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.
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 1.66-4.14 nM) and hCA II inhibitors (Kis of 1.37-3.12 nM) and perfect AChE inhibitors (Kis in the range of 1.87-7.53 nM) compared to acetazolamide as CA inhibitor (Ki: 6.76 nM for hCA I and Ki: 5.85 nM for hCA II) and Tacrine as AChE inhibitor (Ki: 7.64 nM).
A series of carbamate derivatives were synthesized and their carbonic anhydrase I and II isoenzymes and acetylcholinesterase enzyme (AChE) inhibitory effects were investigated. All carbamates were synthesized from the corresponding carboxylic acids via the Curtius reactions of the acids with diphenyl phosphoryl azide followed by addition of benzyl alcohol. The carbamates were determined to be very good inhibitors against for AChE and hCA I, and II isoenzymes. AChE inhibition was determined in the range 0.209-0.291 nM. On the other hand, tacrine, which is used in the treatment of Alzheimer's disease possessed lower inhibition effect (K i : 0.398 nM). Also, hCA I and II isoenzymes were effectively inhibited by the carbamates, with inhibition constants (K i ) in the range of 4.49-5.61 nM for hCA I, and 4.94-7.66 nM for hCA II, respectively. Acetazolamide, which was clinically used carbonic anhydrase (CA) inhibitor demonstrated K i values of 281.33 nM for hCA I and 9.07 nM for hCA II. The results clearly showed that AChE and both CA isoenzymes were effectively inhibited by carbamates at the low nanomolar levels.
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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