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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.