Ferhan Tümer

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.

The human carbonic anhydrase isoenzymes I and II (hCA I and II) inhibition effects of trimethoxyindane derivatives

Abstract Carbonic anhydrases (CAs, EC 4.2.1.1) had six genetically distinct families described to date in various organisms. There are 16 known CA isoforms in humans. Human CA isoenzymes I and II (hCA I and hCA II) are ubiquitous cytosolic isoforms. Acetylcholine esterase (AChE. EC 3.1.1.7) is a hydrolase that hydrolyzes the neurotransmitter acetylcholine relaying the signal from the nerve. In this study, some trimethoxyindane derivatives were investigated as inhibitors against the cytosolic hCA I and II isoenzymes, and AChE enzyme. Both hCA isozymes were inhibited by trimethoxyindane derivatives in the low nanomolar range. These compounds were good hCA I inhibitors (Kis in the range of 1.66–4.14u2009nM) and hCA II inhibitors (Kis of 1.37–3.12u2009nM) and perfect AChE inhibitors (Kis in the range of 1.87–7.53u2009nM) compared to acetazolamide as CA inhibitor (Ki: 6.76u2009nM for hCA I and Ki: 5.85u2009nM for hCA II) and Tacrine as AChE inhibitor (Ki: 7.64u2009nM).

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 Ki values of 2.61-3.69nM against hCA I, 1.64-2.80nM against hCA II, and in the range of 0.45-1.74nM 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.

Acetylcholinesterase Inhibitory and Antioxidant Activities of Novel Symmetric Sulfamides Derived from Phenethylamines

The antioxidant and acetylcholinesterase inhibitory properties of novel symmetric sulfamides derived from phenethylamines were evaluated. Phenethylamines 8–11 were reacted with SO2Cl2 in the presence of Et3N to afford sulfamides in good yields. The synthesized sulfamides were converted to their phenolic derivatives with BBr3. We elucidated the antioxidant activity of novel symmetric sulfamides by using different bioanalytical assays. For this purpose, the radical scavenging activities of the novel symmetric sulfamides were assessed by DPPH•, ABTS•+, DMPD•+, and O2•– radical scavenging tests. In addition, the reducing abilities of the novel symmetric sulfamides were evaluated by Fe3+‐Fe2+ reducing, Cu2+‐Cu+ reducing, and [Fe3+‐(TPTZ)2]3+‐[Fe2+‐(TPTZ)2]2+ reducing activity tests. Also, the Fe2+ chelating activity by the pipyrdyl reagent and the acetylcholinesterase inhibitory activities of the novel symmetric sulfamides were studied. Especially, the novel phenolic and symmetric sulfamides 16–19 showed high antioxidant and acetylcholinesterase inhibitory properties. On the other hand, IC50 values were calculated for the DPPH•, ABTS•+, DMPD•+, and O2•–scavenging, the metal chelating, and the acetylcholinesterase inhibition effects of the novel symmetric sulfamides.

Synthesis of Dopamine, Rotigotin, Ladostigil, Rasagiline Analogues 2-Amino-4,5,6-trimethoxyindane, 1-Amino-5,6,7-trimethoxyindane, and Their Sulfamide Derivatives

Abstract Dopamine, rotigotin, ladostigil, and rasagiline analogues 2-amino-4,5,6-trimethoxyindane and 1-amino-5,6,7-trimethoxyindane were synthesized starting from 5,6,7-trimethoxyindan-1-one for the first time with 34% and 45% total yields. α-Carboxylation of indanone, reduction of ketone group with Et3SiH, basic hydrolysis of ester, Curtius reaction of the acid, and addition of BnOH afforded the corresponding carbamate. Pd-C-catalyzed hydrogenolysis of carbamate and deprotonation of amine hydrochloride with NaOH gave the dopamine and rotigotin analogue 2-aminoindane. Reduction of 5,6,7-trimethoxyindan-1-one with NaBH4 afforded the alcohol, which was then converted to the azide derivative via Mitsunobu reaction with diphenylphosphoryl azide; Pd-C catalyzed hydrogenation of the azide to the amine hydrochloride and then deprotonation of the amine hydrochloride with NaOH furnished the ladostigil and rasagiline analogue 1-aminoindane. These amines and BnOH were reacted with CSI to produce sulfamoyl carbamates, which were converted to sulfamides via Pd-C-catalyzed hydrogenolysis reaction with 20% and 25% total yields. GRAPHICAL ABSTRACT

SOD activity and DNA binding properties of a new symmetric porphyrin Schiff base ligand and its metal complexes.

4-Methoxy-2,6-bis(hydroxymethyl)phenol (1) was prepared from the reaction of 4-methoxyphenol and formaldehyde. The compound (1) was then oxidized to the 4-methoxy-2,6-diformylphenol (2) compound. Molecular structure of compound (2) was determined by X-ray diffraction method. A new symmetric porphyrin Schiff base ligand 4-methoxy-2,6-bis[5-(4-iminophenyl)-10,15,20-triphenylporphyrin]phenol (L) was prepared from the reaction of the 5-(4-aminophenyl)-10,15,20-triphenylporphyrin (TTP-NH2) and the compound (2) in the toluene solution. The metal complexes (Cu(II), Fe(III), Mn(III), Pt(II) and Zn(II)) of the ligand (L) were synthesized and characterized by the spectroscopic and analytical methods. The DNA (fish sperm FSdsDNA) binding studies of the ligand and its complexes were performed using UV-vis spectroscopy. Additionally, superoxide dismutase activities of the porphyrin Schiff base metal complexes were investigated. Additionally, electrochemical, photoluminescence and thermal properties of the compounds were investigated.

Mutagenic assessment of three synthetic pyridine-diaryl ketone derivatives

Nowadays, there are increasing numbers of studies about synthetic chemicals according to the supply demands of bioactive chemicals. The current study aims to investigate genotoxic potential of bioactive synthetic pyridine compounds, phenyl-3-pyridinylmethanone (1), p-tolyl-3-pyridinylmethanone (2), and 4-methoxyphenyl-3-pyridinylmethanone (3), using Ames/Salmonella and Escherichia coli WP2 bacterial reversion mutagenicity test systems. The mutant bacterial tester strains sodium azide-sensitive Salmonella typhimurium TA1535, 9-aminoacridine-sensitive S. typhimurium TA1537, and N-methyl-N′-nitro-N-nitrosoguanidine-sensitive E. coli WP2uvrA were used to detect the mutagenic potential of the test compounds. The results indicated that none of the test substances showed significant mutagenic activity on S. typhimurium TA1535, TA1537, and E. coli WP2uvrA bacterial strains up to 1 µg/plate concentrations.

Synthesis of novel sulfamides incorporating phenethylamines and determination of their inhibition profiles against some metabolic enzymes

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 0.027–0.076u2009nM, 0.075–0.327u2009nM, 0.123–0.678u2009nM, and 0.024–0.688u2009nM, respectively.

CCDC 1567759: Experimental Crystal Structure Determination

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