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Sustainable Development Goals
03 Saúde e Bem-EstarCollections
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IN VITRO, IN VIVO AND IN SILICO EFFECTIVENESS OF LASSBIO-1386, AN N-ACYL HYDRAZONE DERIVATIVE PHOSPHODIESTERASE-4 INHIBITOR, AGAINST LEISHMANIA AMAZONENSIS
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Abstract
Leishmaniasis are group of neglected diseases with worldwide distribution that affect
about 12 million people. The current treatment is limited and may cause severe adverse
effects, and thus, the search for new drugs more effective and less toxic is relevant. We
have previously investigated the immunomodulatory effects of LASSBio-1386, an
N-acylhydrazone derivative. Here we investigated the in vitro and in vivo activity of
LASSBio-1386 against L. amazonensis. LASSBio-1386 inhibited the proliferation of
promastigotes of L. amazonensis (EC50 2.4 ± 0.48 μM), while presenting low
cytotoxicity to macrophages (CC50 74.1 ± 2.9 μM). In vitro incubation with LASSBio-
1386 reduced the percentage of Leishmania-infected macrophages and the number of
intracellular parasites (EC50 9.42 ± 0.64 μM). Also, in vivo treatment of BALB/c mice
infected with L. amazonensis resulted in a decrease of lesion size, parasitic load and
caused histopathological alterations, when compared to vehicle-treated control.
Moreover, LASSBio-1386 caused ultrastructural changes, arrested cell cycle in G0/G1
phase and did not alter the membrane mitochondrial potential of L. amazonensis. Aiming to
its possible molecular interactions, we performed docking and molecular dynamics studies
on Leishmania phosphodiesterase B1 (PDB code: 2R8Q) and LASSBio-1386. The
computational analyses suggest that LASSBio-1386 acts against Leishmania through
the modulation of leishmanial PDE activity. In conclusion, our results indicate that
LASSBio-1386 is a promising candidate for the development of new leishmaniasis
treatment.
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