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.