Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi

Abstract

Chagas disease is a neglected tropical disease caused by the flagellated protozoan Trypanosoma cruzi. The current drugs used to treat this disease have limited efficacy and produce severe side effects. Quinolines, nitrogen heterocycle compounds that form complexes with heme, have a broad spectrum of antiprotozoal activity and are a promising class of new compounds for Chagas disease chemotherapy. In this study, we evaluated the activity of a series of 4-arylaminoquinoline-3-carbonitrile derivatives against all forms of Trypanosoma cruzi in vitro. Compound 1g showed promising activity against epimastigote forms when combined with hemin (IC50<1 μM), with better performance than benznidazole, the reference drug. This compound also inhibited the viability of trypomastigotes and intracellular amastigotes. The potency of 1g in combination with heme was enhanced against epimastigotes and trypomastigotes, suggesting a similar mechanism of action that occurs in Plasmodium spp. The addition of hemin to the culture medium increased trypanocidal activity of analog 1g without changing the cytotoxicity of the host cell, reaching an IC50 of 11.7 μM for trypomastigotes. The mechanism of action was demonstrated by the interaction of compound 1g with hemin in solution and prevention of heme peroxidation. Compound 1g and heme treatment induced alterations of the mitochondrion-kinetoplast complex in epimastigotes and trypomastigotes and also, accumulation of electron-dense deposits in amastigotes as visualized by transmission electron microscopy. The trypanocidal activity of 4-aminoquinolines and the elucidation of the mechanism involving interaction with heme is a neglected field of research, given the parasite's lack of heme biosynthetic pathway and the importance of this cofactor for parasite survival and growth. The results of this study can improve and guide rational drug development and combination treatment strategies.

Effects of astaxanthin in mice acutely infected withTrypanosoma cruzi

“…Vero cells (5 × 10 3 /well) were seeded and cultured for 24 h as previously described and then infected with trypomastigotes (10 parasites/cell) [ 13 ]. Once intracellular parasites were observed (about 96 h after infection), the old medium was replaced with fresh supplemented DMEM with different ASTX doses (1, 5, 10, 20, or 30 μg/100 μL).…”

Current advances in drug discovery for Chagas disease

“…13) that was active against epimastigotes when combined with hemin, with higher potency than BZN (IC 50 ¼ <1 mM, SI ¼ >111.1). In addition, 10 mM of this compound inhibited 65% of amastigotes growth after 72 h [72]. High-performance liquid chromatography analysis showed that heme is enzymatically converted to biliverdin, thus favoring heme oxygenase activity in the parasite.…”

“…High-performance liquid chromatography analysis showed that heme is enzymatically converted to biliverdin, thus favoring heme oxygenase activity in the parasite. The authors also suggested that the formation of heme-quinoline 35 complex could be attributed to the decrease in available heme levels and increase in the production of reactive oxygen species, leading to parasite death [72].…”

Bioprospecting of Nitrogenous Heterocyclic Scaffolds with Potential Action for Neglected Parasitosis: A Review

“…In this sense, the general mechanism of action developed by quinoline compounds is properly elucidated in terms of antimalarial activity, taking into consideration reference quinoline drugs used in the treatment of malaria, which include, among others: chloroquine, quinine, and mefloquine [150]. Their mechanism of action involves the formation of quinoline heme complexes, responsible for inhibiting heme crystallization into hemozoin, leading to high levels of free heme and inducing prooxidant effects that culminate in parasite death [151].…”