4‐Aminoquinoline Derivatives as Potential Antileishmanial Agents

Antinarelli, Luciana Maria Ribeiro; Dias, Rafael M. P.; Souza, Isabela O.; Lima, Wallace Pacienza; Gameiro, Jacy; Silva, Adilson David da; Coimbra, Elaine Soares

doi:10.1111/cbdd.12540

Cited by 42 publications

(29 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The pharmacological properties of the quinoline ring illustrate the number of commercial products containing this heterocyclic system . Quinoline‐based compounds present a variety of biological actions, such as antimalarial and antileishmanial agents . As a consequence, this study illustrates the leishmanicidal activity of 8‐HQN, a quinoline derivate, against distinct Leishmania species .…”

Section: Discussionmentioning

confidence: 85%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 85%

“…at room temperature. The plasma membrane integrity was evaluated by fluorescence intensity as described in . Promastigotes warmed at 65°C were used as a positive control.…”

Section: Methodsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Some molecular targets have been identified for some type of quinolines. For example, 4‐(arylhydrazinyl)‐quinolines, a related 4‐aminoquinoline, have demonstrated to act on the generation of NO into infected macrophages with Leishmania parasite . On the contrary, 4‐substituted quinoline containing terminal N ‐alkylamino moiety (piperazin and morpholine) have the ability to form complexes with NMT enzyme of L. major (structures available in Protein Data Bank), emerging as a potential target to evaluate through molecular docking simulation for our tested derivatives.…”

Section: Resultsmentioning

confidence: 99%

“…Some investigations have put in evidence that 4‐arylhydrazinyl‐quinolines can act on the generation of nitric oxide (NO) into infected macrophage with amastigote of L. braziliensis. 2‐Substituted quinoline alkaloids have demonstrated to affect trypanothione reductase enzymatic activity on Leishmania parasite culture . Recent investigations have demonstrated good in vitro inhibitory response of 4‐substituted quinolines on N‐ myristoyl‐transferase (NMT) enzyme .…”

Section: Introductionmentioning

confidence: 99%

Identification of dehydroxy isoquine and isotebuquine as promising antileishmanial agents

Romero

Rodríguez

López

et al. 2019

Archiv der Pharmazie

View full text Add to dashboard Cite

Traditional antimalarial drugs based on 4‐aminoquinolines have exhibited good antiproliferative activities against Leishmania parasites; however, their clinical use is currently limited. To identify new 4‐aminoquinolines to combat American cutaneous leishmaniasis, we carried out a full in vitro evaluation of a series of dehydroxy isoquines and isotebuquines against two Leishmania parasites such as Leishmania braziliensis and Leishmania mexicana. First, the antiproliferative activity of the quinolines was studied against the promastigote forms of L. braziliensis and L. mexicana parasites, finding that five of them exhibited good antileishmanial responses with micromolar IC50 values ranging from 3.84 to 10 μM. A structure‐activity relationship analysis gave evidence that a piperidine or a morpholine attached as N‐alkyamino terminal substituent as well as the inclusion of an extra phenyl ring attached at the aniline ring of the isotebuquine core constitute important pharmacophores to generate the most active derivatives, with antileishmanial responses by far superior to those found for the reference drug, glucantime. All compounds showed a relatively low toxicity on human dermis fibroblasts, with CC50 ranging from 69 to >250 μM. The five most active compounds displayed moderate to good antileishmanial activity against the intracellular amastigote form of L. braziliensis, compared to the reference drug. In particular, compound 2j was identified as the most potent agent against antimony‐resistant amastigotes of L. braziliensis with acceptable biological response and selectivity, emerging as a promising candidate for further in vivo antileishmanial evaluation. Diverse mechanism‐of‐action studies and molecular docking simulations were performed for the most active 4‐aminoquinoline.

show abstract

“…Adherent macrophages were infected with L. amazonensis promastigotes (MHOM/ Br/75/Josefa), transfected with green protein fluorescent (GFP), in the stationary growth phase, using a ratio of 1:20 at 33 °C for 4 hours. 34,35 Non internalized promastigotes were eliminated and the test compounds were added in several concentrations. After 72 hours of incubation with the compounds, the cells were lysed with distilled water and transferred to black microplates.…”

Section: In Vitro Leishmanicidal Activitymentioning

confidence: 99%

Synthesis, Antitubercular and Leishmanicidal Evaluation of Resveratrol Analogues

Coimbra¹,

Santos²,

Lima³

et al. 2016

Journal of the Brazilian Chemical Society

Self Cite

View full text Add to dashboard Cite

In this paper we continue our efforts in the search for new Schiff bases as resveratrol analogues as promising antitubercular and antileishmanial agents. Compounds were evaluated in vitro against Mycobacterium tuberculosis and Leishmania species. Compounds showed varying activity against promastigotes of all Leishmania species tested (concentration leading to reduction of 50% of parasite growth-IC 50 values ranging from 1.60 to 15.53 µg mL ). Furthermore, the compounds showed comparable or better effect than drugs commonly used in tuberculosis treatment such as Cycloserine®. The analogue that was the most active for M. tuberculosis had minimal inhibitory concentration MIC 90 = 0.78 µg mL -1 . The in vitro cytotoxicity on Vero cells (CC 50 ), as well as the selectivity index (SI = CC 50 /MIC) were also evaluated, and showed that the synthesized analogues are not cytotoxic.

show abstract

4‐Aminoquinoline Derivatives as Potential Antileishmanial Agents

Cited by 42 publications

References 35 publications

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

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

Identification of dehydroxy isoquine and isotebuquine as promising antileishmanial agents

Synthesis, Antitubercular and Leishmanicidal Evaluation of Resveratrol Analogues

Contact Info

Product

Resources

About