Antiparasitic Derivatives of the Furoquinoline Alkaloids Kokusaginine And Flindersiamine

We report the synthesis of 16 new compounds obtained from kokusaginine and flindersiamine, the main alkaloids isolated from the bark of Balfourodendron riedelianum. The activity of the compounds against axenic cultures of Trypanosoma cruzi epimastigtotes and trypomastigotes, as well as intracellular amastigotes, is described, together with their cytotoxic activity against three different human cell lines. The synthetic strategy for the preparation of the new compounds was based on the reactivity at the C4 position of the furoquinoline core towards nucleophiles. The new derivatives were synthesized by a Buchwald-Hartwig reaction, in most cases under green, solvent-free conditions. Compounds 1 c and 1 e displayed better in-vitro activity against trypomastigotes than benznidazole and nifurtimox (positive controls) with IC₅₀<4 μM. In addition, both compounds were not cytotoxic against the three human cell lines K562 (erytroleukimia), LM2 (breast cancer), and HaCat (keratinocyte). Interestingly, when evaluated against intracellular amastigotes, compound 1 c was able to significantly reduce the number of this parasite form, compared to the negative control.     

Structure-Based Virtual Screening and in vitro and in vivo Analyses Revealed Potent Methyltransferase G9a Inhibitors as Prospective Anti-Alzheimer's Agents

G9a is a lysine methyltransferase able to di-methylate lysine 9 of histone H3, promoting the repression of genes involved in learning and memory. Novel strategies based on synthesizing epigenetic drugs could regulate gene expression through histone post-translational modifications and effectively treat neurodegenerative diseases, like Alzheimer's disease (AD). Here, potential G9a inhibitors were identified using a structure-based virtual screening against G9a, followed by in vitro and in vivo screenings. First, screening methods with the AD transgenic Caenorhabditis elegans strain CL2006, showed that the toxicity/function range was safe and recovered age-dependent paralysis. Likewise, we demonstrated that the best candidates direct target G9a by reducing H3 K9me2 in the CL2006 strain. Further characterization of these compounds involved the assessment of the blood-brain barrier-permeability and impact on amyloid-β aggregation, showing promising results. Thus, we present a G9a inhibitor candidate, F , with a novel and potent structure, providing both leads in G9a inhibitor design and demonstrating their participation in reducing AD pathology.     

Twenty years of energy policy in Europe: achievement of targets and lessons for the future

The different energy transition efforts in the EU-27 countries are analysed, paying special attention to the achievement of set energy targets and the real influence on energy dependence and GHG reduction. Various methodologies were used, ranging from construction of timelines to geo-statistical analysis using Geographic Information Systems (GIS) and the implementation of machine learning techniques and models, using R. The results show how different modifications of the energy saving and efficiency targets, along with lower power consumption due to the COVID pandemic, resulted in that although most of the EU-27 countries have achieved their saving and efficiency targets, this has not been reflected in a real reduction in consumption (compared to 1990 levels). In addition, the fulfilment of the objectives has not resulted in a reduction in energy dependence, generating a false sense of security and satisfaction in the fulfilment of the targets. Concerning GHGs, almost all EU-27 countries decrease their GHG emissions per capita compared to 2000 (with the exception of Lithuania, Bulgaria, Croatia and Latvia), with this decrease being mainly related to the fulfilment of renewable energy targets in transport. The conclusion highlights the need to make greater efforts to achieve saving and efficiency in the near future; otherwise, higher power consumption via renewable energy sources, while helping meet future increases in energy demand, will not impact the reduction in energy dependence compared to current levels.

Graphical abstract

Achievement of energy transition targets. Contribution to the reduction in greenhouse gases and energy dependence.

     

Role of Metal Contacts on Halide Perovskite Memristors

Halide perovskites are promising candidates for resistive memories (memristors) due to their mixed electronic/ionic conductivity and the real activation mechanism is currently under debate. In order to unveil the role of the metal contact and its connection with the activation process, four model systems are screened on halide perovskite memristors: Nearly inert metals (Au and Pt), low reactivity contacts (Cu), highly reactive contact (Ag and Al), and pre-oxidized metal in the form of AgI. It is revealed that the threshold voltage for activation of the memory effect is highly connected with the electrochemical activity of the metals. Redox/capacitive peaks are observed for reactive metals at positive potentials and charged ions are formed that can follow the electrical field. Activation proceeds by formation of conductive filaments, either by the direct migration of the charged metals or by an increase in the concentration of halide vacancies generated by this electrochemical reaction. Importantly, the use of pre-oxidized Ag⁺ ions leads to very low threshold voltages of ≈0.2 V indicating that an additional electrochemical reaction is not needed in this system to activate the memristor. Overall, the effect of the metal contact is clarified, and it is revealed that AgI is a very promising interfacial layer for low-energy applications.