Antileishmanial Activity, Cytotoxicity and Mechanism of Action of Clioquinol Against Leishmania infantum and Leishmania amazonensis Species

Abstract

In this study, a quinoline derivate, clioquinol (5-chloro-7-iodoquinolin-8-ol), was evaluated against Leishmania amazonensis and Leishmania infantum promastigotes and amastigotes. The cytotoxicity in murine macrophages and human red blood cells, as well as the efficacy in treating infected macrophages and the inhibition of infection using pre-treated parasites were also evaluated. Results showed that clioquinol inhibited L. amazonensis and L. infantum promastigotes with effective concentration 50% (EC ) values of 2.55 ± 0.25 and 1.44 ± 0.35 μg/mL, respectively, and of 1.88 ± 0.13 and 0.98 ± 0.17 μg/mL against axenic amastigotes, respectively. The cytotoxic EC concentrations of clioquinol in murine macrophages and human red blood cells were, respectively, 255 ± 23 and 489 ± 20 μg/mL. With these results, the selectivity index was calculated, showing values of 99.9 and 177.1 against promastigotes, respectively, and of 135.6 and 260.1 against axenic amastigotes, respectively. Significant reductions in the percentage of infected macrophages after treatment using clioquinol were also observed, as well as when parasites were pre-treated with clioquinol and used to infect murine macrophages. The mechanism of action of clioquinol was investigated in L. amazonensis, and results revealed morphological and biochemical alterations in the clioquinol-treated parasites, including reduction in cell volume, loss of mitochondrial membrane potential, increase in the ROS production and rupture of the plasma membrane. The externalization of phosphatidylserine (PS) at the cell surface was evaluated in treated parasites that had been doubly labelled with annexin and propidium iodide (PI). The results showed no significant difference for PS exposure when compared to the untreated control, although a significant increase in the PI/annexin V-labelled cell population was found in the treated parasites. Results suggest that clioquinol induces a discontinuity of the parasite membrane, possibly related to a characteristic event of cell death caused by necrosis. This study demonstrates, for the first time, the antileishmanial activity of clioquinol against two relevant Leishmania species and suggests that the mitochondria of the parasites may be a possible biological target leading to parasite necrosis. Our findings suggest that clioquinol may have a potential application in treatment of leishmaniasis and further studies should be performed in infected mammalian hosts.

Discovery of Clioquinol and Analogues as Novel Inhibitors of Severe Acute Respiratory Syndrome Coronavirus 2 Infection, ACE2 and ACE2 - Spike Protein Interaction In Vitro

“…Hence, validating its potential as a therapeutic option for the treatment of COVID19. Clioquinol and its derivatives belonging to 8-hydroxyquinoline structural class, have been investigated extensively in basic, translational and clinical studies because of their multiple activities as metal chelators and zinc ionophores, modulating underlying molecular and physiologic switches required for metal homeostatis in vivo [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][36][37][38][39] . Previously, CLQ was used to treat bacterial infections 62 ; however, it was withdrawn from the clinic because of untoward effects of subacute myelo-optic neuropathy (SMON) mostly experienced in Japan in the 1950's 29,62,63 .…”

“…Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a novel RNA betacoronavirus, is the causative agent for coronavirus disease 2019 (COVID- 19), which has emerged as an ongoing global pandemic 1 . Worldwide, SARS-CoV-2 has spread rampantly to more than 188 countries/regions and has resulted in 18,847,261 confirmed cases, 11,390,018 recovered, including 708,540 deaths (https://coronavirus.jhu.edu/map.html).…”

“…Historically, Clioquinol (5-chloro-7-iodo-8-quinolinol (CLQ)) and its derivatives belonging to the 8-hydroxyquinoline structural class, has shown potent broad-spectrum activity against clinically relevant pathogens [14][15][16][17][18][19][20] . More recently, CLQ and its analogues have been extensively investigated as potential treatments for cancer and neurodegenerative diseases [21][22][23][24][25][26][27][28] .…”

Discovery of novel halogenated 8‐hydroxyquinoline‐based anti‐MRSA agents: In vitro and QSAR studies

“…Moreover, 8HQ and clioquinol have been reported to exhibit antileishmanial activity against Leishmania spp. (Duarte et al, ; Tavares et al, ). The result showed that 8HQ exerted high antileishmanial activity against three Leishmaina spp.…”

Synergistic association of clioquinol with antifungal drugs against biofilm forms of clinical Fusarium isolates

“…Tavares et al (2018) reported the effectivity of CLIO (2.55 ± 0.25 and 1.44 ± 0.35 μg/mL) against two species of leishmania 52 . Additionally, the authors determined the cytotoxic effect this drug on murine macrophages and human red blood cells, in which the cytotoxic EC 50 was 255 ± 23 and 489 ± 20 μg/mL, respectively.…”