Abstract
L-Proline is an important amino acid for the pathogenic protists belonging to Trypanosoma and Leishmania genera. In Trypanosoma cruzi, the etiological agent of Chagas disease, this amino acid is involved in fundamental biological processes such as ATP production, differentiation of the insect and intracellular stages, the host cell infection and the resistance to a variety of stresses. In this study, we explore the L-Proline uptake as a chemotherapeutic target for T. cruzi. Novel inhibitors have been proposed containing the amino acid with a linker and a variable region able to block the transporter. A series of sixteen 1,2,3-triazolyl-proline derivatives have been prepared for in vitro screening against T. cruzi epimastigotes and proline uptake assays. We successfully obtained inhibitors that interfere with the amino acid internalization, which validated our design targeting the metabolite's transport. The presented structures are one of few examples of amino acid transporter inhibitors. The unprecedent application of this strategy on the development of new chemotherapy against Chagas disease, opens a new horizon on antiparasitic drug development against parasitic diseases and other pathologies.
Highlights
Chagas disease is one of the most neglected infectious disease
The synthesis started from commercial L-proline, preparing the key intermediate in two steps, including an esterification to produce the methyl prolinate 1 followed by an N-alkylation with propargyl bromide
Azides were prepared by direct substitution of bromide with sodium azide on DMF except for geranyl, farnesyl, and phytylazides, which were synthesized from geraniol, farnesol and phytol, respectively, using diphenylphosphorylazide (DPPA) following Thompson’s procedure (Thompson et al, 1993)
Summary
Chagas disease is one of the most neglected infectious disease It is endemic in the Americas, with 8–10 million people infected and 25 million people at risk (Nunes et al, 2013). The chronic phase has a non-evident parasitemia and a robust IgG response being asymptomatic in 60–70% of the cases (Pérez-Molina and Molina, 2018). The chemotherapy against Chagas disease relies mainly on two drugs introduced more than 40 years ago: Nifurtimox (Nf) and Benznidazole (Bz) (Urbina, 2010). Both drugs are efficient on the acute phase, but in the chronic phase is controversial (Morillo et al, 2015). Severe side effects due to toxicity and the emergence of resistance calls for urgent development of new drugs (Guedes et al, 2011)
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