A Novel Prodrug of a nNOS Inhibitor with Improved Pharmacokinetic Potential

Under different pathological conditions, aberrant induction of neuronal nitric oxide synthase (nNOS) generates overproduction of NO that can cause irreversible cell damage. The aim of this study was to develop an amidoxime prodrug of a potent nNOS inhibitor, the benzhydryl acetamidine. We synthesized the benzhydryl acetamidoxime, which was evaluated in vitro to ascertain the potential NOS inhibitory activity, as well as conducting bioconversion into the parent acetamidine. The prodrug was also profiled for in vitro physicochemical properties, by determining the lipophilicity, passive permeation through the human gastrointestinal tract and across the blood-brain barrier by PAMPA, and chemical, enzymatic, and plasma stability. The obtained data demonstrate that the amidoxime prodrug shows an improved pharmacokinetic profile with respect to the acetamidine nNOS inhibitor, thus suggesting that it could be a promising lead compound to treat all those pathological conditions in which nNOS activity is dysregulated

Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold

A large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives

Development of non evaporable getter pumps for large hydrogen throughput and capacity in high vacuum regimes

In vacuum technology, capture pumps based on Non Evaporable Getters are commonly applied to ultra-high vacuum systems. Recent improvements in the absorption of hydrogenic species, with the introduction of Zr–V–Ti–Al alloys (ZAO®), make them an appealing and viable solution for the application in fusion research, and in particular for the vacuum system of neutral beam injectors (hydrogen pumping speed of thousands of m3/s, pressure of tens of mPa). This paper describes the characterization of the new NEG material in pumps of increasing dimensions, including the development, construction and test of a large mockup pump of modular design, to demonstrate the scalability of the technology. Effective pumping speeds of the order of 14 m3/s or higher at a concentration of 130 Pa m3/kg were achieved by the mockup pump, for an installed getter mass of about 16 kg, and a stability within 10% up to 1300 Pa m3/kg The measured effective pumping speed per unit area of sintered disks is of the order of 3.5 m/s, corresponding to 4.9 m/s at the disk surfaces as derived from numerical simulations. General guidelines for the design of large NEG pumps for hydrogen are discussed, including thermal aspects and duty cycle of the pump

Olea europea L. Leaves and Hibiscus sabdariffa L. Petals Extracts: Herbal Mix from Cardiovascular Network Target to Gut Motility Dysfunction Application

It is well known that diet and nutrition play a critical role in the etiopathogenesis of many disorders. On the other hand, nutrients or bioactive compounds can specifically target and control various aspects of the mechanism underlying the pathology itself, and, in this context, diseases related to intestinal motility disorders stand out. The Herbal Mix (HM) consisting of Olea europea L. leaf (OEE) and Hibiscus sabdariffa L. (HSE) extracts (13:2) has been proven to be a promising nutraceutical option for many diseases, but its potential in inflammatory-driven gastrointestinal disorders is still unexplored. In this study, HM effects on guinea-pig ileum and colon contractility (induced or spontaneous) and on human iNOS activity, as well as on human colorectal adenocarcinoma Caco-2 cells, were studied. Results showed that the HM can control the ileum and colon contractility without blocking the progression of the food bolus, can selectively inhibit iNOS and possesses a strong pro-apoptotic activity towards Caco-2 cells. In conclusion, the present results suggest that, in some diseases, such as those related to motility disorders, an appropriate nutritional approach can be accompanied by a correct use of nutraceuticals that could help not only in ameliorating the symptoms but also in preventing more severe, cancer-related conditions

Emergence of ceftazidime/avibactam resistance in KPC-8–producing Klebsiella pneumoniae in South America

Klebsiella pneumoniae is one of the so-called ESKAPE pathogens. These organisms are the main cause of nosocomial infections worldwide, causing life-threatening infections amongst critically ill and immunocompromised individuals. They are characterized by drug resistance mechanisms. Klebsiella pneumoniae carbapenemase (KPC)-producing isolates display resistance to multiple antimicrobial agents, usually including last-resort alternative options, leading to an urgent need to develop new drugs or combinations. In Argentina sequence type (ST) 258 harbouring bla KPC-2 emerged in 2010 and remained prevalent until the last few years, when the emergence of different STs such as ST25, ST11 and ST307 appeared likely to change the local epidemiology.Fil: García, J.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Nastro, Marcela. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cejas, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Instituto de Investigaciones En Bacteriologia y Virologia Molecular; ArgentinaFil: Santana, G.. No especifíca;Fil: Mancino, M.B.. No especifíca;Fil: Hidalgo, M.. No especifíca;Fil: Maccallini, G.. No especifíca;Fil: Vay, C.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Radice, Marcela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Instituto de Investigaciones En Bacteriologia y Virologia Molecular; ArgentinaFil: Dabos, L.. Université Paris Sud; FranciaFil: Famiglietti, Angela María Rosa. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Rodríguez, H.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentin

Chemical Bond and Charge Transfer Dynamics of a Dye-Hierarchical TiO2 Hybrid Interface

The adsorption of Zn-Tetra-Phenyl-Porphyrin (ZnTPP) on nanoporous hierarchically organized anatase TiO2 structures, and the properties of the corresponding hybrid interface were studied by synchrotron radiation experiments. The molecular structure, electronic properties and the bonding with nanostructured TiO2 surfaces were analyzed by photoemission (XPS and UPS) and x-ray absorption spectroscopy (XAS). The charge transfer at the interface was investigated by means of valence band resonant photoemission experiments (ResPES) at the C K edge. We show that the charge transfer dynamics between the photo-excited ZnTPP and TiO2 is strongly influenced by the presence of defects on the TiO2 surface. On a stoichiometric anatase nanostructure, ZnTPP bonding occurs primarily via carbon atoms belonging to the molecular phenyl rings and this creates a preferential channel for the charge transfer. This phenomenon is reduced in the case of defective TiO2 surface, where ZnTPP interacts mainly through the molecule macrocycle. Our results represent a surface science study of the dye molecule behavior on a nanoporous TiO2 photoanode relevant to dye-sensitized or hybrid solar cell applications and it shows the importance of the surface oxidation state for the charge transfer proces

Clay-fulleropyrrolidine nanocomposites

In this work, we describe the insertion of a water-soluble bisadduct fulleropyrrolidine derivative into the interlayer space of three layered smectite clays. The composites were characterized by a combination of powder X-ray diffraction, transmission electron microscopy, X-ray photoemission and FTIR spectroscopies, and laser flash photolysis measurements. The experiments, complemented by computer simulations, give insight into the formation process, structural details, and properties of the fullerene/clay nanocomposites. The reported composite materials constitute a new hybrid system, where C-60 differs from its crystals or its solutions, and open new perspectives for the design and construction of novel C-60-based organic/clay hybrid materials.</p