RESUMEN

Bilastine (BIL) is a novel 2nd generation antihistamine medication is used to treat symptoms of chronic urticaria and allergic rhinitis. However, its poor solubility limits its therapeutic efficacy. In order to enhance the physicochemical characteristics of BIL, various molecular adducts of BIL (Salt, hydrate and co-crystal) were discovered in this study using two distinct salt-formers: Terephthalic acid (TA), 2,4-Dihydroxybenzoic acid (2,4-DHBA), and three nutraceuticals (Vanillic Acid (VA), Hydroquinone (HQN) and Hippuric acid (HA)). Various analytical methods were used to examine the synthesised adducts, including Powder X-Ray Diffraction (PXRD), Single Crystal X-ray Diffraction (SCXRD), and thermal analysis (Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC)). Single-crystal X-ray diffraction (SCXRD) studies avowed that the architectures of the molecular adducts are maintained in the solid state by an array of strong (N+H⋯O-, NH⋯O, OH⋯O) and weak (CH⋯O) hydrogen bonds. Additionally, a solubility test was performed to establish the in vitro release characteristics of newly synthesised BIL adducts and it observed that most of the molecular adducts exhibit higher rates of dissolution in comparison to pure BIL; in particular, BIL.TA.HYD showed the highest solubility and the fastest rate of dissolution. Moreover, experiments on flux permeability and diffusion demonstrated that the BIL.TA.HYD and BIL.VA salts had strong permeability and a high diffusion rate. In addition, the synthesized adduct's stability was assessed at 25 °C and 90 % ± 5 % relative humidity, and it was found that all the molecular salts were stable and did not undergo any phase changes or dissociation. The foregoing result leads us to believe that the newly synthesized molecular adducts' increased permeability and solubility will be advantageous for the creation of novel BIL formulations.

Asunto(s)

Antagonistas de los Receptores Histamínicos H1 , Cristalografía por Rayos X , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacología , Modelos Moleculares , Estructura Molecular , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacología , Ácidos Ftálicos/síntesis química , Piperidinas/química , Piperidinas/farmacología , Piperidinas/síntesis química , Solubilidad

RESUMEN

The removal of uremic toxins from patients with acute kidney injury is a key issue in improving the quality of life for people requiring peritoneal dialysis. The currently utilized method for the removal of uremic toxins from the human organism is hemodialysis, performed on semipermeable membranes where the uremic toxins, along with small molecules, are separated from proteins and blood cells. In this study, we describe a mixed-linker modulated synthesis of zirconium-based metal-organic frameworks for efficient removal of uremic toxins. We determined that the efficient adsorption of uremic toxins is achieved by optimizing the ratio between -amino functionalization of the UiO-66 structure with 75% of -NH2 groups within organic linker structure. The maximum adsorption of hippuric acid and 3-indoloacetic acid was achieved by UiO-66-NH2 (75%) and by UiO-66-NH2 (75%) 12.5% HCl prepared by modulated synthesis. Furthermore, UiO-66-NH2 (75%) almost completely adsorbs 3-indoloacetic acid bound to bovine serum albumin, which was used as a model protein to which uremic toxins bind in the human body. The high adsorption capacity was confirmed in recyclability test, which showed almost 80% removal of 3-indoloacetic acid after the third adsorption cycle. Furthermore, in vitro cytotoxicity tests as well as hemolytic activity assay have proven that the UiO-66-based materials can be considered as potentially safe for hemodialytic purposes in living organisms.

Asunto(s)

Hipuratos/aislamiento & purificación , Ácidos Indolacéticos/aislamiento & purificación , Riñones Artificiales , Estructuras Metalorgánicas/química , Ácidos Ftálicos/química , Tóxinas Urémicas/aislamiento & purificación , Adsorción , Animales , Chlorocebus aethiops , Eritrocitos/efectos de los fármacos , Células HEK293 , Hipuratos/química , Humanos , Ácidos Indolacéticos/química , Estructuras Metalorgánicas/síntesis química , Estructuras Metalorgánicas/toxicidad , Ácidos Ftálicos/síntesis química , Ácidos Ftálicos/toxicidad , Tóxinas Urémicas/química , Células Vero , Circonio/química

RESUMEN

The application of a coordination container in biomedicine is hindered by single binding domains and unsatisfactory biostability and biocompatibility. Herein, we designed a sulfonylcalix[4]arene-based decahexanuclear zinc(II) coordination container employing a flexible tetracarboxylate ligand as a linker and utilized it as a novel drug delivery system. The coordination container consisting of one endo and four exo cavities provides multiple binding domains for efficient encapsulation of drug molecules as clearly revealed by systematic host-guest studies using NMR techniques of 1H NMR titration experiments and 2D NOESY and diffusion-ordered NMR spectroscopy studies. Incorporation of a flexible p-phenylene-bis(methanamino) spacer into the container via the carboxylate linker allowed a stepwise drug loading process through sequential binding at endo and exo cavities, as well as enabling pH-responsive stepwise drug release. The drug-loaded coordination container not only exhibits excellent biostability and biocompatibility but also provides encouraging therapeutic efficiency toward inflammatory macrophages as revealed by in vitro studies. The novel strategy for engineering the endo cavity of a coordination container provides a new approach to achieving controlled drug delivery and opens up new opportunities for designing novel functional supramolecular materials.

Asunto(s)

Antiinflamatorios/farmacología , Calixarenos/química , Complejos de Coordinación/química , Portadores de Fármacos/química , Naproxeno/farmacología , Animales , Antiinflamatorios/química , Calixarenos/síntesis química , Complejos de Coordinación/síntesis química , Portadores de Fármacos/síntesis química , Liberación de Fármacos , Concentración de Iones de Hidrógeno , Ligandos , Ratones , Pruebas de Sensibilidad Microbiana , Naproxeno/química , Ácidos Ftálicos/síntesis química , Ácidos Ftálicos/química , Células RAW 264.7 , Zinc/química

RESUMEN

A series of metal-organic coordination complexes based on alkaline-earth metal centers [Mg(II), Ca(II), and Ba(II)] and the ligand 5-aminoisophthalate (aip2-) revealed notable structural diversity, both in the materials' dimensionality and in their hydrogen bonding networks: [Mg(H2O)6]∙[Mg2(Haip)(H2O)10]∙(Haip)∙3(aip)∙10(H2O) (1) and [Mg(aip)(phen)(H2O)2]∙(H2O) (2) were isolated as discrete complexes (0D); [Ca(aip)(H2O)2]∙(H2O) (3), [Ca(aip)(phen)(H2O)2]∙(phen)∙(H2O) (4), and [Ba2(aip)2(phen)2(H2O)7]∙2(phen)∙2(H2O) (5) revealed metal-organic chain (1D) structures, while the [Ba(aip)(H2O)] (6) showed a metal-organic layered (2D) arrangement. Furthermore, most of these metal-organic coordination materials revealed interesting thermal stability properties, being stable at temperatures up to 450 °C.

Asunto(s)

Metales/química , Compuestos Orgánicos/química , Enlace de Hidrógeno , Modelos Moleculares , Ácidos Ftálicos/síntesis química , Ácidos Ftálicos/química , Espectroscopía Infrarroja por Transformada de Fourier , Temperatura , Termogravimetría , Vibración

RESUMEN

Ryanodine receptors (RyRs) are calcium release channels located on endoplasmic reticulum (ER) membrane, which play important role in excitation-contraction coupling in muscular response. Flubendiamide represents a novel chemical family of green insecticides which selectively activate invertebrate RyR by interacting with the receptor distinct from the ryanodine binding site and has almost no effect on mammalian ryanodine receptors. Traditional methods to screen RyR modulators involve either radio-labeled RyR substrates or calcium signal-based indirect approaches. However, there is lack of RyR-directed non-isotope molecular tools for RyR agonists/antagonists screening and bioimaging. Here we developed a series of fluorescent probes based on the pharmacophore of flubendiamide with the aims to elucidate the mechanism of diamide insecticides and screen novel RyR-targeting insecticides. These probes revealed the specific RyR staining and in vivo RyR targeting properties in diamondback moth RyR transfected Sf9 cells (Sf9-RyR) and RyR enriched insect tissues. The designed fluorescent probes could induce an effective calcium release from ER membrane of Sf9-RyR cells and also showed competitive RyR binding effect with flubendiamide in cell-based fluorometric assay. Having the non-isotope RyR recognition probes will not only accelerate the screening process of new green agrochemicals but also enables deciphering molecular mechanisms of the high selectivity and the drug resistance associated with the diamides.

Asunto(s)

Amidas/metabolismo , Colorantes Fluorescentes/metabolismo , Ácidos Ftálicos/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Amidas/síntesis química , Animales , Benzamidas/química , Línea Celular , Colorantes Fluorescentes/síntesis química , Insecticidas/química , Ácidos Ftálicos/síntesis química , Spodoptera , Sulfonas/química

RESUMEN

Pseudomonas aeruginosa is a leading cause of hospital-acquired infections in the United States. PqsE, a thioesterase enzyme, is vital for virulence of P. aeruginosa, making PqsE an attractive target for inhibition. Neither the substrate nor the product of PqsE catalysis has been identified. A library of 550 million DNA-encoded drug-like small molecules was screened for those that bind to the purified PqsE protein. The structures of the bound molecules were identified by high throughput sequencing of the attached DNA barcodes. Putative PqsE binders with the strongest affinity features were examined for inhibition of PqsE thioesterase activity in vitro. The most potent inhibitors were resynthesized off DNA and examined for the ability to alter PqsE thermal melting and for PqsE thioesterase inhibition. Here, we report the synthesis, biological activity, mechanism of action, and early structure-activity relationships of a series of 2-(phenylcarbamoyl)benzoic acids that noncompetitively inhibit PqsE. A small set of analogs designed to probe initial structure-activity relationships showed increases in potency relative to the original hits, the best of which has an IC50 = 5 µM. Compound refinement is required to assess their in vivo activities as the current compounds do not accumulate in the P. aeruginosa cytosol. Our strategy validates DNA-encoded compound library screening as a rapid and effective method to identify catalytic inhibitors of the PqsE protein, and more generally, for discovering binders to bacterial proteins revealed by genetic screening to have crucial in vivo activities but whose biological functions have not been well-defined.

Asunto(s)

Proteínas Bacterianas/antagonistas & inhibidores , ADN/química , Inhibidores Enzimáticos/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Tioléster Hidrolasas/antagonistas & inhibidores , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ácidos Ftálicos/síntesis química , Ácidos Ftálicos/farmacología , Pseudomonas aeruginosa/enzimología , Bibliotecas de Moléculas Pequeñas/síntesis química , Relación Estructura-Actividad

RESUMEN

In this work, the chemical cross-linked interaction between chitosan polymeric chains and synthetic terephthaloyl diisothiocyanate as a cross-linker was accomplished in order to fabricate three dimensional cross-linked chitosan hydrogel. This cross-linked hydrogel with considerable characteristics including high stability and homogeneity in aqueous solution (water) and high porosity was applied as new substrate for generation of new magnetic terephthaloyl thiourea cross-linked chitosan nanocomposite. The features of this new magnetic nanocomposite were characterized by FT-IR, EDX, FE-SEM, TEM and VSM analysis. The Size distribution of nanoparticles according to the size histogram of FE-SEM images was estimated between 30 and 40 nm. The performance of designed magnetic nanocomposite was evaluated by magnetic fluid hyperthermia procedure. Under the alternating magnetic field (AMF), the specific absorption rate (66.92 w·g-1) was determined and as well, its saturation magnetization value was reported 78.43 emu·g-1.

Asunto(s)

Quitosano/química , Hidrogeles/química , Nanopartículas de Magnetita/química , Neoplasias/terapia , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Quitosano/síntesis química , Quitosano/farmacología , Humanos , Hidrogeles/síntesis química , Hidrogeles/farmacología , Hipertermia Inducida/métodos , Nanocompuestos/química , Ácidos Ftálicos/síntesis química , Ácidos Ftálicos/química , Espectroscopía Infrarroja por Transformada de Fourier , Tiourea/síntesis química , Tiourea/química

RESUMEN

Fatty acids of specific chain lengths have been shown to inhibit the growth of Mycobacterium tuberculosis. In the present study, specific synthetic aromatic derivatives of n-octyl esters were investigated for their property to inhibit the growth of M. tuberculosis H37Ra. Agar well diffusion assay indicated that the crude synthetic derivatives obtained by the esterification of phthalic acid (PA) and n-octanol exhibited antimycobacterial activity. Further, the activity was authenticated with the Miroplate Alamar Blue Assay (MABA). Subsequently, the active component was purified by bioactivity guided chromatographic fractionation. The structure of the synthetic derivative was deduced by UV-Vis, FT-IR, LC-MS, GC-mass spectrometry, and NMR spectroscopy. Molecular docking and molecular dynamic simulation (MDS) were performed with Autodock 4.0 and GROMACS 5.1.2 softwares, respectively. It was found that mono-n-octyl phthalate (MOP) exhibited antimycobacterial activity with a MIC of 20 µg/mL, and not by any other related compounds, including di-n-octyl phthalate, PA, phthalic anhydride, and n-octanol. Binding of MOP with protein kinase B can participate in the binding cavity region, which was previously reported. Subsequently, we authenticate the stability with MDS. This is first report on the inhibition of M. tuberculosis growth by MOP.

Asunto(s)

Antibacterianos/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Ácidos Ftálicos/farmacología , Proteínas Proto-Oncogénicas c-akt/química , Antibacterianos/síntesis química , Antibacterianos/química , Sitios de Unión/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/crecimiento & desarrollo , Ácidos Ftálicos/síntesis química , Ácidos Ftálicos/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Programas Informáticos

RESUMEN

The solubilization and efficient upgrading of high loadings of polyethylene terephthalate (PET) are important challenges, and most solvents for PET are highly toxic. Herein, a low-cost (ca. $1.2 kg-1 ) and biocompatible ionic liquid (IL), cholinium phosphate ([Ch]3 [PO4 ]), is demonstrated for the first time to play bifunctional roles in the solubilization and glycolytic degradation of PET. A high loading of PET (10 wt %) was readily dissolved in [Ch]3 [PO4 ] at relatively low temperatures (120 °C, 3 h) and under water-rich conditions. In-depth analysis of the solution revealed that high PET solubilization in [Ch]3 [PO4 ] could be ascribed to significant PET depolymerization. Acid precipitation yielded terephthalic acid as the dominant depolymerized monomer with a theoretical yield of approximately 95 %. Further exploration showed that in the presence of ethylene glycol (EG), the [Ch]3 [PO4 ]-catalyzed glycolysis of PET could efficiently occur with approximately 100 % conversion of PET and approximately 60.6 % yield of bis(2-hydroxyethyl)terephthalate under metal-free conditions. The IL could be reused at least three times without an apparent decrease in activity. NMR spectroscopy analysis revealed that strong hydrogen-bonding interactions between EG and the IL played an important role in the activation of EG and promotion of the glycolysis reaction. This study opens up avenues for exploring environmentally benign and efficient IL technology for solubilizing and recycling postconsumer polyester plastics.

Asunto(s)

Líquidos Iónicos , Ácidos Ftálicos/síntesis química , Tereftalatos Polietilenos/química , Glicol de Etileno/química , Glucólisis , Tecnología Química Verde/métodos , Líquidos Iónicos/economía , Poliésteres/química , Solubilidad , Solventes

RESUMEN

Polyethylene terephthalate that is 100 % bioderived is in high demand in the market guided by the ever-more exigent sustainability regulations with the challenge of producing renewable terephthalic acid remaining. Renewable terephthalic acid or its precursors can be obtained by Diels-Alder cycloaddition and further dehydrogenation of biomass-derived muconic acid. The cis,cis isomer of the dicarboxylic acid is typically synthesized by fermentation with genetically modified microorganisms, a process that requires complex separations to obtain a high yield of the pure product. Furthermore, the cis isomer has to be transformed into the trans,trans form and has to be esterified before it is suitable for terephthalate synthesis. To overcome these challenges, we investigated the synthesis of dialkyl muconates by cross-metathesis. The Ru-catalyzed cross-coupling of sorbates with acrylates, which can be bioderived, proceeded selectively to yield diester muconates in up to 41 % yield by using very low catalyst amounts (0.5-3.0 mol %) and no solvent. In the optimized procedure, the muconate precipitated as a solid and was easily recovered from the reaction medium. Analysis by GC-MS and NMR spectroscopy showed that this method delivered exclusively the trans,trans isomer of dimethyl muconate. The Diels-Alder reaction of dimethyl muconate with ethylene was studied in various solvents to obtain 1,4-bis(carbomethoxy)cyclohexene. The cycloaddition proceeded with very high conversions (77-100 %) and yields (70-98 %) in all of the solvents investigated, and methanol and tetrahydrofuran were the best choices. Next, the aromatization of 1,4-bis(carbomethoxy)cyclohexene to dimethyl terephthalate over a Pd/C catalyst resulted in up to 70 % yield in tetrahydrofuran under an air atmosphere. Owing to the high yield of the reaction of dimethyl muconate to 1,4-bis(carbomethoxy)cyclohexene, no separation step was needed before the aromatization. This is the first time that cross-metathesis is used to produce bioderived trans,trans-muconates as precursors to renewable terephthalates, important building blocks in the polymer industry.

Asunto(s)

Tecnología Química Verde , Ácidos Ftálicos/síntesis química , Polímeros/síntesis química , Ácido Sórbico/análogos & derivados , Biomasa , Catálisis , Industrias/métodos , Isomerismo , Polimerizacion , Ácido Sórbico/síntesis química , Ácido Sórbico/química

RESUMEN

Glutaredoxin (Grx1) is a ubiquitously expressed thiol-disulfide oxidoreductase that specifically catalyzes reduction of S-glutathionylated substrates. Grx1 is known to be a key regulator of pro-inflammatory signaling, and Grx1 silencing inhibits inflammation in inflammatory disease models. Therefore, we anticipate that inhibition of Grx1 could be an anti-inflammatory therapeutic strategy. We used a rapid screening approach to test 504 novel electrophilic compounds for inhibition of Grx1, which has a highly reactive active-site cysteine residue (pKa 3.5). From this chemical library a chloroacetamido compound, CWR-J02, was identified as a potential lead compound to be characterized. CWR-J02 inhibited isolated Grx1 with an IC50 value of 32 µM in the presence of 1 mM glutathione. Mass spectrometric analysis documented preferential adduction of CWR-J02 to the active site Cys-22 of Grx1, and molecular dynamics simulation identified a potential non-covalent binding site. Treatment of the BV2 microglial cell line with CWR-J02 led to inhibition of intracellular Grx1 activity with an IC50 value (37 µM). CWR-J02 treatment decreased lipopolysaccharide-induced inflammatory gene transcription in the microglial cells in a parallel concentration-dependent manner, documenting the anti-inflammatory potential of CWR-J02. Exploiting the alkyne moiety of CWR-J02, we used click chemistry to link biotin azide to CWR-J02-adducted proteins, isolating them with streptavidin beads. Tandem mass spectrometric analysis identified many CWR-J02-reactive proteins, including Grx1 and several mediators of inflammatory activation. Taken together, these data identify CWR-J02 as an intracellularly effective Grx1 inhibitor that may elicit its anti-inflammatory action in a synergistic manner by also disabling other pro-inflammatory mediators. The CWR-J02 molecule provides a starting point for developing more selective Grx1 inhibitors and anti-inflammatory agents for therapeutic development.

Asunto(s)

Acetanilidas/farmacología , Antiinflamatorios/farmacología , Glutarredoxinas/antagonistas & inhibidores , Microglía/efectos de los fármacos , Ácidos Ftálicos/farmacología , Acetanilidas/síntesis química , Secuencia de Aminoácidos , Animales , Antiinflamatorios/síntesis química , Sitios de Unión , Biotina/química , Línea Celular , Química Clic , Expresión Génica , Glutarredoxinas/química , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Ensayos Analíticos de Alto Rendimiento , Cinética , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Microglía/citología , Microglía/metabolismo , Simulación de Dinámica Molecular , Ácidos Ftálicos/síntesis química , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Estreptavidina/química , Termodinámica

RESUMEN

In this work we aimed to develop parasite-selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease-causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid-based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC50 : 8->51 µm), with 11 also having sub-micromolar in vitro activity against drug-sensitive (3D7) and multidrug-resistant (Dd2) asexual blood-stage P. falciparum parasites (IC50 ≈0.1-0.5 µm). A subset of compounds were examined for activity against early- and late-stage P. falciparum gametocytes and P. berghei exo-erythrocytic-stage parasites. While only moderate activity was observed against gametocytes (IC50 >2 µm), the most active compound (N1 -((3,5-dimethylbenzyl)oxy)-N4 -hydroxyterephthalamide, 1 f) showed sub-micromolar activity against P. berghei exo-erythrocytic stages (IC50 0.18 µm) and >270-fold better activity for exo-erythrocytic forms than for HepG2 cells. This, together with asexual-stage in vitro potency (IC50 ≈0.1 µm) and selectivity of this compound versus human cells (SI>450), suggests that 1 f may be a valuable starting point for the development of novel antimalarial drug leads with low host cell toxicity and multi-stage anti-plasmodial activity.

Asunto(s)

Antimaláricos/síntesis química , Antimaláricos/farmacología , Diseño de Fármacos , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacología , Plasmodium falciparum/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células HEK293 , Células Hep G2 , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Concentración 50 Inhibidora , Estadios del Ciclo de Vida/efectos de los fármacos , Ácidos Ftálicos/síntesis química , Relación Estructura-Actividad

RESUMEN

Schistosoma mansoni histone deacetylase 8 (SmHDAC8) has been recently identified as a new potential target for the treatment of schistosomiasis. A series of newly designed and synthesized alkoxyamide-based and hydrazide-based HDAC inhibitors were tested for inhibitory activity against SmHDAC8 and human HDACs 1, 6, and 8. The front runner compounds showed submicromolar activity against SmHDAC8 and modest preference for SmHDAC8 over its human orthologue hHDAC8. Docking studies provided insights into the putative binding mode in SmHDAC8 and allowed rationalization of the observed selectivity profile.

Asunto(s)

Inhibidores de Histona Desacetilasas/farmacología , Ácidos Ftálicos/farmacología , Proteínas Represoras/antagonistas & inhibidores , Esquistosomicidas/farmacología , Animales , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas , Humanos , Simulación del Acoplamiento Molecular , Ácidos Ftálicos/síntesis química , Ácidos Ftálicos/química , Schistosoma mansoni/enzimología , Esquistosomicidas/síntesis química , Esquistosomicidas/química , Especificidad de la Especie

RESUMEN

We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6-substituted 2-oxopiperazines as novel P1' and P2' ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (Ki=2nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated. Inhibitor 6j with an oxazolidinone derivative showed a BACE1 inhibitory activity of 23nM and cellular EC50 of 80nM.

Asunto(s)

Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácidos Ftálicos/química , Piperazinas/química , Ácidos Ftálicos/síntesis química , Piperazinas/síntesis química , Relación Estructura-Actividad

RESUMEN

We have identified potent isophthalic acid derivatives armed with imidazol and indolyl groups as potent ß-secretase inhibitors. The most effective analogs demonstrated low nano-molar potency for the BACE1 (ß-secretase cleaving enzyme) as measured by FRET (Fluorescence Resonance Energy Transfer) and cell-based (ELISA) assays. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on previously reported hydroxyethylene transition state inhibitor derived from isophthalic acid I. In the FRET assay, the most potent compound, 10a, displayed an IC50 value for BACE1 of 75 nM, and exhibited cellular activity with an EC50 value of 0.81 µM. On the other hand, compound 11b was found to be the most potent compound in the cell-based assay with an EC50 value of 0.29 µM.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacología , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/química , Ácido Aspártico Endopeptidasas/metabolismo , Línea Celular , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Simulación del Acoplamiento Molecular , Ácidos Ftálicos/síntesis química , Relación Estructura-Actividad

RESUMEN

The synthesis of terephthalic acid from biomass remains an unsolved challenge. In this study, we conducted the selective oxidation of p-cymene (synthesized from biodegradable terpenes, limonene, or eucalyptol) into terephthalic acid over a Mn-Fe mixed-oxide heterogeneous catalyst. The impact of various process parameters (oxidant, temperature, reaction time, catalyst amount, oxygen pressure) on the selectivity to terephthalic acid was evaluated, and some mechanistic aspects were elucidated. An unprecedented synthesis of biobased terephthalic acid (51 % yield) in the presence of O2 is reported.

Asunto(s)

Biomasa , Monoterpenos/química , Oxígeno/química , Ácidos Ftálicos/síntesis química , Catálisis , Cimenos , Oxidación-Reducción , Temperatura

RESUMEN

A new synthetic pathway for the production of p-toluic acid has been developed starting from reagents derived from renewable resources. A Diels-Alder reaction between sorbic and acrylic acids is followed by a combined dehydrogenation/ decarboxylation process, providing p-toluic acid in high yields. This route permits to use milder conditions compared to other Diels-Alder approaches reported in the literature, and therefore can contribute to a more sustainable terephthalic acid production.

Asunto(s)

Benzoatos/síntesis química , Ácidos Ftálicos/síntesis química , Acrilatos/química , Descarboxilación , Hidrógeno/química , Ácido Sórbico/química

RESUMEN

Two dimeric steroidal terephthalates derived from epimeric 4,5-seco-cholest-3-yn-5-ols were prepared starting from cholesterol in a five-step synthetic sequence. X-ray crystallography shows that the obtained compounds display novel supramolecular networks in the solid state in which the facial hydrophobicity of the steroidal skeletons plays an important role. Unambiguous NMR characterization of the obtained dimers is also provided.

Asunto(s)

Colesterol/química , Dimerización , Ácidos Ftálicos/química , Ácidos Ftálicos/síntesis química , Técnicas de Química Sintética , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Estereoisomerismo

RESUMEN

Following the success of the siderophore-inspired 1,2-hydroxypyridonate (HOPO) and 2-hydroxisophthalamide (IAM) chromophores in Eu(III) and Tb(III) luminescence, we designed three new ligands bearing both chromophores. Syntheses of the octadentate ligands 3,4,3-LI-IAM-1,2-HOPO and 3,4,3-LI-1,2-HOPO-IAM, where the chromophores are attached to different positions in the (LI=linear) spermine backbone, are reported in addition to a tetradentate ligand based on 1,5-diaminopentane. The Gd(III) complexes were prepared and revealed localized triplet states typical for the IAM and HOPO chromophores. Photophysical characterization of the Eu(III) and Tb(III) complexes revealed that the chromophores need to reside at a primary amine of the spermine backbone to be efficient in lanthanide excitation. These systems help us to understand the antenna effect in siderophore inspired chromophores and could be potential targets for sensing and biological imaging applications.

Asunto(s)

Amidas/química , Complejos de Coordinación/química , Europio/química , Ácidos Ftálicos/química , Piridonas/química , Terbio/química , Amidas/síntesis química , Materiales Biomiméticos , Técnicas Biosensibles , Complejos de Coordinación/síntesis química , Diaminas/química , Gadolinio/química , Ligandos , Imagen Molecular , Ácidos Ftálicos/síntesis química , Piridonas/síntesis química , Sideróforos/química , Espermina/química , Termodinámica

RESUMEN

In our search for new compounds among the structural analogues of the Picotamide acting on antiplatelet aggregation activities, a new series 2 of 4-ethoxyisophthal-amides were synthesized and their in vitro anti-platelet aggregation activities were evaluated by Born's test in comparison with their structural analogues of the series 1 of 4-methoxyisophthal-amides. The results revealed, among the series 2, six compounds 200, 2a, 2k, 2n, 2q and 2r displayed good antiplatelet aggregation activities in vitro induced by 5.0 mM ADP with IC50 values ranging over 0.35 µM - 0.77 µM. And of which, compound 2a exhibited the highest in vitro activity superior than two control drugs Picotamide and Aspirin. From a structure-affnity-'Relationship (SAR) pointed of some insight in the view of the role played by 4-ethoxy derivatives.

Asunto(s)

Ácidos Ftálicos/síntesis química , Ácidos Ftálicos/farmacología , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Aspirina/farmacología , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ácidos Ftálicos/química , Inhibidores de Agregación Plaquetaria/química , Relación Estructura-Actividad Cuantitativa , Relación Estructura-Actividad