Quinoline derivatives: Synthesis, leishmanicidal activity and involvement of mitochondrial oxidative stress as mechanism of action

Coimbra, Elaine Soares; Antinarelli, Luciana Maria Ribeiro; Silva, Natália P.; Souza, Isabela O.; Meinel, Raíssa Soares; Rocha, Marcele Neves; Soares, Rodrigo Pedro; Silva, Adilson David da

doi:10.1016/j.cbi.2016.10.017

Cited by 53 publications

(23 citation statements)

References 28 publications

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“…The observation that the quinoline alkaloid camptothecin was a potential upstream regulator was also of interest, especially given the progress of the orally active 8‐aminoquinoline sitamaquine (formerly WR‐6026) through preclinical and phase I/II clinical trials against VL in India, Brazil and Kenya (reviewed Ref. ), as well as a similar resurgence of interest in testing known and novel quinoline derivatives . Of interest also in relation to response to drug therapy was the observation of enrichment for a gene set associated with response to arsenic, supporting recent research suggesting that arsenic contamination in drinking water in areas endemic for VL may have led to increased resistance to antimonial compounds like SSB …”

Section: Discussionmentioning

confidence: 84%

Expression profiling of Sudanese visceral leishmaniasis patients pre‐ and post‐treatment with sodium stibogluconate

Salih

Fakiola

Lyons

et al. 2017

Parasite Immunology

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Summary Visceral leishmaniasis (VL) in Sudan caused by Leishmania donovani is fatal in susceptible individuals if untreated. Treatment with sodium stibogluconate (SSG) leads to post‐kala‐azar dermal leishmaniasis (PKDL) in 58% of patients. Here, Affymetrix microarrays were used to identify genes differentially expressed in lymph nodes (N=9 paired samples) pre‐ and post‐treatment with SSG. Using the Bioconductor package limma, 438 genes from 28 869 post‐quality‐control probe sets were differentially expressed (Pnominal≤.02) post‐ vs pretreatment. Canonical pathway analysis using Ingenuity Pathway Analysis™ identified “role of nuclear factor of activated T‐cell in regulation of immune response” (Pnominal=1.35×10−5; PBH‐adjusted=4.79×10−3), “B‐cell development” (Pnominal=2.04×10−4; PBH‐adjusted=.024), “Fcγ receptor‐mediated phagocytosis in macrophages and monocytes” (Pnominal=2.04×10−4; PBH‐adjusted=.024) and “OX40 signalling” (Pnominal=2.82×10−4; PBH‐adjusted=.025) as pathways differentially regulated post‐ vs pretreatment. Major network hub genes included TP53, FN1, MYC, BCL2, JUN, SYK, RUNX2, MMP1 and ACTA2. Top endogenous upstream regulators included IL‐7 (P=2.28×10−6), TNF (P=4.26×10−6), Amyloid Precursor Protein (P=4.23×10−5) and SPI1/PI.1 (P=1.17×10−7). Top predicted chemical drug regulators included the flavonoid genistein (P=4.56×10−7) and the quinoline alkaloid camptothecin (P=5.14×10−5). These results contribute to our understanding of immunopathology associated with VL and response to SSG treatment. Further replication could identify novel therapeutic strategies that improve on SSG treatment and reduce the likelihood of progression to PKDL.

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Section: Discussionmentioning

confidence: 84%

Expression profiling of Sudanese visceral leishmaniasis patients pre‐ and post‐treatment with sodium stibogluconate

Salih

Fakiola

Lyons

et al. 2017

Parasite Immunology

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“…As this organelle is unique in these protozoa, the collapse of the mitochondrial membrane potential is known as one characteristic metabolic process of cell death in these parasites . There are multiple sources of ROS to the cells , and the mitochondrial collapse associated with cell membrane depolarization has been related to apoptosis and/or necrosis events . Here, treatment with clioquinol induced a significant increase in the production of ROS in all of the tested concentrations.…”

Section: Discussionmentioning

confidence: 90%

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

Tavares

Mendonça

Lage

et al. 2018

Basic Clin Pharma Tox

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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.

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“…L. amazonensis transfected with RFP was grown in M199 medium containing 10 %F BS, 40 mm HEPES, 0.0005 %h emin, 0.1 mm adenine, 0.0002 %b iotin, 0.1 %o ft he antibiotic, and maintained at 25 8Ci naBOD incubator. [12] Antipromastigote assay:P romastigotes in logarithmic growth phase were suspended at 2 10 6 cells mL À1 (L. amazonensis WT) or 3 10 6 cells mL À1 (L. braziliensis)a nd incubated in the presence of a serial dilution of each individual compound (100.0-6.25 mm)i n9 6well culture plates for 72 ha t2 58C. The viability of promastigotes was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma-Aldrich, St. Louis, MO, USA) colorimetric method and the absorbance was measured at 570 nm (Multiskan MS microplate reader,LabSystems Oy,Helsinki, Finland).…”

Section: Methodsmentioning

confidence: 99%

“…Miltefosine (supplied by Cayman Chemical Company,A nn Arbor,M I, USA) was used as the reference drug. [12] Cytotoxicity on macrophages:M urine peritoneal macrophages were obtained by peritoneal lavage of female BALB/c mice previously inoculated with 3% sodium thioglycolate. The cells were plated at 2 10 5 cells per well in 96-well culture plates in RPMI 1640 medium (Cultilab, SP,B razil) with 10 %i nactivated FBS (Cultilab) and incubated at 33 8Ca nd 5% CO 2 atmosphere.…”

Section: Methodsmentioning

confidence: 99%

“…Antiamastigote activity:T he assay of activity against intracellular amastigotes of L. amazonensis RFP (IFLA/BR/1967/PH8) was performed as previously described. [12,13] In summary,m urine macrophages were adhered to coverslips placed in 24-well tissue culture plates for 16 h. Adherent macrophages were infected with L. amazonensis RFP promastigotes in stationary growth phase at 10:1 (parasite/macrophage) ratio for 4h at 33 8Ci n5%C O 2 .A fterward, the infected macrophages were treated with various concentrations of compounds (6.25, 12.5, 25.0, 50.0, and 100.0 mm)a nd incubated for 72 ha t3 3 8Ci n5 %C O 2 .S ubsequently,t he parasite burden was determined by measurement of fluorescence intensity of the parasites using ap late reader fluorimeter (FLx800, BioTek In-struments, Inc.,W inooski, VT,U SA) set at 540 nm excitation/ 600 nm emission. The results are expressed as percent inhibition relative to controls represented by L. amazonensis-infected macrophages.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis, Biological Activity, and Mechanism of Action of 2‐Pyrazyl and Pyridylhydrazone Derivatives, New Classes of Antileishmanial Agents

et al. 2018

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In this work, we report the antileishmanial activity of 23 compounds based on 2-pyrazyl and 2-pyridylhydrazone derivatives. The compounds were tested against the promastigotes of Leishmania amazonensis and L. braziliensis, murine macrophages, and intracellular L. amazonensis amastigotes. The most potent antileishmanial compound was selected for investigation into its mechanism of action. Among the evaluated compounds, five derivatives [(E)-3-((2-(pyridin-2-yl)hydrazono)methyl)benzene-1,2-diol (2 b), (E)-4-((2-(pyridin-2-yl)hydrazono)methyl)benzene-1,3-diol (2 c), (E)-4-nitro-2-((2-(pyrazin-2-yl)hydrazono)methyl)phenol (2 s), (E)-2-(2-(pyridin-2-ylmethylene)hydrazinyl)pyrazine (2 u), and (E)-2-(2-((5-nitrofuran-2-yl)methylene)hydrazinyl)pyrazine (2 v)] exhibited significant activity against L. amazonensis amastigote forms, with IC values below 20 μm. The majority of the compounds did not show any toxic effect on murine macrophages. Preliminary studies on the mode of action of members of this hydrazine-derived series indicate that the accumulation of reactive oxygen species (ROS) and disruption of parasite mitochondrial function are important for the pharmacological effect on L. amazonensis promastigotes.

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Quinoline derivatives: Synthesis, leishmanicidal activity and involvement of mitochondrial oxidative stress as mechanism of action

Cited by 53 publications

References 28 publications

Expression profiling of Sudanese visceral leishmaniasis patients pre‐ and post‐treatment with sodium stibogluconate

Expression profiling of Sudanese visceral leishmaniasis patients pre‐ and post‐treatment with sodium stibogluconate

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

Synthesis, Biological Activity, and Mechanism of Action of 2‐Pyrazyl and Pyridylhydrazone Derivatives, New Classes of Antileishmanial Agents

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