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 values in the range of 0.307-0.432 nM for hCA I and 0.149-0.278 nM for hCA II. On the other hand, the K 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.
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 Fe(3+)-Fe(2+) reducing, Cu(2+)-Cu(+) reducing, and [Fe(3+)-(TPTZ)2](3+)-[Fe(2+)-(TPTZ)2](2+) reducing activity tests. Also, the Fe(2+) 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.
In this work, the inhibitory effect of some symmetric sulfamides derived from phenethylamines were determined against human carbonic anhydrase (hCA) I, and II isoenzymes, and compared with standard compound acetazolamide. IC50 values were obtained from the Enzyme activity (%)‐[Symmetric sulfamides] graphs. Also, Ki values were calculated from the Lineweaver‐Burk graphs. Some symmetric sulfamides compounds (11–18) demonstrated excellent inhibition effects against hCA I, and II isoenzymes. These compounds demonstrated effective inhibitory profiles with IC50 values in ranging from 21.66–28.88 nM against hCA I, 14.44–30.13 nM against hCA II. Among these compounds, the best Ki value for hCA I (Ki: 8.34±1.60 nM) and hCA II (Ki: 16.40±1.00 nM) is compound number 11. Besides, the IC50 value of acetazolamide used as a standard was determined as hCA I, hCA II 57.75 nM, 49.50 nM, respectively. Moreover, in silico ADME‐Tox study showed that all synthesized compounds (11–18) had good oral bioavailability in light of Jorgensen's rule of three, and of Lipinski's rule of five.
All chemicals and solvents are commercially available and they were used after distillation or treatment with drying agents. Column Chromatography (CC): silica gel (SiO 2 , 60-mesh; Merck). M.p.: BUCHI 530 a capillary melting-point apparatus; uncorrected. IR spectra: Perkin-Elmer spectrophotometer; solutions in 0.1 mm cells. 1 H-and 13 C-NMR spectra: Varian 400 (400 and 100 MHz, resp.) and Bruker 400 (400 and 100 MHz, resp.) spectrometer; in ppm rel. to Me 4 Si as internal standard, J in Hz. Elemental analysis (EA): Leco CHNS-932 apparatus. PLC: 1 mm of silica gel (SiO 2 , 60 PF; Merck); preparative thinlayer chromatography; on glass plates.
5,6,7-trimethoxy-2,3-dihydro-1H-inden-1-one (8)Compound 8 was prepared as described in the literature. [1] 1 H-and 13 C-NMR data of this compound has been reported previously. [2] Methyl 5,6,7-trimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (9) Into a 250-mL round-bottom flask was placed 5,6,7-trimethoxy-2,3-dihydro-1H-inden-1-one (8) (6 g, 27.02 mmol) in THF (100 mL). Then 3 equiv. (1.95 g, 81.00 mmol) NaH and DMC (5.7 mL, 67.50 mmol) in THF (10 mL) were added to the mixture. The reaction mixture was refluxed for 24 h. The mixture was cooled to room temperature and it was acidified with glacial AcOH (2 mL). Aqueous solution of Na 2 CO 3 (10 mL) was added to the mixture and then it was extracted with EtOAc (3x10 mL). The combined organic phases were washed with water (10 mL) and dried over Na 2 SO 4 . Evaporation of the solvent and column chromatography of the residue on silica gel (50 g) with 30% EtOAc-Hexane gave ester 9
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