Antonia Di Mola

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

Summary New bifunctional chiral ammonium salts were investigated in an asymmetric cascade synthesis of a key building block for a variety of biologically relevant isoindolinones. With this chiral compound in hand, the development of further transformations allowed for the synthesis of diverse derivatives of high pharmaceutical value, such as the Belliotti (S)-PD172938 and arylated analogues with hypnotic sedative activity, obtained in good overall total yield (50%) and high enantiomeric purity (95% ee). The synthetic routes developed herein are particularly convenient in comparison with the current methods available in literature and are particularly promising for large scale applications.

The first organocatalytic asymmetric synthesis of 3-substituted isoindolinones

Herein we describe the first asymmetric organocatalytic synthesis of 3-substituted isoindolinones in a convenient aldol-cyclization-rearrangement tandem reaction of malonates with 2-cyanobenzaldehyde. Bifunctional thiourea-cinchona catalysts proved to be particularly effective, giving the title compounds in high yields and moderate to good enantiomeric excesses. Moreover an efficient process of reverse crystallization led to a further enrichment up to >99% ee.

Organocatalysts and sequential asymmetric cascade reactions in the synthesis of functionalized isoindolinones and benzoindolizidinones

In this article we have disclosed a combination of versatile methodologies for the asymmetric synthesis and manipulation of isoindolinones and fused benzo-indolizidinones. On one hand, two consecutive asymmetric cascade reactions allow the synthesis of isoindolinones and fused benzo-indolizidinones, with the stereoselective construction of up to three stereocenters. On the other hand the study of the heterochiral crystallization and the easy functionalization of the obtained molecular platforms render the chemistry of these heterocyclic compounds particularly useful.

Cascade reactions of glycine Schiff bases and chiral phase transfer catalysts in the synthesis of α-amino acids 3-substituted phthalides or isoindolinones

The tuning of aldol/cyclization cascade reactions of glycine Schiff bases with 2-cyano benzaldehydes provides access to non-natural α-amino acid derivatives substituted alternatively with phthalides or isoindolinones, depending on the strength of the used base. Moreover, a preliminary screening of catalysts and conditions for development of asymmetric versions identified chiral bifunctional phase transfer catalysts as particularly promising, leading to the α-amino esters 3-substituted phthalides in high yields and good diastereo- and enantioselectivity.

Design of inhibitors of influenza virus membrane fusion: synthesis, structure-activity relationship and in vitro antiviral activity of a novel indole series.

The fusion of virus and endosome membranes is an essential early stage in influenza virus infection. The low pH-induced conformational change which promotes the fusogenic activity of the haemagglutinin (HA) is thus an attractive target as an antiviral strategy. The anti-influenza drug Arbidol is representative of a class of antivirals which inhibits HA-mediated membrane fusion by increasing the acid stability of the HA. In this study two series of indole derivatives structurally related to Arbidol were designed and synthesized to further probe the foundation of its antiviral activity and develop the basis for a structure-activity relationship (SAR). Ethyl 5-(hydroxymethyl)-1-methyl-2-(phenysulphanylmethyl)-1H-indole-3-carboxylate (15) was identified as one of the most potent inhibitors and more potent than Arbidol against certain subtypes of influenza A viruses. In particular, 15 exhibited a much greater affinity and preference for binding group 2 than group 1 HAs, and exerted a greater stabilising effect, in contrast to Arbidol. The results provide the basis for more detailed SAR studies of Arbidol binding to HA; however, the greater affinity for binding HA was not reflected in a comparable increase in antiviral activity of 15, apparently reflecting the complex nature of the antiviral activity of Arbidol and its derivatives.

Combined electrochemical/chemical methods for the synthesis and the molecular diversifying of isoindolinone-based heterocyclic scaffolds

By means of C–H acids activation on Pt-cathode, an electrochemically initiated strategy aimed to developing a diversity-oriented synthesis based on the isoindolinone nucleus has been established. Conveniently, the achievement of a small library of new heterocycle-fused isoindolinone compounds with potential interest for drug design was carried out by using tandem reactions and one-pot sequential processes.Graphical Abstract

2,3‐Dihydro‐1,2‐Diphenyl‐substituted 4H‐Pyridinone Derivatives as New Anti Flaviviridae Inhibitors

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 4acis (CC50 > 100 μm; EC50 = 14 μm), compounds 4ccis and 6a showed a significant activity against Flaviviruses (Yellow Fever Virus) (CC50 > 100 μm; EC50 = 18 μm, CC50 > 100 μm; EC50 = 10 μm). Among these, compound 6a displayed great inhibitory activity against Hepaciviruses (hepatitis C virus) in replicon assay [CC50 > 100 μm; EC50(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.

Asymmetric tandem hemiaminal-heterocyclization-aza-Mannich reaction of 2-formylbenzonitriles and amines using chiral phase transfer catalysis: an experimental and theoretical study

The first asymmetric synthesis of 3-amino-substituted isoindolinones was accomplished via cascade hemiaminal-heterocyclization-intramolecular aza-Mannich reaction of benzylamines and 2-formylbenzonitriles using chiral phase transfer conditions (PTC). A theoretical study of the enantioselective step provides a rationale for the mode of action of the best performing phase transfer catalyst and the observed face selectivity.

Quick and easy access to N-Mannich bases of 1-isoindolinones by catalytic electroactivation of primary and secondary amines and tandem reaction with 2-formylbenzonitriles

N-Mannich bases of 1-isoindolinones can be rapidly assembled by reacting 2-formylbenzonitriles with electroactivated amines on a Pt cathode, using a catalytic amount of electricity. Usefully, chiral amines allow the attainment of enantiopure N-Mannich bases by simple chromatographic separation.

Synthesis and pharmacological evaluation of functionalized isoindolinones on GABA-activated chloride currents in rat cerebellum granule cells in culture

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 10μM 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.