Novel 3-nitrotriazole-based amides and carbinols as bifunctional anti-Chagasic agents.

3-Nitro-1H-1,2,4-triazole-based amides with a linear, rigid core and 3-nitrotriazole-based fluconazole analogs were synthesized as dual functioning antitrypanosomal agents. Such compounds are excellent substrates for type I nitroreductase (NTR) located in the mitochondrion of trypanosomatids and, at the same time, act as inhibitors of the sterol 14α-demethylase (T. cruzi CYP51) enzyme. Because combination treatments against parasites are often superior to monotherapy, we believe that this emerging class of bifunctional compounds may introduce a new generation of antitrypanosomal drugs. In the present work, the synthesis and in vitro and in vivo evaluation of such compounds is discussed.This work was supported in part by internal funds of the Radiation Medicine Department at NorthShore University HealthSystem. Experiments on T. cruzi CYP51 were funded by NIH (GM067871, to G.I.L.). In vitro screenings against parasites were funded by DNDi. For that project, DNDi received funding from the following donors: Department for Internationl Development (DFID), U.K.; Bill & Melinda Gates Foundation (BMGF), USA; Reconstruction Credit Institution-Federal Ministry of Education and Research (KfW-BMBF), Germany; and Directorate-General for International Cooperation (DGIS), The Netherlands. B.A.-V. acknowledges financial support by FONDECYT Postdoctorado 3130364

Identification of the transition state for fast reactions: The trapping of hydroxyl and methyl radicals by DMPO - A DFT approach

Up to date, attempts to locate the transition state (TS) for the trapping reaction between ̇OH and ̇DMPO have been unsuccessful, and the lack of molecular mechanisms by which ̇OH binds to the spin-trap constitutes a question still unsolved. Herein, we have taken a step forward on this task by describing the theoretical TS for the trapping of ̇OH and ̇CH 3 by DMPO and the intrinsic reaction coordinates. This work aims to provide new understandings on the molecular orbital (MO) interactions that rule these reaction paths. Besides we assessed the degree of involvement of weak interactions and the charge transfer (CT) phenomenon involved in such interactions. Regarding the trapping of ̇OH, the beginning of the reaction would be ruled by weak interactions to then give way to stronger MO interactions conducive to the formation of the TS. For ̇CH3, the reaction is, instead, early ruled by significant MO interactions, and a relatively small contribution in the weak interactions range. At the

Key proteins in the polyamine-trypanothione pathway as drug targets against Trypanosoma cruzi

In trypanosomatids, redox homeostasis is centered on trypanothione (N 1,N8-bis(glutathionyl)spermidine, T(SH)2), a low molecular weight thiol that is distinctive for this taxonomic family and not present in the mammalian host. Thus, the study of the metabolism of T(SH)2 is interesting as a potential therapeutic target. In this review, we summarize the existing evidence about the metabolism of thiols in Trypanosoma cruzi, focused on those proteins that can be considered the best candidates for selective therapy. Herein, we examine the biosynthetic pathway of T(SH) 2, identifying three key points that are susceptible to attack pharmacologically: the activity of the trypanothione reductase (TR), the function of glutamate-cysteine ligase (GCL) and polyamine transport in T. cruzi. TR has been widely studied and is a good example for the development of the medicinal chemistry of antichagasic compounds. Conversely, GCL and the polyamine uptake system are high flow points in the reductive met

Electrochemical, ESR and theoretical insights into the free radical generation by 1,1'-hydrocarbylenebisindazoles and its evaluation as potential bio-active compounds

A comprehensive multidisciplinary study is conducted here in order to assess the electrochemical behavior of a series of 1,1'-hydrocarbylenebisindazoles derivatives and its potential use as anti-T.cruzi drugs. At first, we have determined the electrochemical reduction mechanisms of this family by cyclic voltammetry (CV) studies, from which three kind of reduction mechanisms -depending on the substituent at positions 3 and 3'- were established, but sharing a first common step corresponding to the generation of a nitro anion radical, which was corroborated by ESR spectroscopy, showing a comparable hyperfine splitting pattern and a strong influence on the ESR spectral linewidths due to the radical-solvent interactions. Furthermore, in order to give a rational description about the electrochemical and ESR results, open- and closed-shell structures of bisindasoles were subjected to theoretical estimations at different levels of theory. For open-shell structures, the hyperfine splitting patterns were confirmed while for the closed-shell systems case, clear evidence about the electrochemical reactivity -in terms of their frontiers orbitals- were obtained. To conclude, all these compounds were assayed as growth inhibitors against T.cruzi, from which some degree of activity was observed for this family, highlighting a compound almost as active as the reference drug. Finally, in order to get some information about the potential action mechanisms involved in the trypanocidal activity, molecular modeling and spin trapping studies were also done © 2012 by ESG.Peer Reviewe

Electrochemical, ESR and theoretical insights into the free radical generation by 1,1'-hydrocarbylenebisindazoles and its evaluation as potential bio-active compounds

A comprehensive multidisciplinary study is conducted here in order to assess the electrochemical behavior of a series of 1,1'-hydrocarbylenebisindazoles derivatives and its potential use as anti-T.cruzi drugs. At first, we have determined the electrochemical reduction mechanisms of this family by cyclic voltammetry (CV) studies, from which three kind of reduction mechanisms -depending on the substituent at positions 3 and 3'- were established, but sharing a first common step corresponding to the generation of a nitro anion radical, which was corroborated by ESR spectroscopy, showing a comparable hyperfine splitting pattern and a strong influence on the ESR spectral linewidths due to the radical-solvent interactions. Furthermore, in order to give a rational description about the electrochemical and ESR results, open- and closed-shell structures of bisindasoles were subjected to theoretical estimations at different levels of theory. For open-shell structures, the hyperfine splitting pat

Synthesis and Biological in vitro and in vivo Evaluation of 2-(5-Nitroindazol-1-yl)ethylamines and Related Compounds as Potential Therapeutic Alternatives for Chagas Disease

© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chagas disease, a neglected tropical disease caused by infection with the protozoan parasite Trypanosoma cruzi, is a potentially life-threatening illness that affects 5–8 million people in Latin America, and more than 10 million people worldwide. It is characterized by an acute phase, which is partly resolved by the immune system, but then develops as a chronic disease without an effective treatment. There is an urgent need for new antiprotozoal agents, as the current standard therapeutic options based on benznidazole and nifurtimox are characterized by limited efficacy, toxicity, and frequent failures in treatment. In vitro and in vivo assays were used to identify some new low-cost 5-nitroindazoles as a potential antichagasic therapeutic alternative. Compound 16 (3-benzyloxy-5-nitro-1-vinyl-1H-indazole) showed improved efficiency and lower toxicity than benznidazole in both in vitro and in vivo experiments, and its trypanocidal activi

Evaluation of the novel antichagasic activity of [1,2,3]triazolo[1,5-a]triazolo[1,5-apyridine derivatives

© 2017 Bentham Science Publishers. Trypanosoma cruzi is the causative agent of Chagas disease. This parasite is vulnerable to the effects of ROS as its main defense mechanism against exogenous agents trypanothione is also another weakness of the parasite that investigated related to the inhibition of enzymes belonging P450 system, mainly CYP51. In our group we have synthesized a series of triazoles known as [1,2,3]triazolo[1,5-a]pyridyl ketones, and pyridyl ketones. These families have shown interesting structural features due to the presence of electron withdrawing moieties attached to the main heterocycle (triazoles and/or pyridines) and are proposed as potential target in the parasite, by the presence of the carbonyl group being able to be reduced and form a free radical that could interact with molecular oxygen generating ROS in the parasite. Furthermore, the triazole ring and pyridines have been considered as potent inhibitors of sterol biosynthesis, the lock being part CYP51. Ou

In vitro assessment of 3-alkoxy-5-nitroindazole-derived ethylamines and related compounds as potential antileishmanial drugs

Leishmaniasis is a widespread neglected tropical disease complex that is responsible of one million new cases per year. Current treatments are outdated and pose many problems that new drugs need to overcome. With the goal of developing new, safe, and affordable drugs, we have studied the in vitro activity of 12 different 5-nitroindazole derivatives that showed previous activity against different strains of Trypanosoma cruzi in a previous work. T. cruzi belongs to the same family as Leishmania spp., and treatments for the disease it produces also needs renewal. Among the derivatives tested, compounds 1, 2, 9, 10, 11, and 12 showed low J774.2 macrophage toxicity, while their effect against both intracellular and extracellular forms of the studied parasites was higher than the ones found for the reference drug Meglumine Antimoniate (Glucantime®). In addition, their Fe-SOD inhibitory effect, the infection rates, metabolite alteration, and mitochondrial membrane potential of the parasites treated with the selected drugs were studied in order to gain insights into the action mechanism, and the results of these tests were more promising than those found with glucantime, as the leishmanicidal effect of these new drug candidates was higher. The promising results are encouraging to test these derivatives in more complex studies, such as in vivo studies and other experiments that could find out the exact mechanism of action.Authors appreciate the financial support from the Spanish Ministry of Science, Innovation and Universities (projects SAF2015-66690-R and RTI2018-093940-B-I00) and Spanish Ministry of Education and Science (project CSD 2010-00065). R.M.E. is grateful for a FPU grant [FPU14/01537] from the Ministry of Education of Spain and B.A.V. is grateful for an initiation into research grant from FONDECYT 11150559Peer Reviewe

Biological and chemical study of fused tri- and tetracyclic indazoles and analogues with important antiparasitic activity

A series of fused tri- and tetracyclic indazoles and analogues compounds (NID) with potential antiparasitic effects were studied using voltamperometric and spectroscopic techniques. Nitroanion radicals generated by cyclic voltammetry were characterized by electron spin resonance spectroscopy (ESR) and their spectral lines were explained and analyzed using simulated spectra. In addition, we examined the interaction between radical species generated from nitroindazole derivatives and glutathione (GSH). Biological assays such as activity against Trypanosoma cruzi and cytotoxicity against macrophages were carried out. Finally, spin trapping and molecular modeling studies were also done in order to elucidate the potentials action mechanisms involved in the trypanocidal activity. © 2012 Elsevier B.V. All rights reserved