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We herein report a protocol for the asymmetric aldol-initiated cascade addition of isoxazolidin-5-ones to ortho-cyanobenzaldehydes by using Takemoto’s bifunctional organocatalyst. This approach allows for the synthesis of various novel β2,2-amino acid-phthalide conjugates with good enantio- and diastereoselectivities in reasonable yields and the further ring-opening of these compounds to acyclic carboxylic acid derivatives was demonstrated too. Fonds zur Förderung der Wissenschaftlichen Forschung P31784 Version of record

We herein report the ammonium saltcatalyzed synthesis of chiral 3,3disubstituted isoindolinones bearing a heteroatom functionality in the 3position. A broad variety of differently substituted CF3S and RSderivatives were obtained with often high enantioselectivities when using Maruoka's bifunctional chiral ammonium salt catalyst. In addition, a first proofofconcept for the racemic synthesis of the analogous Fcontaining products was obtained as well, giving access to one of the rare examples of a fairly stable Famino acid derivative. Version of record

Texto fechado en Madrid, 1860

The research work evaluates the mechanical and thermal performance of a cementitious composite for the preparation of wrapping panels, applied to the architectural design of a prefabricated housing for tropical climate, aiming at the improvement of the thermal and energetic efficiency in the internal environments as an option to the ceramic building blocks. It studies the constructive viability and sustainability of the composite, which uses materials with known thermoisolating properties (vermiculite, expanded clay and metaculin) allied to the projective strategies of the Bioclimatic Architecture, in order to minimize the absorption and transfer of heat incident on the roofs and walls to the internal environments, seeking contributions for studies of these factors in the prefabricated construction process committed to the reduction of material waste. The research methodology is based on the ABNT bibliography and standards conducted the comparative tests for the characterization of composite materials, following a sequence of mix tests where a three-point scale was selected for weighing, axial compression and density tests , with comparative results of 59% lighter weight and 50% resistance of the parameters set for a traditional concrete Pilot trait, surpassing the results of these indicators for masonry of ceramic blocks. The thermal efficiency tests of the composite were initially performed on three series of test specimens submitted to the tests of the Hot Wire and the K 30 Conductivity Meter with coherent comparative results of resistance and thermal conductivity, followed by the molding of three wall prototypes with the respective traces for tests in a thermal chamber simulating and simultaneously recording the daytime and nighttime thermal variation on the two faces of the wall tested, with thermal efficiency results compatible with those of a ceramic block wall. Compounding the final results of weight, strength and thermal performance of the prototype walls compared to a traditional wall of ceramic blocks, the compatibility of the composite for the design of the prefabricated house was evident. Nenhuma O trabalho de pesquisa avalia o desempenho mecânico e térmico de um compósito cimentício para a confecção de painéis envoltórios, aplicados ao projeto arquitetônico de uma habitação popular pré-fabricada para clima tropical, objetivando o melhoramento da eficiência térmica e energética nos ambientes internos como opção ao sistema construtivo tradicional de blocos cerâmicos. Estuda a viabilidade construtiva e a sustentabilidade do compósito, que utiliza materiais com reconhecidas propriedades termoisolantes (vermiculita, argila expandida e metaculim) aliadas às estratégias projetivas da Arquitetura Bioclimática, com o objetivo de minimizar a absorção e transferência de calor incidente nas cobertas e vedações para os ambientes internos, buscando contribuições para estudo desses fatores no processo construtivo pré-fabricado comprometido com a redução dos desperdícios de materiais. A metodologia investigativa fundamentada na bibliografia e nas normas da ABNT conduziu os ensaios comparativos para a caracterização dos materiais integrantes do compósito, seguindo uma sequência de testes de misturas onde foi selecionada uma escala de três traços para ensaios de pesagem, resistência à compressão axial e densidade, com resultados comparativos de peso 59% mais leve e resistência de 50% dos parâmetros fixados para um traço piloto de concreto tradicional, superando os resultados desses indicadores para a alvenaria de blocos cerâmicos. Os testes de eficiência térmica do compósito foram realizados inicialmente em três séries de corpos de prova submetidos aos ensaios do Fio Quente e do Condutivímetro K 30 com resultados comparativos de resistência e condutividade térmica coerentes, seguiu-se a moldagem de três protótipos de paredes com os respectivos traços para ensaios em uma câmara térmica, que simula e registra simultaneamente a variação térmica diurna e noturna nas duas faces da parede testada, com resultados de eficiência térmica compatíveis aos de uma parede de blocos cerâmicos. Compilados os resultados finais de peso, resistência e desempenho térmico das paredes protótipos comparados aos de uma parede tradicional de blocos cerâmicos ficou evidente a compatibilidade do compósito para a estruturação do projeto da casa pré-fabricada.

A novel high yielding, enantio- and diastereoselective protocol for the synthesis of α-allylated highly functionalised β-amino acid derivatives by adding isoxazolidin-5-ones to MBH carbonates under asymmetric phase-transfer catalysis has been developed.

With the aim of identifying novel lead compounds active against emergent human infectious diseases, a series of 2,3-dihydro-4H-pyridinone derivatives has been prepared and evaluated for antiviral activity. Compounds were evaluated in vitro in cell-based assays for cytotoxicity and against a wide spectrum of viruses. In the antiviral screening, several compounds showed to be fairly active against viruses belonging to the Flaviviridae family. The Pestiviruses (bovine viral diarrhoea virus) were inhibited by 4a cis (CC(50)100 μm; EC(50) = 14 μm), compounds 4c cis and 6a showed a significant activity against Flaviviruses (Yellow Fever Virus) (CC(50)100 μm; EC(50) = 18μm, CC(50)100 μm; EC(50) = 10 μm). Among these, compound 6a displayed great inhibitory activity against Hepaciviruses (hepatitis C virus) in replicon assay [CC(50)100 μm; EC(50) (1b) = 4 μm]. In vitro inhibitory activity against the HCV RNA-dependent RNA polymerase (NS5B) of title compounds is discussed. The antiviral screening of viral strains indicated that compound 6a can be selected as promising tool in novel anti-flaviviruses development.

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Stilbenes with well-known antioxidant and antiradical properties are beneficial in different pathologies including cardiovascular diseases. The present research was performed to investigate the potential protective effect of resveratrol (1) and piceatannol (2), against hypoxia-induced oxidative stress in the H9c2 cardiomyoblast cell line, and the underlying mechanisms. Compounds 1 and 2 significantly inhibited the release of peroxynitrite and thiobarbituric acid levels at na no- or submicromolar concentrations, and this effect was more evident in piceatannol-treated cells, that significantly increased MnSOD protein level in a concentration dependent manner. Furthermore, since piceatannol, which is far less abundant in natural sources, displayed a higher bioactivity than the parent compound, we hereby report on a very fast synthesis and detailed structure-based design of a focused stilbene library. Finally, taking into account that hypoxia-induced ROS accumulation also increases expression and activity of 5-lipoxygenase (5-LOX) with production of leukotrienes, we have disclosed structural key factors crucial for 5-LOX activity. Among the synthesized analogues ( 3-7), compound 7 was the most effective in improving cardiomyocytes viability and in 5-LOX inhibition. In conclusion, modeling and experimental studies provided the basis for further optimization of stilbene analogues as multi-target inhibitors of the inflammatory and oxidative pathway. (C) 2019 Elsevier Masson SAS. All rights reserved.

Activated 3-substituted isoindolinones have been investigated as nucleophiles in the organocatalytic asymmetric cross-aldol reaction with formaldehyde for the synthesis of derivatives with tetrasubstituted stereocenters. Among the tested catalysts, bifunctional chiral tertiary amines led to the target products in high yields and moderate enantioselectivity, while chiral ammonium salts, tested under phase-transfer conditions, were less effective. Graphical abstract: [Figure not available: see fulltext.]

The cell membrane is a heterogeneous system constituted mainly by lipids and proteins in which the physical state is finely regulated to guarantee the regular functions. Among the numerous analytical techniques employed in membrane investigation, a special role is the one of fluorescence microscopy. Fluorescence microscopy allows a fast and non-disruptive investigation of model membranes as well as living samples. Numerous fluorescent probes are known, but most of them are unsuitable for membrane studies, since they either alter the membrane structure or they are internalized in the cell. In this work, we report the rational design and the synthesis of a new fluorescent membrane probe and its characterization in model membranes. The probe consists of a fluorescent aromatic nucleus of 7-nitrobenz-2-oxa-1,3-diazole (NBD) that emits in the visible region of the spectrum. The fluorophore has been linked to a zwitterionic structure and a saturated chain of 18 carbon atoms, to prevent the internalization in the cell and to selectively anchor it to the outer membrane layer. It is worth to notice that the probe shows a certain degree of solvatochromism, a feature that can be exploited to evaluate the liquid-ordered and liquid-disordered composition of biological membranes.

In this article we describe a series of new asymmetric Michael reactions of carboxylate-3-substituted isoindolinones used as nucleophiles in the synthesis of valuable chiral tetrasubstituted derivatives. It has been shown that the reactivity and enantioselectivity strongly depend on the substitution pattern of the isoindolinone, requiring either cinchona-alkaloid based phase transfer catalysts or bifunctional tertiary amines organocatalysts. Moreover, prolinol-TMS ether-based secondary amine catalysts permitted the development of Michael/cyclization tandem reaction with cynnamaldehyde for the synthesis of aza-polycyclic derivatives.

We recently identified indole derivatives (IIIe and IIIf) with anti-chikungunya virus (CHIKV) activities at lower micro molar concentrations and a selective index of inhibition higher than the lead compound Arbidol. Here we highlight new structural information for the optimization of the previously identified lead compounds that contain the indole chemical core. Based on the structural data, a series of indole derivatives was synthesized and tested for their antiviral activity against chikungunya virus in Vero cell culture by a CPE reduction assay. Systematic optimization of the lead compounds resulted in tert-butyl-5-hydroxy-1-methyl-2-(2-trifluoromethysulfynyl)methyl)-indole-3-carboxylate derivative IIc with a 10-fold improved anti-CHIKV inhibitory activity (EC50=6.5±1μM) as compared to Arbidol demonstrating a potent, selective and specific inhibition of CHIKV replication with only a moderate cell protective effect against other related alphaviruses. The reported computational insights, together with the accessible synthetic procedure, pave the road towards the design of novel synthetic derivatives with enhanced anti-viral activities. publisher: Elsevier articletitle: Discovery of novel multi-target indole-based derivatives as potent and selective inhibitors of chikungunya virus replication journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2016.10.037 content_type: article copyright: © 2016 Elsevier Ltd. All rights reserved. ispartof: Bioorganic & Medicinal Chemistry vol:25 issue:1 pages:327-337 ispartof: location:England status: published

Following the results we previously reported on a series of ethyl 2-phenylthiomethyl 5-hydroxyindole-3- carboxylate derivatives as 5-lipoxygenase (5-LOX) inhibitors, in order to obtain a more selective compound with respect to the previous generation of derivatives, we decided to modify the structure of the core ligand. The first level of structural modification involved the annelation of benzene to the indole, yielding corresponding benzo[g]indole derivatives, systematic optimization of methyl or chlorine groups in meta- , ortho- and ortho/para-position of 2-phenylthiomethyl moiety were applied. The reported results show that extension of the aromatic core led to a great enhancement of activity, especially in cell-free assay, and the accurate structure-based design provided compounds 6f, 6g and 6l that block 5-LOX activity in cell-free assays with IC50 ranging from 0.17 to 0.22 mM, and suppress 5-LOX product synthesis in polymorphonuclear leukocytes with IC50 ranging from 0.19 to 0.37 mM. Moreover we have identified 6f and 6l as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors and compound 6l significantly reduces inflammatory reactions in the carrageenan-induced mouse paw oedema. The reported in vivo analysis, together with the accessible synthetic procedure, stimulate for the generation of further potent antinflammatory benzoindoles-based agents.

A focused N -substituted 3-(2-piperazin-1-yl-2-oxoethyl)-2-(pyridin-2-yl)iso-indolin-1-ones small library was synthesized for modulation of GABA-A receptor function and compared to Zopiclone for the ability to increase GABA-activated chloride currents. All compounds were tested for their effects on GABA-activated chloride currents in rat cerebellar granule cells by use of the whole-cell patch clamp technique. Electrophysiological studies on cultured cerebellar granule cells revealed 3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-(5-nitropyridin-2-yl)iso-indolin-1-one ( Id ) as a partial agonist displaying 34% increase of the 10 μM GABA evoked peak chloride currents, antagonized by flumazenil. Moreover, a second group of compounds, with bulky functional groups at N-4 position of piperazine, have shown inverse agonist effects. The simple synthetic procedure and the possibility of modulating the efficacy of this class of ligands through additional structural modifications pave the way for further development of new molecules as a novel class of compounds able to interfere with benzodiazepine receptors.

In this article we describe a new accessible methodology for the synthesis of isobenzofuran-1(3H)-ones. In this process we exploited an effective, economic, useful and environmentally benign K2CO3 catalyzed, solvent-free one-pot tandem aldol-lactonization reaction between active methylene compounds and methyl 2-carboxy benzaldehyde. A particularly simple work-up and purification procedure are additional advantages addressed to a general green chemistry approach to this important class of heterocyclic compounds.

The aldol addition of readily enolizable 1,3-dicarbonyl compounds to 2-cyanobenzaldehyde in the presence of a tertiary amine led to a series of new 3-substituted isoindolinones. Despite the instability of the related aldols, this synthesis was possible because of the intramolecular trapping of the adducts with the cyano group due to a tandem process of cyclization and rearrangement. Simple decarboxylation of some derivatives gave access to very useful compounds.

A series of trisubstituted naphthalimides have been synthesized and evaluated as telomeric G-quadruplex ligands by biophysical methods. Affinity for telomeric G-quadruplex AGGG(TTAGGG)(3) binding was first screened by fluorescence titrations. Subsequently, the interaction of the telomeric G-quadruplex with compounds showing the best affinity has been studied by isothermal titration calorimetry and UV-melting experiments. The two best compounds of the series tightly bind the telomeric quadruplex with a 2:1 drug/DNA stoichiometry. These derivatives have been further evaluated for their ability to inhibit telomerase by a TRAP assay and their pharmacological properties by treating melanoma (M14) and human lung cancer (A549) cell lines with increasing drug concentrations. A dose-dependent inhibition of cell proliferation was observed for all cellular lines during short-term treatment.

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