This disease has two consecutive clinical phases: acute phase, in which the selleckbio parasite dissemination can be seen directly on examination of blood. After few weeks, the parasitism burden is controlled by host immune response and the disease moves to the chronic stage. Most of the infected individuals do not present recognizable pathological markers, however, after a long period (about 10�C30 years) of clinical latency called the indeterminate form, some of them show disease manifestations, mainly associated with cardiac and/or digestive disturbances [1], [2]. Benzinidazole (Bz) and Nifurtimox (NF), introduced into clinical therapy about 40 years ago, cause many side effects, besides displaying limited efficacy, especially in later chronic phase [2], [3].

Also, several reports have demonstrated that some strains are refractory to treatment [4], [5]. Presently, posaconazole, a new anti-fungal agent that has been effective against T.cruzi in vitro and in vivo assays, has moved to clinical trials, however, even if effective, its use may be limited due to its high costs [6], [7]. Aromatic amidines (AD) are DNA minor groove binders that recognize enriched AT sequences [8]. In addition to showing high anti-parasitic activity against fungi, amoeba, bacteria and especially protozoan parasites, some of these cationic compounds, such as pentamidine have been used to treat neglected diseases such as African trypanosomiasis and leishmaniasis. Despite having unfavorable characteristics like poor oral solubility and undesirable side effects [9], the broad activity of these compounds has stimulated further screening of new analogs and prodrugs [6].

One class of analogues that have different physiochemical properties are the arylimidamides (AIAs) which have showed high efficacy in vitro and in vivo against T.cruzi [10]�C[14]. Studies in vivo with the AIA DB766 demonstrated a reduction in the parasite load levels in the blood and cardiac tissue with similar trypanocidal activity as that of Bz in a mouse model of acute T.cruzi infection using both Y and Colombian strains [11], [15]. This AIA lead to the recovery of electrocardiographic alterations in addition to reducing hepatic and heart lesions induced by the parasite infection [11].

The excellent activity of DB766 motivated the design and synthesis of novel structurally related compounds including the AIA, DB1831 (hydrochloride salt) and its mesylate salt form (DB1965) for which in Carfilzomib vitro and in vivo studies are reported here with the goal of identifying novel anti-T. cruzi candidates for possible future alternative therapies for Chagas disease. Materials and Methods Compounds The synthesis of DB1831 and DB1965: (Figure 1) was performed as reported for other analogues ([10], [16] – and will be reported elsewhere).