calcd for C11H11NO3: C 64.38 H 5.40, found: C 64.37, H 5.44. 2-(4-Cyanophenoxy)acetic acid (2d) Ethyl 2-(4-cyanophenoxy)acetate 2c (500 mg, 2.44 mmol) was added to 50mL of a 10% solution of KOH in MeOH and the reaction combination was refluxed for 5h. varieties generated from the hosts immune response. In most eukaryotes you will find two major systems based on NADPH-dependent flavoenzymes to regenerate thiols from disulfide substrates and to detoxify reactive oxygen varieties: one is based on the tripeptide glutathione (GSH) and glutathione reductase (GR, E.C. 1.8.1.7) and the other, within the protein thioredoxin (Trx) and thioredoxin reductase (TrxR, E.C. 1.8.1.9). In these two enzymes are absent and replaced by a unique bi-functional seleno-enzyme, thioredoxin-glutathione reductase (thiol redox rate of metabolism and has been identified as a key drug target.[11] The aim of this study was to identify new lead chemical series and to design novel inhibitors of this essential enzyme. A preliminary inhibitor screen led to the identification of the (substituted phenoxy)methyl menadione derivative 1 IL6 (Fig. 1) having a carboxylic acid function, like a potent the preparation of bioisosteres/prodrugs of the -COOH moiety of 1 1 by replacing the benzoic acid group by a nitrile (2), or a difluoromethoxyphenol (3), which are known to enhance the cellular permeability of the parent carboxylic acid, or analogues to introduce chemical diversity, with halogens chloro (4), bromo (5), or CF3 (6, 7) organizations (Fig. 1). From your synthetic perspective, the (substituted phenoxy)methyl menadione derivative 2 bearing a cyano group instead of the benzoic acid function found in 1 was acquired having a 13% global yield from commercially available 4-cyanophenol (Fig. 2, route A). Compound 2 can be considered like a prodrug of 1 1. The side chain of 4-cyanophenol was elongated from the reaction with ethylchloroacetate under fundamental conditions to afford 2c as white crystals with 97% yield. The ethyl ester was then saponified to give the acid 2d with 65% yield. Compound 2d was reacted with menadione in the Kochi-Anderson radical decarboxylation [15] to obtain the final (p-cyanophenoxy)methyl menadione derivative 2 with 21% yield. Starting from the commercially available 16-Dehydroprogesterone difluorophenol, (difluoro phenoxy)methyl menadione derivative 3 was acquired with an overall yield of 5% (Fig. 2, route A). The hydroquinone 3a was acquired through Elbs oxidation [16] having a yield of 44%, and then was subjected to selective methylation with dimethylsulfate under slight basic conditions to give the 4-methoxy-3,5-difluorophenol 3b with 50% yield. The side chain of the phenol 3b was elongated by reaction with ethylchloroacetate under fundamental conditions to afford the ester 3c with 71% yield. Saponification of 3c led to the carboxylic acid 3d having a yield of 77%. The acid 3d was launched in the Kochi-Anderson radical decarboxylation to obtain the final difluorophenol methoxy ether derivative 3 16-Dehydroprogesterone with 41% yield. Then, to expose more structural diversity in the (substituted phenoxy)methyl menadione series, additional analogues were synthesized, such as molecules bearing different halogens. The 16-Dehydroprogesterone addition of halogen increases the lipophilicity of the compounds, changes their redox potential value, and enhances their metabolic stability in the sponsor. Commercially available 2-(4-chlorophenoxy)acetic acid and 2-(4-bromophenoxy)acetic acid were allowed to react with menadione in the Kochi-Anderson radical decarboxylation to afford the related 3-phenoxymenadione derivatives, 4 and 5, with 35% and 24% yield, respectively. Open in a separate windows Fig. 2 Synthesis of 3-phenoxymethylmenadione derivatives (Route A) and its 2-difluoromethyl analogs (Route B). Finally, another series of compounds was investigated by introducing fluorine directly on the methyl group of the menadione core (Fig. 2, route B). Commercially available 1,4-naphthoquinone was reduced using SnCl2/HCl and the producing dihydronaphthoquinone was methylated by dimethylsulfate under slight basic conditions. The dimethoxynaphthalene intermediate was then successively formylated (98% yield) and treated with 2.0 equiv. of diethylaminosulfur trifluoride (DAST) to obtain the 2-(difluoromethyl)-1,4-dimethoxynaphthalene having a yield of 92%, relating described methods.[ 17 ] Subsequent oxidation with cerium ammonium nitrate (CAN) led to the difluorinated menadione with 93% yield. The difluoromethylmenadione derivative and the.Hence, the TGR inactivation from the bioreductible fluorinated alkylating (substituted phenoxy)methyl menadione derivatives was directly correlated to the abolishment of the antischistosomal activity of the parent menadione analogue 2. worms live in the mesenteric veins of their human being hosts, where they can survive for up to 30 years.[9] Residing in an aerobic environment, they must possess effective mechanisms to keep up their cellular redox stabilize. 16-Dehydroprogesterone In addition, worms must be able to reduce reactive oxygen species generated from the hosts immune response. In most eukaryotes you will find two major systems based on NADPH-dependent flavoenzymes to regenerate thiols from disulfide substrates and to detoxify reactive oxygen varieties: one is based on the tripeptide glutathione (GSH) and glutathione reductase (GR, E.C. 1.8.1.7) and the other, within the protein thioredoxin (Trx) and thioredoxin reductase (TrxR, E.C. 1.8.1.9). In these two enzymes are absent and replaced by a unique bi-functional seleno-enzyme, thioredoxin-glutathione reductase (thiol redox rate of metabolism and has been identified as a key drug target.[11] The aim of this study was to identify new lead chemical series and to design novel inhibitors of this essential enzyme. A preliminary inhibitor screen led to the identification of the (substituted phenoxy)methyl menadione derivative 1 (Fig. 1) having a carboxylic acid function, like a potent the preparation of bioisosteres/prodrugs of the -COOH moiety of 1 1 by replacing the benzoic acid group by a nitrile (2), or a difluoromethoxyphenol (3), which are known to enhance the cellular permeability of the parent carboxylic acid, or analogues to introduce chemical diversity, with halogens chloro (4), bromo (5), or CF3 (6, 7) organizations (Fig. 1). From your synthetic perspective, the (substituted phenoxy)methyl menadione derivative 2 bearing a cyano group instead of the benzoic acid function found in 1 was acquired having a 13% global yield from commercially available 4-cyanophenol (Fig. 2, route A). Compound 2 can be considered like a prodrug of 1 1. The side chain of 4-cyanophenol was elongated from the reaction with ethylchloroacetate under fundamental conditions to afford 2c as white crystals with 97% yield. The ethyl ester was then saponified to give the acid 2d with 65% yield. Compound 2d was reacted with menadione in the Kochi-Anderson radical decarboxylation [15] to obtain the final (p-cyanophenoxy)methyl menadione derivative 2 with 21% produce. Beginning with the commercially obtainable difluorophenol, (difluoro phenoxy)methyl menadione derivative 3 was attained with a standard produce of 5% (Fig. 2, path A). The hydroquinone 3a was attained through Elbs oxidation [16] using a produce of 44%, and was put through selective methylation with dimethylsulfate under minor basic conditions to provide the 4-methoxy-3,5-difluorophenol 3b with 50% produce. The side string from the phenol 3b was elongated by response with ethylchloroacetate under simple conditions to cover the ester 3c with 71% produce. Saponification of 3c resulted in the carboxylic acidity 3d using a produce of 77%. The acidity 3d was released in the Kochi-Anderson radical decarboxylation to get the last difluorophenol methoxy ether derivative 3 with 41% produce. Then, to bring in more structural variety in the (substituted phenoxy)methyl menadione series, various other analogues had been synthesized, such as for example substances bearing different halogens. The addition of halogen escalates the lipophilicity from the substances, adjustments their redox potential worth, and boosts their metabolic balance in the web host. Commercially obtainable 2-(4-chlorophenoxy)acetic acidity and 2-(4-bromophenoxy)acetic acidity were permitted to respond with menadione in the Kochi-Anderson radical decarboxylation to cover the matching 3-phenoxymenadione derivatives, 4 and 5, with 35% and 24% produce, respectively. Open up in another home window Fig. 2 Synthesis of 3-phenoxymethylmenadione derivatives (Path A) and its own 2-difluoromethyl analogs (Path B). Finally, another group of substances was looked into by presenting fluorine on the methyl band of the menadione primary (Fig. 2, path B). Commercially obtainable 1,4-naphthoquinone was decreased using SnCl2/HCl as well as the ensuing dihydronaphthoquinone was methylated by dimethylsulfate under minor basic circumstances. The dimethoxynaphthalene intermediate was after that successively formylated (98% produce) and treated with 2.0 equiv. of diethylaminosulfur trifluoride (DAST) to get the 2-(difluoromethyl)-1,4-dimethoxynaphthalene using a produce.