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

Abstract

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 activity seems to be related to its effect at the mitochondrial level. Therefore, compound 16 is a promising candidate for the development of a new anti-Chagas agent, and further preclinical evaluation should be considered.

Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

“…This fact has also been detected with other molecules belonging to these two families of 5-nitroindazole derivatives (Fonseca-Berzal et al ., 2016 a , 2018). This particular behaviour has not been observed in 5-nitroindazole derivatives that are substituted at the positions 1 and 3 of the heterocyclic ring, which show similar anti- T. cruzi profiles in vitro against the two clinically relevant forms of the parasite (Muro et al ., 2014; Martín-Escolano et al ., 2018), being this fact also appreciated in other 1,3-disubstituted 5-nitroindazoles previously studied by us (data not published). Otherwise, substitutions at the positions 1 and 3 of the 5-nitroindazole scaffold do not usually lead to such a remarkable IC 50 over amastigotes and thus, these derivatives are generally not as active as compounds 16 and 24 against intracellular T. cruzi forms (Muro et al ., 2014; Martín-Escolano et al ., 2018).…”

“…The reference drug was also given in suboptimal doses of 25 mg kg −1 , which correspond to 1/4 of the regimen standardized for this model of acute infection: BZ optimal doses of 100 mg kg −1 completely suppress the parasitaemia of T. cruzi Y-infected Swiss Webster mice, either with two unique administrations (de Araújo et al ., 2014; Timm et al ., 2014) or five consecutive daily doses (Fonseca-Berzal et al ., 2014; Timm et al ., 2014; da Silva et al ., 2017; Simões-Silva et al ., 2017, 2019). According to this, the administration of both derivatives and BZ in such a low dosage allows better comparison among the impact of these experimental treatments over T. cruzi infection (Martín-Escolano et al ., 2018). Indeed, trypanocidal effectiveness was not so relevant when 16 and 24 were given alone in two unique doses of 25 mg kg −1 , as happened with the reference drug (Figs 4 and 5).…”

Library of Selenocyanate and Diselenide Derivatives as In Vivo Antichagasic Compounds Targeting Trypanosoma cruzi Mitochondrion

“…Cultures were then centrifuged and filtered, and the metabolites of the supernatants were analyzed using a 1 H NMR spectrometer (VARIAN DIRECT DRIVE 500 MHz Bruker) with AutoX probe, D 2 O as solvent and 2,2-dimethyl-2-silapentane-5-sulphonate as the reference signal [ 61 ]. Chemical shifts were expressed in parts per million (ppm), and analyses were conducted as previously reported [ 62 ].…”

“…Non-stained parasites were also included. After elapsed time, epimastigotes were immediately processed and analyzed by flow cytometry as previously reported [ 62 ].…”

“…[61]. Chemical shifts were expressed in parts per million (ppm), and analyses were conducted as previously reported [62].…”