Benzofuran-2-carboxylic acid

Palladium-Catalyzed Decarboxylative ortho-Amidation of Indole-3-carboxylic Acids with Isothiocyanates Using Carboxyl as a Deciduous Directing Group.[Pubmed:29554415]

J Org Chem. 2018 Apr 20;83(8):4375-4383.

Palladium-catalyzed ortho-amidation of indole-3-carboxylic acids with isothiocyanates by using the deciduous directing group nature of carboxyl functionality to afford indole-2-amides is demonstrated. Both C-H functionalization and decarboxylation took place in one pot, and hence, this carboxyl group served as a unique, deciduous (or traceless) directing group. This reaction offers a broad substrate scope as demonstrated for several other heterocyclic carboxylic acids like chromene-3-carboxylic acid, imidazo[1,2- a]pyridine-2-carboxylic acid, Benzofuran-2-carboxylic acid, pyrrole-2-carboxylic acid, and thiophene-2-carboxylic acid. In the reaction using 2-naphthoic acid, of the two possible isomers, only one isomer of the amide was exclusively formed. The indole-2-amide product underwent palladium-catalyzed C-H functionalization to afford the diindole-fused 2-pyridones by combining two molecules of the indole moiety, with the elimination of an amide group from one of them, attached at the C3-position for the C-C/C-N bond formation. The structures of key products are confirmed by X-ray crystallography.

Determination of patulin in apple juice using magnetic solid-phase extraction coupled with high-performance liquid chromatography.[Pubmed:27899060]

Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017 Feb;34(2):273-281.

An efficient magnetic sorbent consisting of Benzofuran-2-carboxylic acid-loaded magnetic nanocomposite was successfully synthesised for pre-concentration of patulin from apple juice. The prepared magnetic nanocomposite was characterised by scanning electron microscopy, transmission electron microscopy and Fourier-transform infrared spectroscopy. Determination of enriched patulin was performed by high-performance liquid chromatography. The best adsorption conditions were 40 mg of sorbent, 50 ml of apple juice sample, pH 5, ambient temperature and 25 min; the elution conditions were 500 mul methanol, pH 5, ambient temperature, and 4 min. Under optimised conditions, pre-concentration factor was 100, linearity range was 1-400 mug l(-1) of patulin, limit of detection was 0.15 mug l(-1) and limit of quantification was 0.5 mug l(-1). When samples were determined 20 times, the recovery was 93.9-102.6% and the relative standard deviation was below 5.3%. In terms of proposed procedure, the developed method was successfully applied for patulin detection in apple juice samples.

Design, synthesis, and biological evaluation of benzofuran- and 2,3-dihydrobenzofuran-2-carboxylic acid N-(substituted)phenylamide derivatives as anticancer agents and inhibitors of NF-kappaB.[Pubmed:25953156]

Bioorg Med Chem Lett. 2015 Jun 15;25(12):2545-9.

With the aim of developing novel scaffolds as anticancer agents and inhibitors of NF-kappaB activity, 60 novel benzofuran- and 2,3-dihydroBenzofuran-2-carboxylic acid N-(substituted)phenylamide derivatives (1a-s, 2a-k, 3a-s, and 4a-k) were designed and synthesized from the reference lead compound KL-1156, which is an inhibitor of NF-kappaB translocation to the nucleus in LPS-stimulated RAW 264.7 macrophage cells. The novel benzofuran- and 2,3-dihydrobenzofuran-2-carboxamide derivatives exhibited potent cytotoxic activities (measured by the sulforhodamine B assay) at low micromolar concentrations against six human cancer cell lines: ACHN (renal), HCT15 (colon), MM231 (breast), NUGC-3 (gastric), NCI-H23 (lung), and PC-3 (prostate). In addition, these compounds also inhibited LPS-induced NF-kappaB transcriptional activity. The +M effect and hydrophobic groups on the N-phenyl ring potentiated the anticancer activity and NF-kappaB inhibitory activity, respectively. However, according to the results of structure-activity relationship studies, only Benzofuran-2-carboxylic acid N-(4'-hydroxy)phenylamide (3m) was the lead scaffold with both an outstanding anticancer activity and NF-kappaB inhibitory activity. This novel lead scaffold may be helpful for investigation of new anticancer agents that act through inactivation of NF-kappaB.

Expedited Synthesis of Benzofuran-2-Carboxylic Acids via Microwave-Assisted Perkin Rearrangement Reaction.[Pubmed:22736873]

Tetrahedron Lett. 2012 Jun 27;53(26):3319-3321.

3-Halocoumarins are readily converted into Benzofuran-2-carboxylic acids via a Perkin (coumarin-benzofuran ring contraction) rearrangement reaction. This rearrangement entails initial base catalyzed ring fission. The resulting phenoxide anion then attacks a vinyl halide to produce the final benzofuran moiety. We explored this reaction under microwave reaction conditions and were able to significantly reduce reaction times as well as obtain very high yields of a series of Benzofuran-2-carboxylic acid derivatives.

The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors.[Pubmed:21507633]

Bioorg Med Chem Lett. 2011 May 15;21(10):3050-6.

Novel Benzofuran-2-carboxylic acids, exemplified by 29, 38 and 39, have been discovered as potent Pim-1 inhibitors using fragment based screening followed by X-ray structure guided medicinal chemistry optimization. The compounds demonstrate potent inhibition against Pim-1 and Pim-2 in enzyme assays. Compound 29 has been tested in the Ambit 442 kinase panel and demonstrates good selectivity for the Pim kinase family. X-ray structures of the inhibitor/Pim-1 binding complex reveal important salt-bridge and hydrogen bond interactions mediated by the compound's carboxylic acid and amino groups.

Synthesis of 3-aryl-2-arylamidobenzofurans based on the Curtius rearrangement.[Pubmed:21391629]

J Org Chem. 2011 Apr 15;76(8):2502-20.

The synthesis of novel 3-aryl-2-arylamidobenzofurans has been accomplished via a Curtius rearrangement strategy in four steps from Benzofuran-2-carboxylic acids. The requisite Suzuki-Miyaura cross-coupling, with benzyl 3-bromobenzofuran-2-ylcarbamate or 2-arylamido-3-bromobenzofurans, revealed an unusual reductive debromination process due to the presence of the free NH group. This dehalogenation can be suppressed by N-alkylation. DMAP is an efficient reagent for the one-pot conversion of benzyl benzofuran-2-ylcarbamates into the corresponding benzofuran-2-arylamides through aroylation, thus acting both as an acyl transfer reagent and a deprotecting agent of the Cbz group. A mechanism is postulated.

Synthesis and biological evaluation of 3-substituted-benzofuran-2-carboxylic esters as a novel class of ischemic cell death inhibitors.[Pubmed:20943387]

Bioorg Med Chem Lett. 2010 Nov 15;20(22):6362-5.

A series of 3-substituted-benzofuran-2-carboxylic esters was synthesized and evaluated for biological activity as ischemic cell death inhibitors in H9c2 cells and rat primary cardiac myocytes under conditions of oxygen and glucose deprivation. The introduction of a sulfur atom at the three-position substituent of the benzofuran ring markedly improved ischemic cell death inhibitory potency. In particular, 3-[2-(4-nitro-phenylsulfanyl)-acetylamino]-Benzofuran-2-carboxylic acid ester (10) (EC(50)=0.532 muM, cell death=6.18%) and 4-chloro-3-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzofuran-2-carboxylic ester (18) (EC(50)=0.557 muM, cell death=7.02%) were shown to be the most potent in this series of benzofuran analogs.

Hydrogen bonding and pi-pi interactions in 1-benzofuran-2,3-dicarboxylic acid and its 1:1 cocrystals with pyridine, phenazine and 1,4-phenylenediamine.[Pubmed:19966449]

Acta Crystallogr C. 2009 Dec;65(Pt 12):o639-44.

The structure of 1-benzofuran-2,3-dicarboxylic acid (BFDC), C(10)H(6)O(5), (I), exhibits an intramolecular hydrogen bond between one -COOH group and the other, while the second carboxyl function is involved in intermolecular hydrogen bonding to neighbouring species. The latter results in the formation of flat one-dimensional hydrogen-bonded chains in the crystal structure, which are pi-pi stacked along the normal to the plane of the molecular framework, forming a layered structure. 1:1 Cocrystallization of BFDC with pyridine, phenazine and 1,4-phenylenediamine is associated with H-atom transfer from BFDC to the base and charge-assisted hydrogen bonding between the BFDC(-) monoanion and the corresponding ammonium species, while preserving, in all cases, the intramolecular hydrogen bond between the carboxyl and carboxylate functions. The pyridinium 2-carboxylato-1-benzofuran-3-carboxylic acid, C(5)H(6)N(+).C(10)H(5)O(5)(-), (II), and phenazinium 3-carboxylato-1-Benzofuran-2-carboxylic acid, C(12)H(9)N(2)(+).C(10)H(5)O(5)(-), (III), adducts form discrete hydrogen-bonded ion-pair entities. In the corresponding crystal structures, the two components are arranged in either segregated or mixed pi-pi stacks, respectively. On the other hand, the structure of 4-aminoanilinium 2-carboxylato-1-benzofuran-3-carboxylic acid, C(6)H(9)N(2)(+).C(10)H(5)O(5)(-), (IV), exhibits an intermolecular hydrogen-bonding network with three-dimensional connectivity. Moreover, this fourth structure exhibits induction of supramolecular chirality by the extended hydrogen bonding, leading to a helical arrangement of the interacting moieties around 2(1) screw axes. The significance of this study is that it presents the first crystallographic characterization of pure BFDC, and manifestation of its cocrystallization with a variety of weakly basic amine molecules. It confirms the tendency of BFDC to preserve its intramolecular hydrogen bond and to prefer a monoanionic form in supramolecular association with other components. The aromaticity of the flat benzofuran residue plays an important role in directing either homo- or heteromolecular pi-pi stacking in the first three structures, while the occurrence of a chiral architecture directed by multiple hydrogen bonding is the dominant feature in the fourth.

A potent small molecule, nonpeptide inhibitor of cathepsin K (SB 331750) prevents bone matrix resorption in the ovariectomized rat.[Pubmed:11996914]

Bone. 2002 May;30(5):746-53.

Inhibition of the cyteine proteinase, cathepsin K (E.C. 3.4.22.38) has been postulated as a means to control osteoclast-mediated bone resorption. The preferred animal models for evaluation of antiresorptive activity are in the rat. However, the development of compounds that inhibit rat cathepsin K has proven difficult because the human and rat enzymes differ in key residues in the active site. In this study, a potent, nonpeptide inhibitor of rat cathepsin K (K(i) = 4.7 nmol/L), 5-(2-morpholin-4-yl-ethoxy)-Benzofuran-2-carboxylic acid ((S)-3-methyl-1-(3-oxo-1-[2-(3-pyridin-2-yl-phenyl)-ethenoyl]-azepan-4-ylcarbanoy l)-butyl)-amide (SB 331750), is described, which is efficacious in rat models of bone resorption. SB 331750 potently inhibited human cathepsin K activity in vitro (K(i) = 0.0048 nmol/L) and was selective for human cathepsin K vs. cathepsins B (K(i) = 100 nmol/L), L (0.48 nmol/L), or S (K(i) = 14.3 nmol/L). In an in situ enzyme assay, SB 331750 inhibited osteoclast-associated cathepsin activity in tissue sections containing human osteoclasts (IC(50) approximately 60 nmol/L) and this translated into potent inhibition of human osteoclast-mediated bone resorption in vitro (IC(50) approximately 30 nmol/L). In vitro, SB 331750 partially, but dose-dependently, prevented the parathyroid hormone-induced hypercalcemia in an acute rat model of bone resorption. To evaluate the ability of SB 331750 to inhibit bone matrix degradation in vivo, it was administered for 4 weeks at 3, 10, or 30 mg/kg, intraperitoneally (i.p.), u.i.d. in the ovariectomized (ovx) rat. Both 10 and 30 mg/kg doses of compound prevented the ovx-induced elevation in urinary deoxypyridinoline and prevented the ovx-induced increase in percent eroded perimeter. Histological evaluation of the bones from compound-treated animals indicated that SB 331750 retarded bone matrix degradation in vivo at all three doses. The inhibition of bone resorption at the 10 and 30 mg/kg doses resulted in prevention of the ovx-induced reduction in percent trabecular area, trabecular number, and increase in trabecular spacing. These effects on bone resorption were also reflected in inhibition of the ovx-induced loss in trabecular bone volume as assessed using microcomputerized tomography (microCT; approximately 60% at 30 mg/kg). Together, these data indicate that the cathepsin K inhibitor, SB 331750, prevented bone resorption in vivo and this inhibition resulted in prevention of ovariectomy-induced loss in trabecular structure.

Synthesis and conformational analysis of a coumarinic acid-based cyclic prodrug of an opioid peptide with modified sensitivity to esterase-catalyzed bioconversion.[Pubmed:11972752]

J Pept Res. 2002 Apr;59(4):183-95.

The coumarinic acid-based cyclic DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH) prodrug 1a exhibited more favorable physicochemical properties than did DADLE for permeation across the intestinal mucosa. However, prodrug 1a, whose bioconversion to DADLE was slow, was subject to extensive biliary clearance when administered to rats in vivo. To increase the rate of esterase-catalyzed bioconversion of prodrug 1a, thus decreasing its biliary clearance, the oxymethyl-modified prodrug 1, in which an aldehyde equivalent is inserted between the phenolic group of the promoiety and the carboxylic acid group of the peptide, was synthesized from Benzofuran-2-carboxylic acid 16 via a nine-step procedure. Briefly, phenacyl-protected 3-(2-hydroxyphenyl)-propynoic acid 17 was coupled with Boc-d-Leu-OCH(2)I 5 to give the intermediate 18, which was further elaborated and conjugated with tetrapeptide 4 to give linear precursor 2. Precursor 2 was then deprotected and cyclized to obtain compound 1 using a high dilution technique. In an attempt to investigate the effect of the physicochemical properties and the conformation of prodrug 1 on its permeation characteristics, we calculated its physicochemical parameters and determined its solution conformation using spectroscopic techniques (CD and NMR) and molecular dynamics simulations. Prodrug 1 showed a cLogP value and a molecular size similar to that of prodrug 1a. The deconvoluted CD spectra indicated that prodrug 1 has more random component (71%) than prodrug 1a (42%). 2D-NMR studies of prodrug 1 showed no signals for amide-amide hydrogen interactions and few ROE cross-peaks in ROESY spectra. Using distance restraints constructed from ROESY spectra, molecular dynamics simulations of prodrug 1 generated five conformation families. One family satisfied most of the distance restraints and all of the dihedral angles measured by NMR coupling constants. In summary, prodrug 1 showed favorable physicochemical properties for permeation of the intestinal mucosa. Prodrug 1 adopted a more random conformation in solution than prodrug 1a. These differences in solution conformation could affect the permeation of the prodrugs across the intestinal mucosa by passive diffusion and/or their ability to interact with efflux transporter(s) that would limit their transcellular permeation.

Thromboxane A2 synthase inhibitors. 5-(3-Pyridylmethyl)benzofuran-2-carboxylic acids.[Pubmed:3735314]

J Med Chem. 1986 Aug;29(8):1461-8.

The synthesis and screening of a series of 5-(3-pyridylmethyl)Benzofuran-2-carboxylic acids as selective thromboxane A2 (TxA2) synthase inhibitors is outlined. The ability of these compounds to inhibit TxA2 biosynthesis was assayed using microsomal enzyme from human platelets. Substitution of the benzofuran ring caused small changes in potency; modification of the carboxylic acid group caused modest reductions in potency, and substitution of the pyridine ring resulted in large reductions of potency. 5-(3-Pyridylmethyl)Benzofuran-2-carboxylic acid sodium salt (9b, sodium furegrelate) was chosen for further evaluation as a TxA2 synthase inhibitor.

Diuretic and uricosuric activity of 6,7-dichloro-2,3-dihydro-5-(2-thienylcarbonyl)benzofuran-2-carboxylic acid and stereoisomers in chimpanzee, dog and rat.[Pubmed:7351631]

J Pharmacol Exp Ther. 1980 Feb;212(2):190-7.

The racemate and the d-isomer of 6,7-dichloro-2,3-dihydro-5-(2-thienylcarbonyl)Benzofuran-2-carboxylic acid exhibited diuretic activity in the chimpanzee, dog and rat. In the chimpanzee, the diuresis and natriuresis presumably resulted from a site of action in the thick ascending limb of Henle's loop. The l-isomer was uricosuric but devoid of any diuretic action in the chimpanzee and similarly was not diuretic in the dog and rat. Various proportions of the two isomers were tested in the chimpanzee in an attempt to produce an optimal diuretic and uricosuric profile. It was concluded that the racemic mixture, under these experimental conditions, was responsible for the most effective overall response. This is apparently the first time in which there is a distinct separation of diuretic and uricosuric actions in the enantiomers of a racemic diuretic uricosuric agent.