Ana Sofia Marques Ressurreição

Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin–proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still a concern. The purpose of this study was the discovery of novel scaffolds of proteasome inhibitors with anticancer activity, aiming to overcome the limitations of the existing proteasome inhibitors. Thus, a structure-based virtual screening protocol was developed using the structure of the human 20S proteasome, and 246 compounds from virtual databases were selected for in vitro evaluation, namely proteasome inhibition assays and cell viability assays. Compound 4 (JHG58) was shortlisted as the best hit compound based on its potential in terms of proteasome inhibitory activity and its ability to induce cell death (both with IC₅₀ values in the low micromolar range). Molecular docking studies revealed that compound 4 interacts with key residues, namely with the catalytic Thr1, Ala20, Thr21, Lys33, and Asp125 at the chymotrypsin-like catalytic active site. The hit compound is a good candidate for additional optimization through a hit-to-lead campaign.

Leishmaniasis is one of the most challenging neglected tropical diseases and remains a global threat to public health. Currently available therapies for leishmaniases present significant drawbacks and are rendered increasingly inefficient due to parasite resistance, urging the need for more effective, safer, and cheaper drugs. In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, we have screened in house antiplasmodial libraries against axenic and intracellular forms of Leishmania infantum, L. amazonensis and L. major. Several of the screened compounds showed IC₅₀ values against intracellular L. infantum parasites in the submicromolar range (1h: IC₅₀ 0.9 μM and 1n: IC₅₀ 0.7 μM) and selectivity indexes of 11 and 9.7, respectively. Compounds also displayed activity against L. amazonensis and L. major, albeit in the low micromolar range. Mechanistic studies revealed that 1n efficiently inhibits oxygen consumption and significantly decreases the mitochondrial membrane potential in L. infantum axenic amastigotes, suggesting that this chemotype acts, at least in part, by interfering with mitochondrial function. Structure-activity analysis suggests that 1n is a promising antileishmanial lead and emphasize the potential of the quinoline-(1H)-imine chemotype for the future development of new antileishmanial agents.

Guanine‐rich nucleic acid sequences able to form four‐stranded structures (G‐quadruplexes, G4) play key cellular regulatory roles and are considered as promising drug targets for anticancer therapy. On the basis of the organization of their structural elements, G4 ligands can be divided into three major families: one, fused heteroaromatic polycyclic systems; two, macrocycles; three, modular aromatic compounds. The design of modular G4 ligands emerged as the answer to achieve not only more drug‐like compounds but also more selective ligands by targeting the diversity of the G4 loops and grooves. The rationale behind the design of a very comprehensive set of ligands, with particular focus on the structural features required for binding to G4, is discussed and combined with the corresponding biochemical/biological data to highlight key structure–G4 interaction relationships. Analysis of the data suggests that the shape of the ligand is the major factor behind the G4 stabilizing effect of the ligands. The information here critically reviewed will certainly contribute to the development of new and better G4 ligands with application either as therapeutics or probes.

Heterocycles occupy a central position in organic chemistry, and are of significant importance in the search for new bioactive scaffolds in both the agrochemica

Amides are an important class of organic chemicals and amide bonds are often found in synthetic and naturally occurring organic molecules. Some familiar example

Flavonoids represent a large class of natural products in the plant kingdom, exhibiting a strong and broad variety of biological activities. Among this large fa

A new series of naphthalene-based molecular tongs containing polar groups at the 3-position of the naphthalene scaffold was synthesized and its anti-dimerization activity was evaluated against HIV-1 protease. The polar groups were introduced mainly via metal-catalysed cross coupling reactions such as the Buchwald–Hartwig amination, the Sonogashira reaction and the Beller cyanation. Kinetic analyses showed that by introducing specific polar substituents on the naphthalene scaffold the inhibitory activity of molecular tongs against wild-type and mutated HIV-1 proteases is maintained, while increasing their water solubility.

Discovery of novel effective and safe antimalarials has been traditionally focused on targeting erythrocytic parasite stages that cause clinical symptoms. However, elimination of malaria parasites from the human population will be facilitated by intervention at different life-cycle stages of the parasite, including the obligatory developmental phase in the liver, which precedes the erythrocytic stage. We have previously reported that N-Mannich-based quinolon-4(1H)-imines are potent antiplasmodial agents but present several stability liabilities. We now report our efforts to optimize quinolon-4(1H)-imines as dual-stage antiplasmodial agents endowed with chemical and metabolic stability. We report compounds active against both the erythrocytic and exoerythrocytic forms of malaria parasites, such as the quinolon-4(1H)-imine 5p (IC₅₀ values of 54 and 710 nM against the erythrocytic and exoerythrocytic forms), which constitute excellent starting points for further lead optimization as dual-stage antimalarials.

Significance: Plasmodium parasites have two distinct intracellular growth stages inside the mammalian host—the first stage, which is clinically silent, in liver hepatocytes, and the second, which causes the symptoms of malaria, in red blood cells. This study reports the discovery of a class of antimalarial compounds called torins, which are extremely potent inhibitors of both intracellular stages of Plasmodium . We show that torins block trafficking of liver stage parasite proteins to the physical host–parasite interface, called the parasitophorous vacuole membrane (PVM), and that without continuous trafficking of PVM-resident proteins, the parasite is subject to elimination by its host hepatocyte.