AUTHOR=Baldissera Fernanda Giesel , Fazolo Tiago , da Silva Matheus Brasil , de Santana Filho Paulo Cesar , da Silva Vinícius Demétrio , Rivillo Perez David Max , Klitzke Joice Sandra , de Oliveira Soares Eduardo Giovanni , Rodrigues Júnior Luiz Carlos , Peres Alessandra , Dallegrave Eliane , Navegantes-Lima Kely Campos , Monteiro Marta Chagas , Schrekker Henri Stephan , Torres Romão Pedro Roosevelt 

TITLE=Imidazolium salts as an alternative for anti-Leishmania drugs: Oxidative and immunomodulatory activities

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1096312

DOI=10.3389/fimmu.2022.1096312

ISSN=1664-3224

ABSTRACT=<p>In this study we explored the previously established leishmanicidal activity of a complementary set of 24 imidazolium salts (IS), 1-hexadecylimidazole (C<sub>16</sub>Im) and 1-hexadecylpyridinium chloride (C<sub>16</sub>PyrCl) against <italic>Leishmania (Leishmania) amazonensis</italic> and <italic>Leishmania (Leishmania) infantum chagasi</italic>. Promastigotes of <italic>L. amazonensis</italic> and <italic>L. infantum chagasi</italic> were incubated with 0.1 to 100 μM of the compounds and eight of them demonstrated leishmanicidal activity after 48 h – C<sub>10</sub>MImMeS (IC<sub>50</sub><italic><sub>L. amazonensis</sub></italic> = 11.6), C<sub>16</sub>MImPF<sub>6</sub>(IC<sub>50</sub><italic><sub>L. amazonensis</sub></italic> = 6.9), C<sub>16</sub>MImBr (IC<sub>50</sub><italic><sub>L. amazonensis</sub></italic> = 6), C<sub>16</sub>M<sub>2</sub>ImCl (IC<sub>50</sub><italic><sub>L. amazonensis</sub></italic> = 4.1), C<sub>16</sub>M<sub>4</sub>ImCl (IC<sub>50</sub><italic><sub>L. amazonensis</sub></italic> = 1.8), (C<sub>10</sub>)<sub>2</sub>MImCl (IC<sub>50</sub><italic><sub>L. amazonensis</sub></italic> = 1.9), C<sub>16</sub>Im (IC<sub>50</sub><italic><sub>L. amazonensis</sub></italic> = 14.6), and C<sub>16</sub>PyrCl (IC<sub>50</sub><italic><sub>L. amazonensis</sub></italic> = 4).The effect of IS on reactive oxygen species production, mitochondrial membrane potential, membrane integrity and morphological alterations of promastigotes was determined, as well as on <italic>L. amazonensis</italic>-infected macrophages. Their cytotoxicity against macrophages and human erythrocytes was also evaluated. The IS C<sub>10</sub>MImMeS, C<sub>16</sub>MImPF<sub>6</sub>, C<sub>16</sub>MImBr, C<sub>16</sub>M<sub>2</sub>ImCl, C<sub>16</sub>M<sub>4</sub>ImCl and (C<sub>10</sub>)<sub>2</sub>MImCl, and the compounds C<sub>16</sub>Im and C<sub>16</sub>PyrCl killed and inhibited the growth of promastigote forms of <italic>L. amazonensis</italic> and <italic>L. infantum chagasi</italic> in a concentration-dependent manner, contributing to a better understanding of the structure-activity relationship of IS against <italic>Leishmania</italic>. These IS induced ROS production, mitochondrial dysfunction, membrane disruption and morphological alterations in infective forms of <italic>L. amazonensis</italic> and killed intracellular amastigote forms in very low concentrations (IC<sub>50 amastigotes</sub> ≤ 0.3), being potential drug candidates against <italic>L. amazonensis</italic>.</p>