Synthesis of Novel Bromophenol with Diaryl Methanes-Determination of Their Inhibition Effects on Carbonic Anhydrase and Acetylcholinesterase.

In this work, nine new bromophenol derivatives were designed and synthesized. The alkylation reactions of (2-bromo-4,5-dimethoxyphenyl)methanol (7) with substituted benzenes 8-12 produced new diaryl methanes 13-17. Targeted bromophenol derivatives 18-21 were synthesized via the O-Me demethylation of diaryl methanes with BBr3. Moreover, the synthesized bromophenol compounds were tested with some metabolic enzymes such as acetylcholinesterase (AChE), carbonic anhydrase I (CA I), and II (CA II) isoenzymes. The novel synthesized bromophenol compounds showed Ki values that ranged from 2.53 ± 0.25 to 25.67 ± 4.58 nM against hCA I, from 1.63 ± 0.11 to 15.05 ± 1.07 nM against hCA II, and from 6.54 ± 1.03 to 24.86 ± 5.30 nM against AChE. The studied compounds in this work exhibited effective hCA isoenzyme and AChE enzyme inhibition effects. The results show that they can be used for the treatment of glaucoma, epilepsy, Parkinson's as well as Alzheimer's disease (AD) after some imperative pharmacological studies that would reveal their drug potential.

Synthesis and characterization of novel bromophenols: Determination of their anticholinergic, antidiabetic and antioxidant activities.

In this paper, a series of novel bromophenol derivatives were synthesized and evaluated for their acetylcholinesterase and α-glycosidase enzymes inhibition properties and antioxidant activity. Diarylmethanones were synthesized and their bromination was carried out. During bromination, some compounds gave new bromophenols via regioselective O-demethylation. Demethylation of brominated diarylmethanones was also performed with BBr3 to give novel bromophenols. In addition, we examines the antioxidant capacity of novel bromophenol derivatives using several in vitro bioanalytical methodologies such as 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS⋅+) and 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH) radical scavenging activity, Fe3+ and Cu2+ reducing activities and ferrous (Fe2+) ions chelating activities. Also, novel bromophenols and methoxylated bromophenols derivatives were tested against acetylcholinesterase and α-glycosidase, which associated with some metabolic diseases. The novel bromophenols showed Ki values in range of 8.94 ±â€¯0.73-59.45 ±â€¯14.97 nM against AChE and 4.31 ±â€¯1.93-44.14 ±â€¯2.19 nM against α-glycosidase.

Novel antioxidant bromophenols with acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase inhibitory actions.

In this study, a series of novel bromophenols were synthesized from benzoic acids and methoxylated bromophenols. The synthesized compounds were evaluated by using different bioanalytical antioxidant assays including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS+) radical scavenging assays. Also, reducing power of novel bromophenols were evaluated by Cu2+-Cu+ reducing, Fe3+-Fe2+ reducing and [Fe3+-(TPTZ)2]3+-[Fe2+-(TPTZ)2]2+ reducing and ferrous ions (Fe2+) chelating abilities. The compounds demonstrate powerful antioxidant activities when compared to standard antioxidant molecules of α-tocopherol, trolox, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT). Also in the last part of this studies novel bromophenols were tested against some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE) enzymes and carbonic anhydrase I, and II (hCA I and hCA II) isoenzymes. The newly synthesized bromophenols showed Ki values in a range of 6.78±0.68 to 126.07±35.6nM against hCA I, 4.32±0.23 to 72.25±12.94nM against hCA II, 4.60±1.15 to 38.13±5.91nM against AChE and 7.36±1.31 to 29.38±3.68nM against BChE.

Synthesis of diaryl ethers with acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase inhibitory actions.

A series of diaryl ethers were synthesized and their human (h) carbonic anhydrase (CA) isoenzymes hCA I and II, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) inhibitory actions were investigated. The new compounds were synthesized from the corresponding phenols and bromobenzenes via the Ullmann reaction, by using dipicolinic acid as a copper (I) complexing ligand. hCA I and II were inhibited with Kis in the low nanomolar range of 102.01-127.13 nM against hCA I, and of 73.71-113.40 nM against hCA II, whereas the inhibition constants against AChE were of 15.35-18.34 nM and against BChE in the range of 9.07-22.90 nM. The CA inhibition mechanism with these ethers is unknown, but may be similar to that of aryl methyl ethers investigated earlier by computational approaches.

Synthesis and carbonic anhydrase inhibitory effects of novel sulfamides derived from 1-aminoindanes and anilines.

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).

Diarylmethanon, bromophenol and diarylmethane compounds: Discovery of potent aldose reductase, α-amylase and α-glycosidase inhibitors as new therapeutic approach in diabetes and functional hyperglycemia.

Diabetes mellitus (DM) is a chronic metabolic disease in which there are high blood sugar levels over a prolonged period. Aldose reductase (AR) belongs to aldo-keto reductase superfamily and plays a key role in the polyol pathway. α-Glycosidase and α-amylase are important enzymes in glucose metabolism. In this study, AR was purified from purified from cow liver. The enzyme was obtained with 139.17 purification fold and with a specific activity of 1.67 EU/mg protein. Then, it is observed the inhibition effect of diarylmethanons (1a-d), bromophenols (2a-d and 4a-d) and diarylmethanes (3a-d) on aldose reductase, α-glycosidase and α-amylase enzymes. In these series, compound 2a showed lowest inhibitory activity against AR with a Ki value of 1.09 ±â€¯0.29 µM while compound 2d showed highest inhibitory activity against AR with a Ki value of 0.092 ±â€¯0.015 µM. Additionally, α-glycosidase and α-amylase enzymes were easily inhibited by these compounds. All compounds were tested for their inhibition effects against of α-glycosidase enzyme and demonstrated efficient inhibition profiles with Ki values in the range of 14.44 ±â€¯0.88-43.53 ±â€¯9.06 nM, and IC50 values in the range of 11.72-46.11 nM. Also, inhibition of the α-amylase enzyme, which determined an effective inhibition profile with IC50 values, is in the range of 3.84-29.61 nM.

Effect of nimesulide on the indomethacin- and ibuprofen-induced ulcer in rat gastric tissue.

In this study, we examined the effect of nimesulide and ranitidine on the indomethacin- and ibuprofen-induced ulcer. In addition, we investigated whether there was a direct chemical interaction of nimesulide and ranitidine with indomethacin, and also whether nimesulide and ranitidine neutralized the gastric acid in vitro. Our studies showed that nimesulide (100, 300, 500 mg/kg) prevented the indomethacin-induced gastric ulcers completely. Ranitidine at a dose of 150 mg/kg reduced the mean ulcer area to 2.5 +/- 0.76 mm2 in the indomethacin-treated and to 2.0 +/- 0.81 mm2 in ibuprofen-treated rats. The mean ulcer areas in rats given only indomethacin and only ibuprofen were 20.3 +/- 1.58 mm2 and 9.5 +/- 1.43 mm2, respectively. There were no chemical reactions between nimesulide and indomethacin or ranitidine and indomethacin in vitro. Nimesulide and ranitidine did not neutralize the gastric acid in vitro.