Chagas disease (also known as American trypanosomiasis) is an NTD whose etiological agent is T. cruzi, a protozoan of the Trypanosomatidae family. It is a major public health concern worldwide, with 6 to 7 million people infected in endemic areas and 75 million at risk of infection. The main population affected has lower socioeconomic resources and less access to health care (Sanmartino et al., 2021). The current treatment is based on two drugs, Benznidazole and Nifurtimox, but their effectiveness changes according to the phase of the disease, being more effective in the acute phase compared to the chronic phase, besides having high toxicity (Aldasoro et al., 2018). In addition, resistance to the current treatment has been reported by some strains of T. cruzi (Campos, Leon, Taylor, & Kelly, 2014; Mejia et al., 2012).

One of the great challenges in the fight against Chagas is the study and discovery of new drugs that are more selective for the parasite and less toxic to the infected individual (Martín-Escolano, Medina-Carmona, & Martín-Escolano, 2020). Different classes of compounds have been investigated as promising for Chagas disease. Thiazoles, thio, and semicarbazone derivatives are privileged structures extensively studied concerning antiparasitic activity (Álvarez et al., 2017, 2014; Perdomo et al., 2021; Scarim et al., 2018). Thiosemicarbazone derivatives have been the subject of biological studies, including those on antiviral, anti-inflammatory, antiprotozoal, and antitumor properties (De Moraes Gomes et al., 2016; Espíndola et al., 2015; Gupta, Singh, Sonar, & Saraf, 2016; Kobylinska et al., 2016; Moreira et al., 2012). These molecules have been shown to be particularly active against several species, such as Leishmania spp. and T. cruzi, making this class of compounds potential chemotherapeutic agents to combat diseases caused by these parasites, such as Chagas disease.

Moreover, advances in in silico methods (Scarim et al., 2018) made it possible to study the parasite, find important targets, and plan synthetic compounds that act on these selected targets. One of these strategies is the use of spacers between the phenyl ring and the thiosemicarbazone portion. It was observed that this method improved the trypanocide activity of the compounds. Another strategy is cyclic bioisosterism between thiosemicarbazones and thiazoles (Scheme 1). In addition, molecular docking has been an ally to biological assays, reducing the time and cost of developing new drugs that are more specific and induce fewer adverse effects. This method allows predictions of targets, toxicity, pharmacokinetic, and pharmacodynamic characteristics, among others (Pinzi & Rastelli, 2019).

Additionally, treatment efficacy is a keystone during drug development and is highly associated with the individual’s immune response. Therefore, it is nowadays of utmost importance that new compounds are screened and investigated for their additional capacity to modulate the immune system (Rao et al., 2019). However, so far, studies have been testing new compounds in a variety of strains with different levels of resistance to current treatment, aiming to better understand the behavior of these compounds and decrease failures as they advance through the study phases (de Figueiredo Diniz, Mazzeti, Caldas, Ribeiro, & Bahia, 2018).

The aim of this work was to design, synthesize, and characterize 13 new phenoxy-hydrazino-thiazol compounds with potential anti-T. cruzi activity. To investigate the mechanistic properties of these compounds, we took advantage of modern computational methods.