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Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.

Malaria is still one of the most prevalent parasitic infections in the world, with half of the world's population at risk for malaria. The effectiveness of current antimalarial therapies, even that of the most recent class of antimalarial drugs (artemisinin-combination therapies, ACTs), is under continuous threat by the spread of resistant Plasmodium strains. As a consequence, there is still an urgent requirement for new antimalarial drugs. We previously reported the identification of 4(1 H)-pyridones as a novel series with potent antimalarial activities. The low solubility was identified as an issue to address. In this paper, we describe the synthesis and biological evaluation of 4(1 H)-pyridones with potent antimalarial activities in vitro and in vivo and improved pharmacokinetic profiles. Their main structural novelties are the presence of polar moieties, such as hydroxyl groups, and the replacement of the lipophilic phenyl rings with pyridines on their lipophilic side chains.

Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.

Antiparasitic oral drugs have been associated to lipophilic molecules due to their intrinsic permeability. However, these kind of molecules are associated to numerous adverse effects, which have been extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and simple hits that even presenting antiplasmodial activities in the range of 0.4-0.5 μM are able to show in vivo activity.

Alkylation reactions of the benzyllithiums derived from enantiomerically pure 2-p-tolylsulfinyl alkylbenzenes have been carried out with excellent yields and high de. A lithiation-substitution sequence, stereochemically controlled by a remote sulfoxide, accounts for the experimental results.

Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.

Chronic administration of isoproterenol (IPR) results in a marked hypertrophy and in the induction of a group of putative proline-rich polypeptides in the mouse parotid glands. Some of these polypeptides (pps C-G) have been considered as molecular markers of the parotid gland enlargement. Given the secretory character of polypeptides C-G, the polypeptide composition of mouse saliva was used to monitor the IPR-induced salivary gland hypertrophy. Whole saliva was collected after an oral administration of pilocarpine (PIL). Under those conditions, PIL provoked a massive salivary secretion both in normal control mice and during the whole course of the IPR-induced gland enlargement. Striking changes in the polypeptide composition of saliva obtained from chronically IPR-stimulated animals were observed. Those changes consisted basically in the appearance and progressive increase in concentration of parotid polypeptides C-G and in the progressive diminution in concentration of a couple of normal salivary polypeptides (polypeptides A-B). The appearance of new polypeptides in saliva could be established unequivocally within the 24 h following the trophic adrenergic stimulation. On the other hand, salivary polypeptides induced in response to a single administration of IPR could be demonstrated as late as 7-9 days after the stimulation. Accordingly, detection of parotid polypeptides C-G in PIL-produced saliva obtained from IPR-stimulated mice has proved to be a highly advantageous method to evaluate salivary gland hypertrophy both at very early stages after the trophic stimulation and late after the occurrence of the trophic episode.

Mouse salivary secretion provoked by single or multiple oral administrations of the cholinergic agent pilocarpine was characterized. An accessory ad hoc device, manipulated by a single operator, was used to collect saliva from various mice simultaneously. A single challenge by pilocarpine in the range 40-400 µg provoked a dose-dependent secretory response. The secretory response lasted for about 40 minutes and was constituted by four clearly defined stages, namely: lag (5-10 min), maximal flow (10 min), slowering (15-20 min) and postsecretory rest. In this response, usual parameters were: maximal flow rate, 30-40 µl/min; total volume of saliva, 250-350 µl/mouse and total salivary protein, about 700 µg/mouse. Temporal desensitization of the secretory response was observed within the first hour following a single stimulation by pilocarpine. However, recurrent stimulations by this agonist given at 24-h intervals produced an equally intense secretory response, thus suggesting resensitization during that period. The polypeptide composition of salivas obtained from a number of mice after a first pilocarpine stimulation were undistinguishable from each other. That salivary polypeptide pattern was also observed in a series of salivas obtained day by day from single animals stimulated at 24-h intervals by the agonist. Thus, both the characteristics of the secretory response as well as the polypeptide composition of mouse saliva after short-term or long-term challenges by pilocarpine were found to be highly consistent. Accordingly, these studies open the possibility of accomplishing a systematic molecular typing of saliva from individual living mice either from natural populations or from mice subjected to experimental laboratory conditions Se caracterizó la secreción salival murina producida por administraciones orales únicas o múltiples del agente colinérgico pilocarpina. La saliva fue colectada desde varios ratones a la vez mediante un accesorio diseñado para tal fin y manipulado por un solo operador. Una simple estimulación mediante una dosis del agonista en el rango 40-400 µg provocó una respuesta secretoria dependiente de la dosis. La respuesta secretoria duró alrededor de 40 min y en ella se pudo definir cuatro etapas, a saber: lag (5-10 min), flujo máximo (10 min), enlentecimiento (15-20 min) y reposo post-secretorio. En la respuesta, los parámetros usuales fueron: velocidad de flujo máxima, 30-40 µl/min; volumen total de saliva, 250-350 µl/ratón y proteína salival total, alrededor de 700 µg/ratón. Se observó desensibilización temporal de la respuesta secretoria durante la primera hora siguiente a una estimulación simple por pilocarpina. Sin embargo, estimulaciones sucesivas a intervalos de 24 h con este agonista produjeron una respuesta secretoria igualmente intensa, lo que sugirió resensibilización en tales intervalos. La composición polipeptídica de cada una de las salivas obtenidas a partir de una serie de ratones estimulados por una vez con pilocarpina fueron indistinguibles entre sí. Tal patrón polipeptídico salival también fue observado en series de salivas obtenidas dia a dia a partir de ratones únicos estimulados con pilocarpina a intervalos de 24 h. De esta manera, tanto las características de la respuesta secretoria como la composición polipeptídica de la saliva murina obtenida mediante estimulaciones únicas o múltiples con pilocarpina resultaron altamente consistentes. Así, estos estudios abren la posibilidad de emprender una tipificación molecular sistemática de la saliva de ratones individuales vivos obtenidos ya sea de poblaciones naturales o de aquellos sometidos a condiciones experimentales de laboratorio

In this work, we present a new method for measuring the pressure and the temperature of a supersonic airflow. These quantities are necessary to evaluate mathematical models applied to the study of shock waves. By means of a microphone and a thermocouple we measure these quantities through perturbations produced inside the flow by shock waves. We applied Fourier transform and several statistic methods in order to analyze and evaluate the signals obtained.

In the airways, very complex flows occur because of different conditions and the existence of a lot of complications: constantly changing temperature and pressure during the respiration process, a normally turbulent flow in the trachea which, in heavy breathing, remains so in the first three or four generations of airways, changes of the direction of the flow over the breathing cycle, from inspiration to expiration, etc. We also know the air that flows in the bronchial tree is perturbed by several sources such as the heart and the circulatory system, the diaphragm and stomach movements, etc., which produce sound waves. Thus an acoustical analysis of the phenomenon can lead us to a physical model which could help us to better understand the phenomena and to demonstrate the importance to clinical applications such as the pneumocardiograms. To this purpose we use a thermodynamical model that originally was developed to analyze supersonic air jets to explain the production of shock waves in the bronchial tree.