2 research outputs found
New L-proline uptake inhibitors with anti-Trypanosoma cruzi activity
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, including nutritional and osmotic as well as oxidative imbalance.
In this study, we explore the L-Proline uptake as a chemotherapeutic target for
T. cruzi. For this, we propose a novel rational to design inhibitors
containing this amino acid as a recognizable motif. This rational consists of
conjugating the amino acid (proline in this case) to a linker and a variable
region able to block the transporter. We obtained a series of sixteen 1,2,3-triazolyl-proline
derivatives through alkylation and copper(I)-catalyzed azide-alkyne cycloaddition
(click chemistry) for in vitro screening against T. cruzi epimastigotes,
trypanocidal activity and proline uptake. We successfully obtained inhibitors
that are able to interfere with the amino acid uptake, which validated the
first example of a rationally designed chemotherapeutic agent targeting a
metabolite\u27s transport. Additionally, we designed and prepared fluorescent
analogues of the inhibitors that were successfully taken up by T. cruzi, allowing following up their intracellular
fate. In conclusion, we successfully designed and produced a series of
metabolite uptake inhibitors. This is one of few examples of rationally designed
amino acid transporter inhibitor, being the first case where the strategy is
applied on the development of chemotherapy against Chagas disease. This
unprecedented development is remarkable having in mind that only a small
percent of the metabolite transporters has been studied at the structural
and/or molecular level
A minimalistic approach to develop new anti-apicomplexa polyamines analogs
The development of new chemical entities against the major diseases caused by parasites is highly desired. A library of thirty diamines analogs following a minimalist approach and supported by chemoinformatics tools have been prepared and evaluated against apicomplexan parasites. Different member of the series of N,N′-disubstituted aliphatic diamines shown in vitro activities at submicromolar concentrations and high levels of selectivity against Toxoplasma gondii and in chloroquine-sensitive and resistant-strains of Plasmodium falciparum. In order to demonstrate the importance of the secondary amines, ten N,N,N′,N′-tetrasubstituted aliphatic diamines derivatives were synthesized being considerably less active than their disubstituted counterpart. Theoretical studies were performed to establish the electronic factors that govern the activity of the compounds