Novel 2,5-Diketopiperazines with In Vitro Activities against Protozoan Parasites of Tropical Diseases.

Malaria, Chagas disease, and leishmaniasis are tropical diseases caused by protozoan parasites of the genera Plasmodium, Trypanosoma and Leishmania, respectively. These diseases constitute a major burden on public health in several regions worldwide, mainly affecting low-income populations in economically poor countries. Severe side effects of currently available drug treatments and the emergence of resistant parasites need to be addressed by the development of novel drug candidates. Natural 2,5-Diketopiperazines (2,5-DKPs) constitute N-heterocyclic secondary metabolites with a wide range of biological activities of medicinal interest. Its structural and physicochemical properties make the 2,5-DKP ring a versatile, peptide-like, and stable pharmacophore attractive for synthetic drug design. In the present work, twenty-three novel synthetic 2,5-DKPs, previously synthesized through the versatile Ugi multicomponent reaction, were assayed for their anti-protozoal activities against P. falciparum, T. cruzi, and L. infantum. Some of the 2,5-DKPs have shown promising activities against the target protozoans, with inhibitory concentrations (IC50) ranging from 5.4 to 9.5 µg/mL. The most active compounds also show low cytotoxicity (CC50), affording selectivity indices ≥ 15. Results allowed for observing a clear relationship between the substitution pattern at the aromatic rings of the 2,5-DKPs and their corresponding anti-Plasmodium activity. Finally, calculated drug-like properties of the compounds revealed points for further structure optimization of promising drug candidates.

Tyrosol 1,2,3-triazole analogues as new acetylcholinesterase (AChE) inhibitors.

The present work proposed the preparation of triazolic analogues of tyrosol, a biophenol found in olive oil and whose wide range of bioactivities has been the target of many studies. We obtained fifteen novel tyrosol derivatives and the compounds of the series were later evaluated as acetylcholinesterase (AChE) inhibitors. The study of AChE inhibition is important for the development of new drugs and pesticides, and especially the research for managing Alzheimer's disease. The most active compound, namely 7-({1-[2-(4-hydroxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}methoxy)-4-methyl-2H-chromen-2-one (30), showed IC50 value of 14.66 ±â€¯2.29 µmol L-1. Docking experiments corroborated by kinetic assay are suggestive of a competitive inhibition mechanism. Derivatives interacted with amino acids from the AChE active site associated to the development of Alzheimer's disease. The results indicate that the compounds synthesized have a high potential as prototypes for the development of new acetylcholinesterase inhibitors.

New rubrolide analogues as inhibitors of photosynthesis light reactions.

Natural products called rubrolides have been investigated as a model for the development of new herbicides that act on the photosynthesis apparatus. This study comprises a comprehensive analysis of the photosynthesis inhibitory ability of 27 new structurally diverse rubrolide analogues. In general, the results revealed that the compounds exhibited efficient inhibition of the photosynthetic process, but in some cases low water solubility may be a limiting factor. To elucidate their mode of action, the effects of the compounds on PSII and PSI, as well as their partial reaction on chloroplasts and the chlorophyll a fluorescence transients were measured. Our results showed that some of the most active rubrolide analogues act as a Hill reaction inhibitors at the QB level by interacting with the D1 protein at the reducing side of PSII. All of the active analogues follow Tice's rule of 5, which indicates that these compounds present physicochemical properties suitable for herbicides.

Cyclopent-4-ene-1,3-diones: a new class of herbicides acting as potent photosynthesis inhibitors.

In a recent paper, we reported the synthesis and photosynthesis-inhibitory activity of a series of analogues of rubrolides. From quantitative structure-activity relationship (QSAR) studies, we found that the most efficient compounds are those having higher ability to accept electrons. On the basis of those findings, we directed our effort to synthesize new analogues bearing a strong electron-withdrawing group (nitro) in the benzylidene ring and evaluate their effects on photosynthesis. However, the employed synthetic approach led to novel cyclopent-4-ene-1,3-diones as major products. Here, we report the synthesis and mechanism of action of such cyclopent-4-ene-1,3-diones as a new class of photosynthesis inhibitors. These compounds block the electron transport at the QB level by interacting at the D1 protein at the reducing side of Photosystem II and act as Hill reaction inhibitors, with higher activity than the corresponding rubrolides. To the best of our knowledge, this is the first report on the photosynthesis inhibitory activity of cyclopentenediones.

Benzocaine complexation with p-sulfonic acid calix[n]arene: experimental ((1) H-NMR) and theoretical approaches.

The aim of this work was to study the interaction between the local anesthetic benzocaine and p-sulfonic acid calix[n]arenes using NMR and theoretical calculations and to assess the effects of complexation on cytotoxicity of benzocaine. The architectures of the complexes were proposed according to (1) H NMR data (Job plot, binding constants, and ROESY) indicating details on the insertion of benzocaine in the cavity of the calix[n]arenes. The proposed inclusion compounds were optimized using the PM3 semiempirical method, and the electronic plus nuclear repulsion energy contributions were performed at the DFT level using the PBE exchange/correlation functional and the 6-311G(d) basis set. The remarkable agreement between experimental and theoretical approaches adds support to their use in the structural characterization of the inclusion complexes. In vitro cytotoxic tests showed that complexation intensifies the intrinsic toxicity of benzocaine, possibly by increasing the water solubility of the anesthetic and favoring its partitioning inside of biomembranes.

Arsenic and trace metals in river water and sediments from the southeast portion of the Iron Quadrangle, Brazil.

The Iron Quadrangle has been one of the most important gold production regions in Brazil since the end of the seventeenth century. There, arsenic occurs in close association with sulfide-rich auriferous rocks. The most abundant sulfide minerals are pyrite and arsenopyrite, yet trace metal sulfides occur in subordinate phases as well. Historical mining activities have been responsible for the release of As and trace metals to both aquatic and terrestrial environments close to mining sites in the region. Therefore, this study was aimed to evaluate the distribution and mobility of As, Cd, Co, Cr, Cu, Ni, Pb, and Zn in streams in the southeast portion of the Iron Quadrangle between the municipalities of Ouro Preto and Mariana, the oldest Brazilian Au mining province. Total concentrations of some trace metals and arsenic in water were determined. The four-stage sequential extraction procedure proposed by the commission of the European Communities Bureau of Reference (BCR) was used to investigate the distribution of these elements in stream sediments. Arsenic concentration in water was > 10 µg L⁻¹ (maximum limit permitted by Brazilian environmental regulations for water destined for human consumption) at all sampling sites, varying between 36.7 and 68.3 µg L⁻¹. Sequential extraction in sediments showed high concentrations of As and trace metals associated with easily mobilized fractions.

Mercury fractionation in stream sediments from the Quadrilátero Ferrífero gold mining region, Minas Gerais State, Brazil.

The Iron Quadrangle (IQ) region, located in the state of Minas Gerais, has been the most important gold producing area in Brazil since the end of seventeenth century. The use of mercury for gold amalgamation in small scale mines has been responsible for large release of Hg to aquatic and terrestrial environments during 300 years of mining. The present work sought to evaluate the fractionation of Hg in stream sediments is the southern region of the IQ by utilizing sequential extraction. Since mobility and availability of Hg are related to its distribution among sediment partitions, fractionation methods provide detailed information on the ecotoxicological impact and risks associated to the presence of Hg in sediments. The total Hg concentration varied from 179.3 to 690.1 microg kg( - 1) and Hg(0) accounted for the majority at all sample sites, ranging from 42% to 56% of the total.