKBABA, Yusuf/0000-0002-7770-0473 WOS: 000320473000003 PubMed: 23649517 Here, we provide an alternative synthesis of the natural bromophenol 3,4-dibromo-5-(2,3-dibromo-4,5-dihydroxybenzyl)-6-(ethoxymethyl) benzene-1,2-diol (3) and the first synthesis of (4,5-dihydroxy-2methylphenyl)( 3,4-dihydroxyphenyl) methanone (18) and its brominated derivatives 19-21. The compounds were characterized and tested against the two most studied members of the pH regulatory enzyme family, carbonic anhydrase (CA). The inhibitory potencies of the novel compounds and two natural bromophenols 2, 3 were analyzed at the human isoforms hCA I and hCA II as targets and the K-I values were calculated. The K-I values of the novel compounds were measured in the range of 13.7-32.7 mu M for the hCA I isozyme and 0.65-1.26 mu M for the hCA II isozyme. The structurally related compound 14 was also tested in order to understand the structure-activity relationship, and the clinically used sulfonamide acetazolamide (AZA) was tested for comparison reasons. All of the compounds exhibited competitive inhibition with 4-nitrophenylacetate as substrate. The compounds showed strong inhibitory activity against hCA I, being more effective as compared to the clinically used AZA (K-I: 36.2 mu M), but rather less activity against hCA II. TUBITAK (The Scientific and Technological Research Council of Turkey)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [TBAG-107T348]; Ataturk UniversityAtaturk University We thank TUBITAK (The Scientific and Technological Research Council of Turkey, Project no: TBAG-107T348), Ataturk University for their financial support of this work and A. Bilal Altundas, for linguistic corrections.

A series of ureas derived from phenethylamines were synthesized and evaluated for human carbonic anhydrase (hCA) I and II, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzyme inhibitory activities and antioxidant properties. The ureas were synthesized from the reactions of substituted phenethylamines with N,N-dimethylcarbamoyl chloride; then, the synthesized compounds were converted to their corresponding phenolic derivatives via O-demethylation. hCA I and II were effectively inhibited by the newly synthesized compounds, with K-i values in the range of 0.307-0.432nM for hCA I and 0.149-0.278nM for hCA II. On the other hand, the K-i parameters of these compounds for AChE and BChE were determined in the range of 0.129-0.434 and 0.095-0.207 nM, respectively. Phenolic ureas also showed good antioxidant activities.

Carbonic anhydrase (CA, EC 4.2.1.1) is a member of the metalloenzyme family. It catalyzes the rapid conversion of carbon dioxide (CO

Sulfamates have a large spectrum of biological activities including enzyme inhibition. Eight sulfamates derived from menthol (2a-h) were synthesized. Also, in the other section of this study, novel sulfamate derivatives of menthol were tested against some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carbonic anhydrase I and II enzymes (hCAs I and II). The newly synthesized novel menthol sulfamate and menthol carbonyl sulfamate derivatives showed K-i values in the range of 34.37 +/- 8.17 to 53.40 +/- 10.61 nM against hCA I, 12.91 +/- 4.57 to 38.67 +/- 6.22 nM against hCA II, 111.17 +/- 52.36 to 522.86 +/- 120.08 nM against AChE, and 50.01 +/- 11.73 to 109.63 +/- 50.08 nM against BChE. As a result, the novel menthol sulfamate and menthol carbonyl sulfamate derivatives can be promising Alzheimer's disease drug candidates and novel hCA I and hCA II enzymes inhibitors.

A series of sulfamides were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carbonic anhydrase inhibition properties. The synthesis of sulfamides was achieved by the reactions of phenethylamines with N,N-dimethylsulfamoyl chloride in the presence of Et3N. The methoxylated sulfamides were converted into their phenolic derivatives with BBr3 for structure-activity relationships. The synthesized sulfamide/phenolic sulfamide derivatives were investigated as cholinesterase inhibitors and their relative role in AChE versus BChE inhibition was defined. Sulfamide/phenolic sulfamide derivatives are known as important carbonic anhydrase inhibitors; therefore, the synthesized compounds were investigated for inhibitory effects on both carbonic anhydrase isoenzymes. Additionally, we evaluated four different enzymes, which were inhibited in the low nanomolar range by these compounds. According to the present studies, for AChE, BChE, and carbonic anhydrase I and II, the ranges of results are recorded as 0.027-0.076nM, 0.075-0.327nM, 0.123-0.678nM, and 0.024-0.688nM, respectively., Ataturk University [BAP 2014/67], Ataturk University, Grant number: BAP 2014/67

Three series of symmetrical Schiff bases were synthesized from 1,2-diaminoethane, 1,3-diaminopropane and 1,4-diaminobutane and substituted benzaldehydes, and reduced by sodium borohydride to the corresponding benzylic diamines 4-6. All of the compounds obtained were characterized using elemental analysis, FT-IR, H-1 NMR, and C-13 NMR spectroscopy. The enzyme inhibitory properties of these compounds were tested and the influence of the alkane chain length and the substituents on the phenyl group on the enzyme inhibition activity were examined. The novel Schiff bases and their amine derivatives (1a-d, 2a-d, 3b-d, 4a-c, 5a-c, 6a, 6c, 6d) were effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) with K-i values in the range of 159.43 +/- 30.03 to 563.73 +/- 115.30nM for hCA I, 104.88 +/- 18.44 to 524.32 +/- 95.03nM for hCA II, and 3.95 +/- 0.74 to 30.83 +/- 6.81nM for AChE.

Three series of imidazolidinium ligands (NHC precursors) substituted with 4-vinylbenzyl, 2-methyl-1,4-benzodioxane, and N-propylphthalimide were synthesized. N-Heterocyclic carbene (NHC) precursors were prepared from N-alkylimidazoline and alkyl halides. The novel NHC precursors were characterized by 1H NMR, 13C NMR, FTIR spectroscopy, and elemental analysis techniques. The enzymes inhibition activities of the NHC precursors were investigated against the cytosolic human carbonic anhydrase I and II isoenzymes (hCA I and II) and the acetylcholinesterase (AChE) enzyme. The inhibition parameters (IC50 and Ki values) were calculated by spectrophotometric method. The inhibition constants (Ki) were found to be in the range of 166.65–635.38 nM for hCA I, 78.79–246.17 nM for hCA II, and 23.42–62.04 nM for AChE. Also, the inhibitory effects of the novel synthesized NHCs were compared to acetazolamide as a clinical CA isoenzymes inhibitor and tacrine as a clinical cholinergic enzymes inhibitor.

The antioxidant and radical scavenging activities of the synthesized compounds 3, 5, and 6 were determined by various in vitro assays such as 2,2-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid radical (ABTS(·+) ) scavenging, ferric ion (Fe(3+) ) reducing power and ferrous ion (Fe(2+) ) chelating activities. Moreover, these activities were compared to those of standard antioxidants such as butylated hydroxyanisole, butylated hydroxytoluene, and trolox. The results showed that the new compounds (3, 5, and 6) had potential antioxidant activity. Besides, inhibition of the two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II with some nitrobenzene compounds was investigated. Compounds 1-6 showed Ki values in the range of 4.88-193.4 µM and 5.295-54.75 µM for hCA I and hCA II, respectively.

Three 1-aminoindanes, four anilines and BnOH or t-BuOH were reacted with chlorosulfonyl isocyanate to give sulfamoyl carbamates. Pd-C catalysed hydrogenolysis reactions of carbamates or deprotection of the Boc group of the carbamates with CF3 CO2 H afforded seven novel sulfamides. Human carbonic anhydrase (hCA) isoenzymes I and II (hCA I and hCA II) were purified from fresh human blood erythrocytes with one-step affinity chromatography on Sepharose 4B-tyrosine-sulfanilamide. The inhibitory properties of the novel sulfamides on both isoenzymes were determined using the esterase activity with 4-nitrophenyl acetate (NPA) as substrate. The tested novel sulfamides derived from 1-aminoindanes and anilines effectively inhibited hCA I and II competitively in the nanomolar range. Among these compounds, the novel sulfamide derivative 17 showed the most potent inhibitory effect against hCA I (Ki : 153.88 nM), while sulfamide derivative 26 showed the highest inhibitory potential against hCA II (Ki : 117.80 nM).

Known and novel derivatives including CO, Br, and OH (benzylic and phenolic), and the corresponding benzylic alcohols of (3,4-dimethoxyphenyl)(2,3,4-dimethoxyphenyl)methanone were synthesized, and their inhibitory effects on the carbonic anhydrase (CA) isoenzymes I and II were investigated. CAs are the metalloenzymes catalyzing the reversible hydration of carbon dioxide (CO2 ) to bicarbonate (HCO3 (-) ). The inhibitory effects of diphenylmethanone derivatives 5-18 were tested on human CA (hCA, EC 4.2.1.1) isoenzymes (hCA I and hCA II) and they inhibited both isoenzymes at micromolar levels. Compounds 5 and 10 were found to be the best inhibitors against both CA isoenzymes. According to our data, compound 10 was the best inhibitor for isoenzyme hCA I (IC50 = 3.48 µM, Ki = 2.19 µM) whereas compound 5 was found to be the best inhibitor for isoenzyme hCA II (IC50 = 1.33 µM, Ki = 2.09 µM). Probably, stable conformations of 5 and 10 are more convenient for interaction with CA isoenzymes than those of the other compounds.

Reactions of amino, aminomethyl tetralins and benzyl alcohol with chlorosulphonyl isocyanate (CSI) afforded sulphamoyl carbamates. The sulphamoyl carbamates were converted to sulphamides by palladium-catalysed hydrogenolysis. Sulphonamides were synthesized from the reactions of amines with MeSO2 Cl. Inhibition of human (h) carbonic anhydrase (CA) isoenzymes (hCA I, hCA II) and acetylcholine esterase (AChE) was investigated with the synthesized compounds. hCA I and hCA II were inhibited in the low micromolar or sub-micromolar range. The Ki values were in the range of 0.91-9.56 µM against hCA I and of 3.70-27.88 µM against hCA II. Sulphamides 11-13 and sulphonamides 14-16 had moderate inhibition capacity toward AChE. These findings suggest the novel sulphamides 11-13 and sulphonamides 14-16 as AChE and CA isoenzyme inhibitory agents.