Búsqueda y optimización de potenciales alternativas terapéuticas para el tratamiento de la enfermedad de chagas

La enfermedad de Chagas, causada por Trypanosoma cruzi, es una parasitosis endémica en 21 países de América Latina, donde se transmite por las heces contaminadas de triatominos, provoca más de 7.000 muertes anuales y cerca de 25 millones de personas están en riesgo de contraer la infección. Clasificada por la OMS como una de las 17 enfermedades tropicales desatendidas, principalmente se extiende entre la población más desfavorecida de las zonas rurales. Sin embargo, vías de trasmisión alternativas como la transfusional o la congénita, y los movimientos migratorios, han hecho de ella una enfermedad emergente en países como EE.UU, Australia o España, afectando a más de 7 millones de personas en el mundo. La fase aguda aparece una semana tras la infección y posee baja mortalidad (<10%), asociada a fallo cardíaco y/o meningoencefalitis. En la mayoría de los casos es asintomática u oligosintomática y se resuelve espontáneamente. Tras 12 meses, la respuesta inmune controla parcialmente la infección y aunque no la erradica, el 6070% de los pacientes nunca la manifiesta (fase indeterminada). El 3040% restante entra en fase crónica durante los 1030 años posteriores, con afectación cardíaca y/o digestiva (megaesófago y megacolon). Después de más de un siglo desde su descubrimiento, no se dispone de fármacos adecuados para su tratamiento, basado en dos nitroderivados introducidos hace más de 40 años: benznidazol (BZ) y nifurtimox, recomendados para tratar los casos agudos y crónicos recientes, pero con actividad limitada en la fase crónica avanzada. Su controvertida eficacia, elevada toxicidad y la aparición de cepas de T. cruzi resistentes, afecta al éxito de estas terapias..

Imidazole derivatives as promising agents for the treatment of Chagas disease

More than 100 years later after being firstly described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, caused by the protozoan parasite Trypanosoma cruzi, is no longer just a problem for the American continent but has become a global health threat. Current therapies, nifurtimox and benznidazole (Bz), are far from being adequate due to undesirable effects and their lack of efficacy in the chronic phases of the disease. In this work, we present an in-depth phenotypical evaluation in T.cruzi of a new class of imidazole compounds, discovered in a previous phenotypic screening against different trypanosomatids and designed as potential inhibitors of cAMP phosphodiesterases (PDEs). The confirmation of several activities similar or superior to Bz prompted a synthesis program of hit optimization and extended SAR, aimed at improving drug-like properties such as aqueous solubility, resulting in additional hits with IC50 similar to Bz. The cellular effects of one representative hit, compound 9, on bloodstream trypomastigotes were further investigated. Transmission electron microscopy revealed cellular changes, after just 2 h of incubation with the IC50 concentration, that were consistent with induced autophagy and osmotic stress - mechanisms previously linked to cAMP signaling. Compound 9 induced highly significant increases in both cellular and medium cAMP, confirming that inhibition of T.cruzi PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against T.cruzi constitutes a successful repurposing of research into inhibitors of mammalian PDEs

Promising hit compounds against resistant trichomoniasis: Synthesis and antiparasitic activity of 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles

A series of 11 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles (2–12) has been prepared starting from 1-benzyl-5-nitroindazol-3-ol 13, and evaluated against sensitive and resistant isolates of the sexually transmitted protozoan Trichomonas vaginalis. Compounds 2, 3, 6, 9, 10 and 11 showed trichomonacidal profiles with IC50 < 20 µM against the metronidazole-sensitive isolate. Moreover, all these compounds submitted to cytotoxicity assays against mammalian cells exhibited low non-specific cytotoxic effects, except compounds 3 and 9 which displayed moderate cytotoxicity (CC50 = 74.7 and 59.1 µM, respectively). Those compounds with trichomonacidal effect were also evaluated against a metronidazole-resistant culture. Special mention deserve compounds 6 and 10, which displayed better IC50 values (1.3 and 0.5 µM respectively) than that of the reference drug (IC50 MTZ = 3.0 µM). The high activity of these compounds against the resistant isolate reinforces the absence of cross-resistance with the reference drug. The remarkable trichomonacidal results against resistant T. vaginalis isolates suggest the interest of 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles to be considered as good prototypes to continue in the development of new drugs with enhanced trichomonacidal activity, aiming to increase the non-existent drugs to face clinical resistance efficiently for those patients in whom therapy with 5-nitroimidazoles is contraindicated

Modelos tridimensionales para el aprendizaje práctico de la Inmunología

Depto. de Microbiología y ParasitologíaFac. de FarmaciaFALSEsubmitte

Thio- and selenosemicarbazones as antiprotozoal agents against Trypanosoma cruzi and Trichomonas vaginalis

Herein, we report the preparation of a panel of Schiff bases analogues as antiprotozoal agents by modification of the stereoelectronic effects of the substituents on N-1 and N-4 and the nature of the chalcogen atom (S, Se). These compounds were evaluated towards Trypanosoma cruzi and Trichomonas vaginalis. Thiosemicarbazide 31 showed the best trypanocidal profile (epimastigotes), similar to benznidazole (BZ): IC50 (31)=28.72 μM (CL-B5 strain) and 33.65 μM (Y strain), IC50 (BZ)=25.31 μM (CL-B5) and 22.73 μM (Y); it lacked toxicity over mammalian cells (CC50 > 256 µM). Thiosemicarbazones 49, 51 and 63 showed remarkable trichomonacidal effects (IC50 =16.39, 14.84 and 14.89 µM) and no unspecific cytotoxicity towards Vero cells (CC50 ≥ 275 µM). Selenoisosters 74 and 75 presented a slightly enhanced activity (IC50=11.10 and 11.02 µM, respectively). Hydrogenosome membrane potential and structural changes were analysed to get more insight into the trichomonacidal mechanism.Junta de Andalucía Grant PID2020- 116460RB-I00, funded by MCIN/AEI/10.13039/50110001103

B-learning en Helmintología: su aplicación al laboratorio virtual

Presentaciones animadas de esquemas morfológicos y ciclos biológico de los principales cestodos y nematodos parásitos del hombr

Further insights into biological evaluation of new anti-Trypanosoma cruzi 5-nitroindazoles

Twelve molecules from a series of 35 new 5-nitroindazole derivatives, selected from a successful primary screening on Trypanosoma cruzi epimastigotes, have been evaluated against intracellular amastigotes according to the previous results of their trypanocidal activity and unspecific cytotoxicity. 2-Benzyl-1-propyl (22), 2-benzyl-1-isopropyl (23), and 2-benzyl-1-butyl (24) 5-nitroindazolin-3-ones have inhibited the growth of amastigotes similarly to the reference drugs benznidazole and nifurtimox, inducing complete growth inhibition at concentrations lower than 8 μM (IC50 30). Further in vivo assays were developed only for two of the most active molecules (22 and 24), reaching significant reductions in parasitemia levels (52 % and 77 %, respectively) after their oral administration to infected mice. In addition, none of the mice in experimental and benznidazole groups died, unlike in the control group which is only treated with the vehicle. The trypanocidal properties found in some of the 5-nitroindazole derivatives assayed in the present work represent an interesting contribution to the urgent need for searching new antichagasic drugs. © 2014 Springer-Verlag Berlin Heidelberg.Peer Reviewe

In Vitro Primary Screening of a Synthetic Series of Chromenoazoldiones against Trypanosoma cruzi

Similarities between parasites and cancer have prompted parasitologists to take advantage of several approaches enabled by cancer research to identify antiparasitic agents [1]. [...