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

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 immu...

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Published in:	Frontiers in pharmacology Vol. 11; p. 590544
Main Authors:	Silva, Dahara Keyse Carvalho, Teixeira, Jessicada Silva, Moreira, Diogo Rodrigo Magalhães, da Silva, Tiago Fernandes, Barreiro, Eliezer Jesus de Lacerda, de Freitas, Humberto Fonseca, Pita, Samuel Silva da Rocha, Teles, André Lacerda Braga, Guimarães, Elisalva Teixeira, Soares, Milena Botelho Pereira
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 16-12-2020
Subjects:	LASSBio-1386 Leishmania amazonensis N-acyl hydrazones Pharmacology phosphodiesterase treatment treatment phosphodiesterase Leishmania amazonensis N-acyl hydrazones LASSBio-1386
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Summary:	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 -acylhydrazone derivative. Here we investigated the and activity of LASSBio-1386 against . LASSBio-1386 inhibited the proliferation of promastigotes of (EC = 2.4 ± 0.48 µM), while presenting low cytotoxicity to macrophages (CC = 74.1 ± 2.9 µM). incubation with LASSBio-1386 reduced the percentage of -infected macrophages and the number of intracellular parasites (EC = 9.42 ± 0.64 µM). Also, treatment of BALB/c mice infected with 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 . Aiming to its possible molecular interactions, we performed docking and molecular dynamics studies on phosphodiesterase B1 (PDB code: 2R8Q) and LASSBio-1386. The computational analyses suggest that LASSBio-1386 acts against 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.
Bibliography:	Edited by: Salvatore Salomone, University of Catania, Italy Reviewed by: Fernanda Tomiotto-Pellissier, Carlos Chagas Institute (ICC), Brazil Danilo Ciccone Miguel, Campinas State University, Brazil This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology
ISSN:	1663-9812 1663-9812
DOI:	10.3389/fphar.2020.590544