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Type: Artigo
Title: N, N ', N ''-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity
Author: do Espirito Santo, Rafael Dias
Arenas Velasquez, Angela Maria
Gushiken Passianoto, Luana Vitorino
Lopera Sepulveda, Alex Arbey
Clementino, Leandro da Costa
Assis, Renata Pires
Baviera, Amanda Martins
Kalaba, Predrag
dos Santos, Fabio Neves
Eberlin, Marcos Nogueira
Jose da Silva, Gil Valdo
Zehl, Martin
Lubec, Gert
Silva Graminha, Marcia Aparecida
Perez Gonzalez, Eduardo Rene
Abstract: Leishmaniasis is a group of diseases caused by protozoan parasites from the genus Leishmania. There are estimated 1.3 million new cases annually with a mortality of 20,000-30,000 per year, when patients are left untreated. Current chemotherapeutic drugs available present high toxicity and low efficacy, the latter mainly due to the emergence of drug-resistant parasites, which makes discovery of novel, safe, and efficacious antileishmanial drugs mandatory. The present work reports the synthesis, characterization by ESI-MS, H-1 and C-13 NMR, and FTIR techniques as well as in vitro and in vivo evaluation of leishmanicidal activity of guanidines derivatives presenting lower toxicity. Among ten investigated compounds, all being guanidines containing a benzoyl, a benzyl, and a substituted phenyl moiety, LQOF-G2 (IC50-ama 5.6 mu M: SI = 131.8) and LQOF-G7 (IC50-ama 7.1 mu M; SI = 87.1) were the most active against L. amazonensis intracellular amastigote, showing low cytotoxicity to the host cells according to their selectivity index. The most promising compound, LQOF-G2, was further evaluated in an in vivo model and was able to decrease 60% of the parasite load in foot lesions at a dose of 0.25 mg/kg/day. Moreover, this guanidine derivative demonstrated reduced hepatotoxicity compared to other leishmanicidal compounds and did not show nephrotoxicity, as determined by the analyses of biomarkers of hepatic damage and renal function, which make this compound a potential new hit for therapy against leishmaniasis. (C) 2019 Elsevier Masson SAS. All rights reserved
Subject: Leishmania amazonensis
Country: França
Editor: Elsevier
Rights: Fechado
Identifier DOI: 10.1016/j.ejmech.2019.03.032
Date Issue: 2019
Appears in Collections:IQ - Artigos e Outros Documentos

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