Chagas disease (CD) is a centenarian neglected parasitosis caused by the protozoan Trypanosoma cruzi (T. cruzi). Despite the continuous efforts of many organizations and institutions, CD is still an important human health problem worldwide. A lack of a safe and affordable treatment has led drug discovery programmes to focus, for years, on the search for molecules enabling interference with enzymes that are essential for T. cruzi survival. In this work, the authors want to offer a brief overview of the different validated targets that are involved in diverse parasite pathways: glycolysis, sterol synthesis, the de novo biosynthesis of pyrimidine nucleotides, the degradative processing of peptides and proteins, oxidative stress damage and purine salvage and nucleotide synthesis and metabolism. Their structural aspects, function, active sites, etc. were studied and considered with the aim of defining molecular bases in the search for new effective treatments for CD. This review also compiles, as much as possible, all the inhibitors reported to date against these T. cruzi targets, serving as a reference for future research in this field.

Inclusion complexation of rifampicin (RIF) with several types of cyclodextrins (beta CD, hydroxypropyl-beta CD, gamma CD, hydroxypropyl-gamma CD) in aqueous solutions at different pH values was investigated to assess the interactions between RIF and cyclodextrins (CDs). Molecular modeling was performed to determine the possible interactions between RIF and CDs at several pH values. The inclusion complexes were characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffractometry, and scanning electron microscopy. Moreover, this study evaluated the dissolution profile and antibacterial activity of the formed complexes. Phase solubility analysis suggested the formation of RIF-CD affirmed 1:1 stoichiometry at all pH values (except RIF-beta CD at pH 4.0 and both beta CD and gamma CD at pH 9.0). The inclusion complexation of RIF with CD successfully increased the percentage of RIF released in in vitro studies. The inclusion complexes of RIF exhibited more than 60% of RIF released in 2 h which was significantly higher (p < 0.05) than release of pure RIF, which was only less than 10%. Antibacterial activity of RIF-CD complexes (measured by the minimum inhibitory concentration of RIF against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus) was lower for both RIF-beta CD and RIF-HP gamma CD at pH 7.0 to pure RIF suspension. In conclusion, this work reports that both beta CD and gamma CD can be used to enhance the solubility of RIF and thus, improve the effectivity of RIF by decreasing the required daily dose of RIF for the treatment of bacterial infections.

Humans are widely exposed to a great variety of mycotoxins and their mixtures. Therefore, it is important to design strategies that allow prioritizing mycotoxins based on their toxic potential in a time and cost-effective manner. A strategy combining in silico tools (Phase 1), including an expert knowledge-based (DEREK Nexus(R)(,) Lhasa Limited, Leeds, UK) and a statistical-based platform (VEGA QSAR (c), Mario Negri Institute, Milan, Italy), followed by the in vitro SOS/umu test (Phase 2), was applied to a set of 12 mycotoxins clustered according to their structure into three groups. Phase 1 allowed us to clearly classify group 1 (aflatoxin and sterigmatocystin) as mutagenic and group 3 (ochratoxin A, zearalenone and fumonisin B1) as non-mutagenic. For group 2 (trichothecenes), contradictory conclusions were obtained between the two in silico tools, being out of the applicability domain of many models. Phase 2 confirmed the results obtained in the previous phase for groups 1 and 3. It also provided extra information regarding the role of metabolic activation in aflatoxin B1 and sterigmatocystin mutagenicity. Regarding group 2, equivocal results were obtained in few experiments; however, the group was finally classified as non-mutagenic. The strategy used correlated with the published Ames tests, which detect point mutations. Few alerts for chromosome aberrations could be detected. The SOS/umu test appeared as a good screening test for mutagenicity that can be used in the absence and presence of metabolic activation and independently of Phase 1, although the in silico-in vitro combination gave more information for decision making.

A molecular modeling study has been carried out on two previously reported series of methylselenocarbamate derivatives that show remarkable antiproliferative and cytotoxic in vitro activity, against a panel of human cancer cell lines. These derivatives can be considered as having been constructed by a selenomethyl fragment located over a carbon atom which is decorated with two carbamate moieties, both aliphatic and aromatic, one of them attached by a single bond to the central carbon atom, while the second is connected by a double bond. According to the data obtained, these derivatives can undergo a water-mediated nucleophilic attack on the carbons with marked electrophilic character, which leads to the rupture of C-Se and carbamate C-O bonds. The aliphatic derivatives, series 1, show an early release of methylselenol and a further release of hydroxyl derivatives (alcohols), whereas the aromatic carbamates, series 2, show an early release of phenols followed by the subsequent release of methylselenol. Thus, the activity of the compounds can be related to the progressive release of active fragments. The data that support this connection are related to the overall molecular topology, volume and surface area as well as to quantum parameters such as the relative electrophilic character of the target carbon atoms (measured in terms of positive charge values) or the bond order values, especially concerning the central C-SeCH3 bond and the carbamate ones. Moreover, the data obtained regarding the chromatographic behavior of some representative compounds confirm this proposal.

Glibenclamide is a sulfonylurea used for the oral treatment of type II diabetes mellitus. This drug shows low bioavailability as consequence of its low solubility. In order to solve this problem, the interaction with cyclodextrin has been proposed. This study tries to provide an explanation about the processes involved in the formation of GB-beta CDs complexes, which have been interpreted in different ways by several authors. Among native cyclodextrins, beta CD presents the most appropriate cavity to host glibenclamide molecules showing A(L) solubility diagrams (K-1:1 approximate to 1700 M-1). However, A(L)- solubility profiles were found for pa) derivatives, highlighting the coexistence of several phenomena involved in the drug solubility enhancement. At low CD concentration, the formation of inclusion complexes can be studied and the stability constants can be calculated (K-1:1 approximate to 1700 M-1) Whereas at high CD concentration, the enhancement of GB solubility would be mainly attributed to the formation of nanoaggregates of CD and GB-CD complexes (sizes between 100 and 300 nm). The inclusion mode into beta CD occurs through the cyclohexyl ring of GB, adopting a semi-folded conformation which maximizes the hydrogen bond network. As consequence of all these phenomena, a 150-fold enhancement of drug solubility has been achieved using beta-cyclodextrin derivatives. Thus, its use has proven to be an interesting tool to improve the oral administration of glibenclamide in accordance with dosage bulk and dose/solubility ratio requirements. (C) 2017 Elsevier B.V. All rights reserved.

Glibenclamide is an antidiabetic drug showing low bioavailability as consequence of its low solubility. To solve this drawback, the interaction with cyclodextrins has been proposed. The formation of GB-beta CDs inclusion complexes was carried out using different methods, beta CD derivatives and drug-to-cyclodextrin ratios. The structures of the corresponding complexes have been studied by molecular modelling, X-ray diffraction and differential thermal analysis. The dissolution behavior of inclusion complexes has been compared to that of pure GB. Dimeric inclusion complexes were obtained with different CD disposals, head-to-head for beta CD and head-to-tail for HP beta CD and RM beta CD. Amorphous inclusion complexes were obtained by employing methods of freeze-drying or coevaporation in ammonia-water. However, crystalline structures were formed by kneading and coevaporation in ethanol/water in the case of GB-beta CD complexes. The arrangement of these structures depended on the GB:beta CD ratio, yielding cage type structures for 1:3 and 1:5 ratios and channel-type structures for higher GB contents. The amount of GB released and its dissolution rate was considerably increased by the use of amorphous inclusion complexes; whereas, slower GB release rates were found from crystalline inclusion complexes formed by kneading or coevaporation in ethanol/water. In addition, it was found that the porous structure strongly conditioned the GB dissolution rate from crystalline products.

A molecular modeling study has been carried out on a previously reported series of (diselanediyldibenzene-4,1-diylnide)biscarbamate derivatives that show cytotoxic and antiproliferative in vitro activity against MCF-7 human cell line; radical scavenging properties were also confirmed when these compounds were tested for their ability to scavenge DPPH and ABTS radicals. The data obtained allowed us to classify the compounds into two different groups: (a) aliphatic carbamates for which the activity could be related with a first nucleophilic attack (mediated by H2O, for example) on the selenium atoms of the central scaffold, followed by the release of the alkyl N-(4-selanylphenyl) and N-(4-selenenophenyl)carbamate moieties. Then, a second nucleophilic attack on the carbamate moiety, to yield 4-aminobenzeneselenol and 4-selenenoaniline respectively, which can ultimately be responsible for the activity of the compounds; (b) aromatic carbamates, for which we propose a preferred nucleophilic attack on the carbamate moiety, yielding 4-[(4-aminophenyl)diselanyl]aniline, the common structural fragment for this series, for which we have previously demonstrated its cytotoxic profile. Then, selenium atoms of the central fragment may later undergo a new nucleophilic attack, to yield 4-selenenoaniline and 4-aminobenzeneselenol. The phenolic moieties released in this process may also have a synergistic cytotoxic and redox activity.

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 ¿M and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3'-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.

Patients affected by cutaneous leishmaniasis need a topical treatment which cures lesions without leaving scars. Lesions are produced not only by the parasite but also by an uncontrolled and persistent inflammatory immune response. In this study, we proposed the loading of ß-lapachone (ß-LP) in lecithin-chitosan nanoparticles (NP) for targeting the drug to the dermis, where infected macrophages reside, and promote wound healing. Although the loading of ß-LP in NP did not influence the drug antileishmanial activity it was critical to achieve important drug accumulation in the dermis and permeation through the skin. When topically applied in Leishmania major infected BALB/c mice, ß-LP NP achieved no parasite reduction but they stopped the lesion progression. Immuno-histopathological assays in CL lesions and quantitative mRNA studies in draining lymph nodes confirmed that ß-LP exhibited anti-inflammatory activity leading to the down-regulation of IL-1ß and COX-2 expression and a decrease of neutrophils infiltrate.

A molecular modeling study has been carried out on two previously reported series of symmetric diselenide derivatives that show remarkable antileishmanial in vitro activity against Leishmania infantum intracellular amastigotes and in infected macrophages (THP-1 cells), in addition to showing favorable selectivity indices. Series 1 consists of compounds that can be considered as central scaffold constructed with a diaryl/dialkylaryl diselenide central nucleus, decorated with different substituents located on the aryl rings. Series 2 consists of compounds constructed over a diaryl diselenide central nucleus, decorated in 4 and 4' positions with an aryl or heteroaryl sulfonamide fragment, thus forming the diselenosulfonamide derivatives. With regard to the diselenosulfonamide derivatives (2 series), the activity can be related, as a first approximation, with (a) the ability to release bis(4-aminophenyl) diselenide, the common fragment which can be ultimately responsible for the activity of the compounds. (b) the anti-parasitic activity achieved by the sulfonamide pharmacophore present in the analyzed derivatives. The data that support this connection include the topography of the molecules, the conformational behavior of the compounds, which influences the bond order, as well as the accessibility of the hydrolysis point, and possibly the hydrophobicity and polarizability of the compounds.

Esta Neuropsicología de las doctoras López Moratalla y Font Arellano es una respuesta fascinante, interdisciplinar, rigurosamente científica, fruto de años de investigación y experiencia, de extraordinaria utilidad para cuantos forman a niños y adolescentes, pero también para mejor comprenderse a uno mismo. Nuestro cerebro no es un órgano más. Tiene una especial naturaleza y organización, a diferencia del resto de sistemas del organismo corporal, para comunicarse directa, inmediata y en doble dirección con la «mente» de su persona: ese «quien» único, singular e irrepetible que entiende, quiere, siente y ama. Algunas de sus temáticas: el trazado y proceso de maduración del cerebro masculino y femenino; los circuitos de recompensa y de bienestar cerebrales y la adquisición de hábitos de gobierno; la herencia genealógica, las predisposiciones y los trastornos de origen genético; el cerebro emocional y su restructuración durante la adolescencia; la gestión de las emociones y de los sentimientos; la dislexia, el estrés, la adquisición de resiliencia; los maltratos al niño y al adolescente con sus alteraciones cerebrales y conductuales; el cerebro en la adicción a las drogas (alcohol, cocaína, opiáceos, psicoestimulantes, alucinógenos, nicotina) y a las nuevas tecnologías; la anorexia y la bulimia; la empatía, su proceso de maduración y sus trastornos; la vida afectiva, la fuerza de saberse y sentirse amado para poder amar; las carencias y las soledades; y el sugestivo estudio del cerebro enamorado.

According to World Health Organization, neglected tropical diseases encompass all diseases that occur solely, or principally, in the tropics. In practice, the term is often taken to refer to infectious diseases that thrive in hot, humid conditions. Clinical and epidemiological studies suggest that selenium (Se) play an important role in tropical diseases, such as tuberculosis, leishmaniasis, filariasis and chagas, acting as preventive agent or in diagnosis and prognosis. Recent studies have evinced the importance of selenium in oxidative status and antioxidant defense capabilities during the course of infection and progression of the illness in human patients and experimental models. For this reason, one of the most relevant mechanism of action proposed involve selenoproteins, i.e. glutathione peroxidase (GPx), an enzyme that protects against oxidative stress and modulates the redox processes. In addition, it was observed that low Se levels were positively correlated with an increased susceptibility to infections. Besides, Se supplementation is proposed as an adjuvant therapy for treatment of these chronic diseases. However, there is a lack in the literature references related to synthesis and biological evaluation of novel derivatives containing selenium moiety against these diseases. During the last years our research group is interested in the design and synthesis of organoselenium compounds as new class of agents for treatment of neglected tropical diseases. In the present year we have reported two general structures with leishmanicidal activity, corresponding both of them to symmetrical compounds. The firsts are alkyl imidoselenocarbamates (alkyl isoselenourea) which possessed a moderate effect in vitro and the second ones are selenocyanates and diselenides. It is remarkable that some of them showed stronger in vitro antileishmanial activity than edelfosine and miltefosine, used as reference drugs, and combined high potency and low cytotoxicity against Jurkat and THP-1 cells. Selenium and Tropical Diseases (PDF Download Available). Available from: https://www.researchgate.net/publication/235745925_Selenium_and_Tropical_Diseases [accessed Jun 21, 2017].