Inhibitory activity of pentacyano(isoniazid)ferrate(II), IQG-607, against promastigotes and amastigotes forms of Leishmania braziliensis

Abstract

M. tuberculosis and parasites of the genus Leishmania present the type II fatty acid biosynthesis system (FASII). The pentacyano(isoniazid)ferrate(II) compound, named IQG-607, inhibits the enzyme 2-trans-enoyl-ACP(CoA) reductase from M. tuberculosis, a key component in the FASII system. Here, we aimed to evaluate the inhibitory activity of IQG-607 against promastigote and amastigote forms of Leishmania (Viannia) braziliensis isolated from patients with different clinical forms of L. braziliensis infection, including cutaneous, mucosal and disseminated leishmaniasis. Importantly, IQG-607 inhibited the proliferation of three different isolates of L. braziliensis promastigotes associated with cutaneous, mucosal and disseminated leishmaniasis. The IC50 values for IQG-607 ranged from 32 to 75 μM, for these forms. Additionally, IQG-607 treatment decreased the proliferation of intracellular amastigotes in infected macrophages, after an analysis of the percentage of infected cells and the number of intracellular parasites/100 cells. IQG-607 reduced from 58% to 98% the proliferation of L. braziliensis from cutaneous, mucosal and disseminated strains. Moreover, IQG-607 was also evaluated regarding its potential toxic profile, by using different cell lines. Cell viability of the lineages Vero, HaCat and HepG2 was significantly reduced after incubation with concentrations of IQG-607 higher than 2 mM. Importantly, IQG-607, in a concentration of 1 mM, did not induce DNA damage in HepG2 cells, when compared to the untreated control group. Future studies will confirm the mechanism of action of IQG-607 against L. braziliensis.

Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis?

“…In vitro evaluations are complementary to in vivo tests (Andrade et al, 2016 ). The cytotoxicity of IQG-607 was thus assessed against macrophages derived from peripheral blood mononuclear cells, and against three additional cell lineages: Vero, HaCat, and HepG2 (Amorim et al, 2017 ). Incubations (for 72 h) with varying concentrations of IQG-607 up to 2,000 μM did not significantly affect cell viability, while treatments with higher concentrations (4, 8 or 16 mM) reduced the cell viability to percentages lower than 50 % for the three lineages evaluated.…”

“…Incubations (for 72 h) with varying concentrations of IQG-607 up to 2,000 μM did not significantly affect cell viability, while treatments with higher concentrations (4, 8 or 16 mM) reduced the cell viability to percentages lower than 50 % for the three lineages evaluated. It was estimated that the IC 50 value was larger than 2,000 μM for the eukaryotic cell lines tested (Amorim et al, 2017 ). Comparatively, the IC 50 value for INH was determined to be approximately 1,100 μM after incubation for 72 h in cultured human hepatocytes (Shen et al, 2008 ), or approximately 1,500 μM after incubation for 48 h in HepG2 cells (Anju et al, 2016 ), both assessed by the MTT method.…”

“…Comparatively, the IC 50 value for INH was determined to be approximately 1,100 μM after incubation for 72 h in cultured human hepatocytes (Shen et al, 2008 ), or approximately 1,500 μM after incubation for 48 h in HepG2 cells (Anju et al, 2016 ), both assessed by the MTT method. The selectivity index (SI) for IQG-607 was estimated (SI = IC 50 /MIC) to be higher than 4,000, considering the value of MIC = 0.25 μg/ml, which corresponds to 0.5 μM (Basso et al, 2010 ) and IC 50 of 2,000 μM (Amorim et al, 2017 ). Accordingly, as suggested by the Tuberculosis Antimicrobial Acquisition & Coordinating Facility of USA, for a compound to move forward through screening programs, its SI values should be >10.…”

“…Incidentally, the SI value for INH can be estimated to be larger than 6,000, considering the value of MIC = 0.025 μg/ml, which corresponds to 0.18 μM (Rastogi et al, 1996 ). Noteworthy, IQG-607 did not exhibit genotoxic effects even when IQG-607 was incubated at high concentration (1 mM), as revealed by the alkaline comet assay, and it did not induce DNA damage in HepG2 cells (Amorim et al, 2017 ). The mutagenic potential of IQG-607 is currently being tested by using different strains of Salmonella typhimurium (Ames test, unpublished data).…”

“…The findings regarding toxicity investigation protocols have shown an overall favorable safety profile for IQG-607 in cells, mice, rats, and minipigs (Basso et al, 2010 ; Amorim et al, 2017 ; Rodrigues-Junior et al, 2017a , b ). However, comparative toxicological studies are currently underway to investigate whether or not IQG-607 could be employed as an alternative to INH as the latter may cause may cause toxic side effects (Kass and Shandera, 2010 ; Wang et al, 2016 ) such as drug-induced liver injuries (Saukkonen et al, 2006 ).…”