Süleyman Göksu

Synthesis, Antioxidant, and Antiacetylcholinesterase Activities of Sulfonamide Derivatives of Dopamine-Related Compounds

A series of sulfonamides were synthesized from dopamine derivatives. The reactions of amines with methanesulfonyl chloride followed by O‐demethylation with BBr3 afforded phenolic sulfonamides. The antioxidant activities of the synthesized phenolic sulfonamides were investigated by thiocyanate method, 2,2′‐azino‐bis(3‐ethylbenzthiazoline‐6‐sulfonic acid) (ABTS•+), 1,1‐diphenyl‐2‐picryl‐hydrazyl (DPPH•), N,N‐dimethyl‐p‐phenylenediamine (DMPD•+), and superoxide anion (O2•−) radical scavenging, reducing power, and ferrous ion (Fe2+) chelating assays. Sulfonamides 13–16 showed around 75–85% inhibition on linoleic acid peroxidation. On the other hand, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α‐tocopherol, and trolox indicated an inhibition of 90.0%, 85.73%, 73.33%, and 85.73% on peroxidation, respectively, in the same system at the same concentration (10 µg/mL). Also, the inhibition effects of the synthesized compounds on acetylcholinesterase (AChE) activity were evaluated. AChE was effectively inhibited by sulfanomides 13–16, with Ki values in the range of 33.04 ± 4.3 to 131.68 ± 8.8 nM.

Synthesis and carbonic anhydrase inhibitory properties of sulfamides structurally related to dopamine

A series of novel sulfamides incorporating the dopamine scaffold were synthesized. Reaction of amines and tert-butyl-alcohol/benzyl alcohol in the presence of chlorosulfonyl isocyanate (CSI) afforded sulfamoyl carbamates, which were converted to the title compounds by treatment with trifluoroacetic acid or by palladium-catalyzed hydrogenolysis. Inhibition of six α-carbonic anhydrases (CAs, EC 4.2.1.1), that is, CA I, CA II, CA VA, CA IX, CA XII and CA XIV, and two β-CAs from Candida glabrata (CgCA) and Mycobacterium tuberculosis (Rv3588) with these sulfamides was investigated. All CA isozymes were inhibited in the low micromolar to nanomolar range by the dopamine sulfamide analogues. K(i)s were in the range of 0.061-1.822 μM for CA I, 1.47-2.94 nM for CA II, 2.25-3.34 μM for CA VA, 0.041-0.37 μM for CA IX, 0.021-1.52 μM for CA XII, 0.007-0.219 μM for CA XIV, 0.35-5.31 μM for CgCA and 0.465-4.29 μM for Rv3588. The synthesized sulfamides may lead to inhibitors targeting medicinally relevant CA isoforms with potential applications as antiepileptic, antiobesity antitumor agents or anti-infective.

Antioxidant and acetylcholinesterase inhibition properties of novel bromophenol derivatives.

In this study, series of novel bromophenol derivatives were synthesized and investigated for their antioxidant and AChE inhibition properties. Novel brominated diarylmethanones were obtained from the acylation reactions of benzoic acids with substituted benzenes. One of the bromodiarylmethanone was synthesized from the bromination of diarylmethanone with molecular bromine. All diarylmethanones were converted into their bromophenol derivatives with BBr3. The antioxidant activities of all synthesized compounds were elucidated by using various bioanalytical assays. Radical scavenging activities of compounds 10-24 were evaluated by means of DPPH and ABTS(+) scavenging activities. In addition, reducing ability of 10-24 were determined by Fe(3+), Cu(2+), and [Fe(3+)-(TPTZ)2](3) reducing activities. α-Tocopherol, trolox, BHA, and BHT were used as positive antioxidant and radical scavenger molecules. On the other hand, IC50 values were calculated for DPPH, ABTS(+) scavenging, and AChE inhibition effects of novel compounds. The results obtained from the current studies clearly show that novel bromophenol derivatives 20-24 have considerable antioxidant, antiradical, and AChE inhibition effects.

Novel sulfamides as potential carbonic anhydrase isoenzymes inhibitors.

Sulfamides represent an important class of biologically active compounds. A series of novel sulfamides were synthesized from 1-aminoindanes, 1-aminotetralin, 2-aminoindanes and 2-aminotetralin via the reactions of free amines, benzyl alcohol and chlorosulfonyl isocyanate (CSI) followed by hydrogenolysis of the obtained sulfamoylcarbamates. Carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the new sulfamides have been investigated. The human (h) isozymes hCA I and hCA II have been investigated in this study by using an esterase assay with 4-nitrophenyl acetate as substrate. The new sulfamides showed inhibition constants in the micro-submicromolar range, with one compound (N-(indane-1-yl)sulfamide) showing a Ki of 0.45μM against hCA I and of 1.07μM against hCA II.

Kinetic and docking studies of phenol-based inhibitors of carbonic anhydrase isoforms I, II, IX and XII evidence a new binding mode within the enzyme active site

Carbonic anhydrases (CAs, EC 4.2.1.1) are inhibited by sulfonamides, inorganic anions, phenols, coumarins (acting as prodrugs) and polyamines. A novel class of CA inhibitors (CAIs), interacting with the CA isozymes I, II (cytosolic) and IX, XII (transmembrane, tumor-associated) in a different manner, is reported here. Kinetic measurements allowed us to identify hydroxy-/methoxy-substituted benzoic acids as well as di-/tri-methoxy benzenes as submicromolar-low micromolar inhibitors of the four CA isozymes. Molecular docking studies of a set of such inhibitors within CA I and II allowed us to understand the inhibition mechanism. This new class of inhibitors binds differently compared to all other classes of inhibitors known to date: they were found between the phenol-binding site and the coumarin-binding site, filling thus the middle of the enzyme cavity. They exploit different interactions with amino acid residues and water molecules from the CA active site compared to other classes of inhibitors, offering the possibility to design CAIs with an interesting inhibition profile compared to the clinically used sulfonamides/sulfamates.

Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: Novel sulfamoylcarbamates and sulfamides derived from acetophenones

In this study, several novel sulfamides were synthesized and evaluated for their acetylcholine esterase (AChE) and human carbonic anhydrase I, and II isoenzymes (hCA I and II) inhibition profiles. Reductive amination of methoxyacetophenones was used for the synthesis of amines. Amines were converted to sulfamoylcarbamates with chlorosulfonyl isocyanate (CSI) in the presence of BnOH. Pd-C catalyzed hydrogenolysis of sulfamoylcarbamates afforded sulfamides. These novel compounds were good inhibitors of the cytosolic hCA I, and hCA II with Ki values in the range of 45.9±8.9-687.5±84.3 pM for hCA I, and 48.80±8.2-672.2±71.9pM for hCA II. The inhibitory effects of the synthesized novel compounds on AChE were also investigated. The Ki values of these compounds were in the range of 4.52±0.61-38.28±6.84pM for AChE. These results show that hCA I, II, and AChE were effectively inhibited by the novel sulfamoylcarbamates 17-21 and sulfamide derivatives 22-26. All investigated compounds were docked within the active sites of the corresponding enzymes revealing the reasons of the effective inhibitory activity.

Carbonic anhydrase and acetylcholinesterase inhibitory effects of carbamates and sulfamoylcarbamates

Abstract Carbonic anhydrases (CA), as a family of metalloenzymes, are found in almost every type of tissue and play an important role in catalyzing the equilibration of carbon dioxide and carbonic acid. In this study, a series of carbamate derivative was synthesized, and their inhibition effects on hCA I, hCA II and acetylcholinesterase (AChE) enzymes were investigated. They were determined to be very good inhibitor against for both isoenzymes (hCA I and hCA II) and AChE. The hCA I and hCA II were effectively inhibited by the carbamate derivatives, with inhibition constants (Ki) in the range of 194.4–893.5 nM (for hCA I) and 103.9–835.7 nM (for hCA II). On the other hand, Ki parameters of these compounds for AChE enzyme inhibition were determined in the range of 12.0–61.3 nM. The results clearly showed that both CA isoenzymes and AChE were inhibited by carbamate derivatives at the nM levels.

Novel Sulphamides and Sulphonamides Incorporating the Tetralin Scaffold as Carbonic Anhydrase and Acetylcholine Esterase Inhibitors

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 MeSO2Cl. 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.

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. Ki values were in the range of 28.48±0.01-837.09±0.19nM and 112.01±0.01-268.01±0.22nM for hCAI and hCA II isoenzymes, respectively. Molecular modeling approaches were also applied for studied compounds.

Carbonic anhydrase inhibitory properties of novel sulfonamide derivatives of aminoindanes and aminotetralins.

Abstract Six sulfonamides derived from indanes and tetralines were synthesized. The human carbonic anhydrase isozymes hCA I and hCA II inhibition effects of the synthesized sulfonamides were determined. From these compounds, while N-(5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)methane sulfonamide showed the most potent inhibitory effect against hCA I (Ki = 46 ± 5.4 µM, r2 = 0.978), N-(1,2,3,4-tetrahydronaphthalene-2-yl)methanesulfonamide was found to have the best inhibitory effect against hCA II (Ki = 94 ± 7.6 µM, r2 = 0.982).