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Synthesis, Biological Activity, and Mechanism of Action of 2‐Pyrazyl and Pyridylhydrazone Derivatives, New Classes of Antileishmanial Agents
Author(s) -
Coimbra Elaine S.,
Antinarelli Luciana M. R.,
de A. Crispi Mariana,
Nogueira Thais C. M.,
Pinheiro Alessandra C.,
de Souza Marcus V. N.
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800328
Subject(s) - amastigote , chemistry , mechanism of action , stereochemistry , biological activity , mode of action , pyrazine , leishmania , biochemistry , in vitro , parasite hosting , world wide web , computer science
In this work, we report the antileishmanial activity of 23 compounds based on 2‐pyrazyl and 2‐pyridylhydrazone derivatives. The compounds were tested against the promastigotes of Leishmania amazonensis and L. braziliensis , murine macrophages, and intracellular L. amazonensis amastigotes. The most potent antileishmanial compound was selected for investigation into its mechanism of action. Among the evaluated compounds, five derivatives [( E )‐3‐((2‐(pyridin‐2‐yl)hydrazono)methyl)benzene‐1,2‐diol ( 2 b ), ( E )‐4‐((2‐(pyridin‐2‐yl)hydrazono)methyl)benzene‐1,3‐diol ( 2 c ), ( E )‐4‐nitro‐2‐((2‐(pyrazin‐2‐yl)hydrazono)methyl)phenol ( 2 s ), ( E )‐2‐(2‐(pyridin‐2‐ylmethylene)hydrazinyl)pyrazine ( 2 u ), and ( E )‐2‐(2‐((5‐nitrofuran‐2‐yl)methylene)hydrazinyl)pyrazine ( 2 v )] exhibited significant activity against L. amazonensis amastigote forms, with IC 50 values below 20 μ m . The majority of the compounds did not show any toxic effect on murine macrophages. Preliminary studies on the mode of action of members of this hydrazine‐derived series indicate that the accumulation of reactive oxygen species (ROS) and disruption of parasite mitochondrial function are important for the pharmacological effect on L. amazonensis promastigotes.