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

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