Synthesis and Structure–Activity Relationship Studies of Pyrido [1,2-e]Purine-2,4(1H,3H)-Dione Derivatives Targeting Flavin-Dependent Thymidylate Synthase in Mycobacterium tuberculosis

In 2002, a new class of thymidylate synthase (TS) involved in the de novo synthesis of dTMP named Flavin-Dependent Thymidylate Synthase (FDTS) encoded by the thyX gene was discovered; FDTS is present only in 30% of prokaryote pathogens and not in human pathogens, which makes it an attractive target for the development of new antibacterial agents, especially against multi-resistant pathogens. We report herein the synthesis and structure-activity relationship of a novel series of hitherto unknown pyrido[1,2-e]purine-2,4(1H,3H)-dione analogues. Several synthetics efforts were done to optimize regioselective N¹-alkylation through organopalladium cross-coupling. Modelling of potential hits were performed to generate a model of interaction into the active pocket of FDTS to understand and guide further synthetic modification. All those compounds were evaluated on an in-house in vitro NADPH oxidase assays screening as well as against Mycobacterium tuberculosis ThyX. The highest inhibition was obtained for compound 23a with 84.3% at 200 µM without significant cytotoxicity (CC₅₀ > 100 μM) on PBM cells.     

Word and Face Recognition Processing Based on Response Times and Ex-Gaussian Components

The face is a fundamental feature of our identity. In humans, the existence of specialized processing modules for faces is now widely accepted. However, identifying the processes involved for proper names is more problematic. The aim of the present study is to examine which of the two treatments is produced earlier and whether the social abilities are influent. We selected 100 university students divided into two groups: Spanish and USA students. They had to recognize famous faces or names by using a masked priming task. An analysis of variance about the reaction times (RT) was used to determine whether significant differences could be observed in word or face recognition and between the Spanish or USA group. Additionally, and to examine the role of outliers, the Gaussian distribution has been modified exponentially. Famous faces were recognized faster than names, and differences were observed between Spanish and North American participants, but not for unknown distracting faces. The current results suggest that response times to face processing might be faster than name recognition, which supports the idea of differences in processing nature.     

Phenyl Silicates with Substituted Catecholate Ligands: Synthesis,Structural Studies and Reactivity

While the generation of aryl radicals by photoredox catalysis under reductive conditions is well documented, it has remained challenging under an oxidative pathway. Because of the easy photo-oxidation of alkyl bis-catecholato silicates, a general study of phenyl silicates bearing substituted catecholate ligands has been achieved. The newly synthesized phenyl silicates have been fully characterized, and their reactivity has been explored. It was found that, thanks to the substitution of the catecholate moiety, notably with the 4-cyanocatecholato ligand, the phenyl radical could be generated and trapped. Computational studies provided a rationale for these findings.     

Design,Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood–brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.     

Synthesis and Properties of the Perfluoroethyl Martin Silicate: Reactivity in Solution and Solid-State Mechanochemistry

We herein report the first synthesis of a Martin silicate bearing a pentafluoroethyl chain. The full characterisation of this new pentacoordinated silicon species is detailed. Insights on its electronic properties based on structural, physicochemical and computational data are provided. A comparative study of reactivity in solution and in solid state by mechanochemistry has been performed in order to assess the ability of this bench-stable salt to act as a safe C₂F₅-alkylation reagent in a nucleophilic or radical manner.