Mutagenic and Cytotoxicity LQB 123 Profile: Safety and Tripanocidal Effect of a Phenyl-t-Butylnitrone Derivative

Abstract

The therapeutic options for Chagas disease are limited and its treatment presents a number of drawbacks including toxicity, drug resistance, and insufficient effectiveness against the chronic stage of the disease. Therefore, new therapeutical options are mandatory. In the present work, we evaluated the effect of a phenyl-tert-butylnitrone (PBN) derivate, LQB 123, against Trypanosoma cruzi forms. LQB 123 presented a trypanocidal effect against bloodstream trypomastigotes (IC50 = 259.4 ± 6.1 μM) and intracellular amastigotes infecting peritoneal macrophages (IC50 = 188.2 ± 47.5 μM), with no harmful effects upon the mammalian cells (CC50 values greater than 4 mM), resulting in a high selectivity index (CC50/IC50 > 20). Additionally, metacyclic trypomastigotes submitted to LQB 123 presented an IC50 of about 191.8 ± 10.5 μM and epimastigotes forms incubated with different concentrations of LQB 123 presented an inhibition of parasite growth with an IC50 of 255.1 ± 3.6 μM. Finally, we investigated the mutagenic potential of the nitrone by the Salmonella/microsome assay and observed no induction of mutagenicity even in concentrations as high as 33000 μM. Taken together, these results present a nonmutagenic compound, with trypanocidal activity against all relevant forms of T. cruzi, offering new insights into CD treatment suggesting additional in vivo tests.

The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi

“…LQB303 reduced the number of both the extracellular and intracellular amastigotes of T. cruzi in vitro, and this inhibitory effect on parasite growth was irreversible. Recently, another PBN derivative, LQB123 showed trypanocidal activity against the intracellular amastigotes and other clinically relevant forms of the parasite (Cupello et al, 2017). When comparing the IC 50 /48 h for amastigotes incubated with LQB123 (188 μM) with parasites challenged with LQB303 (3 μM), we observed that LQB303 was 63 times more active than LQB123.…”

“…However, mice treated with PBN alone did not show decreased parasite persistence (Wen et al, 2010). Modifications to the PBN molecule increases its trypanocidal effect, as seen with the PBN derivative, LQB123, which demonstrates trypanocidal effects on the proliferative and infective forms of T. cruzi, as well as low cytotoxicity to mammalian cells (Cupello et al, 2017).…”