Design, synthesis and biological evaluation of N-oxide derivatives with potent in vivo antileishmanial activity

Leishmaniasis is a neglected disease that affects 12 million people living mainly in developing countries. Herein, 24 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antileishmanial activity. Compound 4f, a furoxan derivative, was particularly r...

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Bibliographic Details
Published in:PloS one 2021-11, Vol.16 (11), p.e0259008-e0259008
Main Authors: Clementino, Leandro da Costa, Fernandes, Guilherme Felipe Santos, Prokopczyk, Igor Muccilo, Laurindo, Wilquer Castro, Toyama, Danyelle, Motta, Bruno Pereira, Baviera, Amanda Martins, Henrique-Silva, Flávio, Santos, Jean Leandro Dos, Graminha, Marcia A S
Format: Article
Language:English
Subjects:
Animals
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Biology and Life Sciences
Biomarkers - metabolism
Biotransformation
Carbon-13 Magnetic Resonance Spectroscopy
Chemistry
Chromatography
Cysteine
Cysteine proteinase
Developing countries
Drug Design
Enzymes
Health aspects
In vivo methods and tests
LDCs
Leishmania infantum - drug effects
Leishmaniasis
Ligands
Macrophages
Macrophages, Peritoneal - drug effects
Macrophages, Peritoneal - parasitology
Male
Medicine and Health Sciences
Mice
Molecular Docking Simulation
Nitric oxide
Nitric Oxide - analysis
Nitrites - analysis
NMR
Nuclear magnetic resonance
Oxadiazoles - chemical synthesis
Oxadiazoles - chemistry
Oxides - chemical synthesis
Oxides - chemistry
Oxides - pharmacology
Parasite Load
Parasites
Parasitic diseases
Peritoneum
Pharmaceutical sciences
Physical Sciences
Pichia - metabolism
Prevention
Properties
Proton Magnetic Resonance Spectroscopy
Protozoan Proteins - metabolism
Research and Analysis Methods
Spleen
Vector-borne diseases
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Summary:Leishmaniasis is a neglected disease that affects 12 million people living mainly in developing countries. Herein, 24 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antileishmanial activity. Compound 4f, a furoxan derivative, was particularly remarkable in this regard, with EC50 value of 3.6 μM against L. infantum amastigote forms and CC50 value superior to 500 μM against murine peritoneal macrophages. In vitro studies suggested that 4f may act by a dual effect, by releasing nitric oxide after biotransformation and by inhibiting cysteine protease CPB (IC50: 4.5 μM). In vivo studies using an acute model of infection showed that compound 4f at 7.7 mg/Kg reduced ~90% of parasite burden in the liver and spleen of L. infantum-infected BALB/c mice. Altogether, these outcomes highlight furoxan 4f as a promising compound for further evaluation as an antileishmanial agent.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0259008