AUTHOR=Silva Dahara Keyse Carvalho , Teixeira Jessicada Silva , Moreira Diogo Rodrigo Magalhães , da Silva Tiago Fernandes , Barreiro Eliezer Jesus de Lacerda , Freitas Humberto Fonseca de , Pita Samuel Silva da Rocha , Teles André Lacerda Braga , Guimarães Elisalva Teixeira , Soares Milena Botelho Pereira 

TITLE=In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.590544

DOI=10.3389/fphar.2020.590544

ISSN=1663-9812

ABSTRACT=<p>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 <italic>N</italic>-acylhydrazone derivative. Here we investigated the <italic>in vitro</italic> and <italic>in vivo</italic> activity of LASSBio-1386 against <italic>L. amazonensis</italic>. LASSBio-1386 inhibited the proliferation of promastigotes of <italic>L. amazonensis</italic> (EC<sub>50</sub> = 2.4 ± 0.48 µM), while presenting low cytotoxicity to macrophages (CC<sub>50</sub> = 74.1 ± 2.9 µM). <italic>In vitro</italic> incubation with LASSBio-1386 reduced the percentage of <italic>Leishmania</italic>-infected macrophages and the number of intracellular parasites (EC<sub>50</sub> = 9.42 ± 0.64 µM). Also, <italic>in vivo</italic> treatment of BALB/c mice infected with <italic>L. amazonensis</italic> 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 <italic>L. amazonensis</italic>. Aiming to its possible molecular interactions, we performed docking and molecular dynamics studies on <italic>Leishmania</italic> phosphodiesterase B1 (PDB code: 2R8Q) and LASSBio-1386. The computational analyses suggest that LASSBio-1386 acts against <italic>Leishmania</italic> 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.</p>