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Este libro reune escritos que vinculan la antropologia cristiana con las ciencias de la salud mental para un reenfoque en clave humanista del estudio de la psique humana. Estas paginas quieren promover un debate academico vivo entre profesionales cristianos de multiples confesiones y, al mismo tiempo, crear un espacio de encuentro entre la reflexion antropologica y las aportaciones de las disciplinas de salud mental. Ademas, en los ensayos aqui presentados, hay una apuesta por superar el efecto reduccionista de los modelos imperantes en las ciencias de la salud mental que, con frecuencia, dejan fuera cualquier alusion a lo trascendente.

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.

Microbial resistance to chemotherapy has caused countless deaths where malaria is endemic. Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in pfatp4, cytochrome bc1, pfcarl, pfdhod, pfcrt, pfmdr, pfdhfr, cytoplasmic prolyl t-RNA synthetase or hsp90. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 in vitro selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance., It is unclear whether new antimalarial compounds may rapidly lose effectiveness in the field because of parasite resistance. Here, Corey et al. investigate the acquisition of drug resistance and the extent to which common resistance mechanisms decrease susceptibility to a diverse set of 50 antimalarial compounds.

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.

From the 13 533 chemical structures published by GlaxoSmithKline in 2010, we identified 47 quality starting points for lead optimization. One of the most promising hits was the TCMDC-139046, a molecule presenting an indoline core, which is well-known for its anxiolytic properties by interacting with serotonin antagonist receptors 5-HT2. The inhibition of this target will complicate the clinical development of these compounds as antimalarials. Herein, we present the antimalarial profile of this series and our efforts to avoid interaction with this receptor, while maintaining a good antiparasitic potency. By using a double-divergent structure-activity relationship analysis, we have obtained a novel lead compound harboring an indoline core.

Malaria is a global health problem that causes significant mortality and morbidity, with more than 1 million deaths per year caused by P. falciparum. Most antimalarial drugs face decreased efficacy due to the emergence of resistant parasites. Therefore, the efforts to improve current treatments are focused on the identification of new antimalarial drugs displaying novel mechanisms of action. To increase the probability of success to identify compounds active against all relevant parasite drug targets, phenotypic assays have been used to screen large compound libraries against P. falciparum blood stages. At GSK, 2M compounds were screened and 13500 confirmed hits (TCAMS-Tres Cantos Antimalarial Set) were selected which inhibited P. falciparum growth with IC50s below 2 μM. In order to select chemotypes with a presumptive novel mechanism of action, an early profiling is carried out which involves several phases: 1. In the first phase, compounds are tested against a wide panel of P. falciparum strains with well characterized genetic linkage to drug resistance to establish which series had no cross-resistance with already known antimalarial compounds. Panel includes laboratory strains as well as clinical isolates. 2. In a second phase, compounds are tested using functional assays to identify those molecules interfering with parasite pathways that are targets of already known antimalarials (electron transport, folate and isoprenoid). Both mitochondrial electron transport and pyrimidine biosynthesis inhibitors are identified using transgenic parasites overexpressing Saccharomyces cerevisiae DHODH. Addition of proguanil to cultures restores cytochrome bc1 blockage but not DHODH inhibition. Antifolates are identified by supplementing the growth medium with folic acid and, similarly, inhibitors of the isoprenoid biosynthesis pathway by adding geranyl geranyol or isopentenyl pyrophosphate, which shifts the IC50 of inhibitors of these pathways. 3. Finally compounds are subjected to hematin polymerization assays to establish the interference with this essential pharmacological target of malaria parasites. New scaffolds with novel modes of action can be selected using these approaches avoiding the interference with pathways which are known to develop resistance. This strategy has already been succesful and our current antimalarial pipeline is based on scaffolds displaying new mechanisms of action. Chemoproteomics and chemical genomics efforts are being used to decipher new MoA.