Síntesis organocatalizada de azúcares raros y derivados

Los carbohidratos, o hidratos de carbono, son el grupo más abundante de compuestos orgánicos hallados en la naturaleza. Durante décadas, se creía que la función de estos compuestos se limitaba a ser la fuente de energía necesaria para hacer funcionar los procesos bioquímicos. Sin embargo, la importancia de la diversidad de estos compuestos y el papel fundamental que juegan en los procesos bioquímicos,1 fue reconocida recién en la década de 1980. Entre las funciones biológicas de los carbohidratos, se pueden destacar el reconocimiento intercelular, la participación en los procesos de infección bacterial y viral, procesos de inflamación, y desarrollo neuronal

Garbage in, garbage out: how reliable training data improved a virtual screening approach against SARS-CoV-2 MPro

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 μM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12–20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7–45 μM).Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known “garbage in, garbage out” machine learning principle

Green and Catalytic Synthesis of Dominicalure I, Major Component of the Aggregation Pheromone of <i>Rhyzopertha dominica</i> (Fabricius) (Coleoptera: Bostrichidae)

<div><p></p><p>A new concise and efficient catalytic synthesis of dominicalure I, the male-produced aggregation pheromone of the grain borer <i>Rhyzopertha dominica</i>, is herein reported. The synthetic route was designed starting from easily available propanal through an organocatalytic key step and completed with biocatalytic procedures.</p></div

Continuous Flow Enantioselective Three-Component anti-Mannich Reactions Catalyzed by a Polymer-Supported Threonine Derivative

A series of primary amino acid-derived polystyrene-supported organocatalysts was tested in anti-selective Mannich reactions. The polystyrene-immobilized threonine derivative showed the best performance in three-component (hydroxyacetone, anilines and aldehydes) Mannich reactions to provide anti-b-amino-a-hydroxycarbonyl compounds (11 examples; up to 95% ee) and its use could be extended to dihydroxyacetone and protected hydroxyacetones (7 examples; up to 90% ee). The high activity depicted by the catalyst has allowed its implementation in continuous flow. Under this operation mode, the supported threonine catalyst produces anti-Mannich adducts with generally higher diastereo- and enantioselectivity than in batch. A family of five different enantioenriched anti-Mannich adducts has been sequentially prepared in flow by passing different combinations of anilines and aromatic aldehydes over the same sample of catalyst. This confirms the suitability of this methodology for the rapid access to small libraries of enantioenriched compounds.</p

The indole motif is essential for the antitrypanosomal activity of N5-substituted paullones.

Severe infections with potentially fatal outcomes are caused by parasites from the genera Trypanosoma and Leishmania (class Kinetoplastea). The diseases affect people of remote areas in the tropics and subtropics with limited access to adequate health care. Besides insufficient diagnostics, treatment options are limited, with tenuous developments in recent years. Therefore, new antitrypanosomal antiinfectives are required to fight these maladies. In the presented approach, new compounds were developed and tested on the target trypanothione synthetase (TryS). This enzyme is crucial to the kinetoplastids' unique trypanothione-based thiol redox metabolism and thus for pathogen survival. Preceding studies have shown that N5-substituted paullones display antitrypanosomal activity as well as TryS inhibition. Herein, this compound class was further examined regarding the structure-activity relationships (SAR). Diverse benzazepinone derivatives were designed and tested in cell-based assays on bloodstream Trypanosoma brucei brucei (T. b. brucei) and intracellular amastigotes of Leishmania infantum (L. infantum) as well as in enzyme-based assays on L. infantum TryS (LiTryS) and T. b. brucei TryS (TbTryS). While an exchange of just the substituent in the 9-position of paullones led to potent inhibitors on LiTryS and T. b. brucei parasites, new compounds lacking the indole moiety showed a total loss of activity in both assays. Conclusively, the indole as part of the paullone structure is pivotal for keeping the TryS inhibitory and antitrypanosomal activity of this substance class