Antileishmanial activity of a new chloroquine analog in an animal model of Leishmania panamensis infection

Herrera, Lizzi; Llanes, Alejandro; Álvarez, Jennifer; Degracia, Kissy; Restrepo, Carlos M.; Rivera, Rene; Stephens, David E.; Dang, Hang T.; Larionov, Oleg V.; Lleonart, Ricardo; Fernández, Patricia L.

doi:10.1016/j.ijpddr.2020.08.002

Cited by 8 publications

(6 citation statements)

References 51 publications

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“…This similarity further supports the use of BALB/c mice as the preferred model for studying L . panamensis immunopathogenesis and evaluating potential drug candidates [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Leishmania panamensis PSC-1 strain (MHOM/PA/1994/PSC-1) promastigotes were axenically maintained in Schneider’s insect medium (Sigma-Aldrich, St. Louis, MO, USA) at pH 7.2 supplemented with 20% (v/v) heat-inactivated fetal bovine serum (Gibco, Gaithersburg, MD, USA), 50 μg/mL gentamicin (Sigma-Aldrich, St. Louis, MO, USA), and incubated at 25 °C. Parasites were previously adapted to mice by serial passages in the hind footpad of BALB/c mice for a period of 24 months [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

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Gene expression patterns associated with Leishmania panamensis infection in macrophages from BALB/c and C57BL/6 mice

et al. 2021

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Leishmania parasites can trigger different host immune responses that result in varying levels of disease severity. The C57BL/6 and BALB/c mouse strains are among the host models commonly used for characterizing the immunopathogenesis of Leishmania species and the possible antileishmanial effect of novel drug candidates. C57BL/6 mice tend to be resistant to Leishmania infections, whereas BALB/c mice display a susceptible phenotype. Studying species-specific interactions between Leishmania parasites and different host systems is a key step to characterize and validate these models for in vivo studies. Here, we use RNA-Seq and differential expression analysis to characterize the transcriptomic profiles of C57BL/6 and BALB/c peritoneal-derived macrophages in response to Leishmania panamensis infection. We observed differences between BALB/c and C57BL/6 macrophages regarding pathways associated with lysosomal degradation, arginine metabolism and the regulation of cell cycle. We also observed differences in the expression of chemokine and cytokine genes associated with regulation of immune responses. In conclusion, infection with L. panamensis induced an inflammatory gene expression pattern in C57BL/6 macrophages that is more consistently associated with a classic macrophage M1 activation, whereas in BALB/c macrophages a gene expression pattern consistent with an intermediate inflammatory response was observed.

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“…This similarity further supports the use of BALB/c mice as the preferred model for studying L . panamensis immunopathogenesis and evaluating potential drug candidates [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Gene expression patterns associated with Leishmania panamensis infection in macrophages from BALB/c and C57BL/6 mice

et al. 2021

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“…Further studies showed that these derivatives inhibit the production of IL-10 by macrophages infected with Leishmania , suggesting that the compound-induced parasite-killing mechanism may be associated with the regulation of macrophage activation. Four years later, in 2020, the same research group evaluated derivative 37 in an animal model of L. panamensis infection, which corroborated this compound’s potential against Leishmania and the compound-induced inhibition of IL-10 production by macrophages [ 37 ].…”

Section: Quinolines As Antileishmanial Agentsmentioning

confidence: 93%

Evolution of the Quinoline Scaffold for the Treatment of Leishmaniasis: A Structural Perspective

Silva,

Pinto,

Fernandes

et al. 2024

Pharmaceuticals

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Since the beginning of the XXI century, Leishmaniasis has been integrated into the World Health Organization’s list of the 20 neglected tropical diseases, being considered a public health issue in more than 88 countries, especially in the tropics, subtropics, and the Mediterranean area. Statistically, this disease presents a world prevalence of 12 million cases worldwide, with this number being expected to increase shortly due to the 350 million people considered at risk and the 2–2.5 million new cases appearing every year. The lack of an appropriate and effective treatment against this disease has intensified the interest of many research groups to pursue the discovery and development of novel treatments in close collaboration with the WHO, which hopes to eradicate it shortly. This paper intends to highlight the quinoline scaffold’s potential for developing novel antileishmanial agents and provide a set of structural guidelines to help the research groups in the medicinal chemistry field perform more direct drug discovery and development programs. Thus, this review paper presents a thorough compilation of the most recent advances in the development of new quinoline-based antileishmanial agents, with a particular focus on structure–activity relationship studies that should be considerably useful for the future of the field.

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“…In this respect, chloroquine combined with diminazene merited further development [ 17 ]; however, the combination with paromomycin did not yield encouraging results [ 18 ]. Several chloroquine derivatives have been evaluated on Leishmania models in vitro and in vivo [ 19 ]. However, the major source of drug candidates was the 8-aminoquinoline series.…”

Section: The Place Of Quinolines As Drug Candidates In the Treatment ...mentioning

confidence: 99%

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

et al. 2022

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There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the 2-substituted quinoline series as a source of molecules with antileishmanial activity and low toxicity. This review documents the development of the series from the first isolated natural compounds through several hundred synthetized molecules to an optimized compound exhibiting an in vitro IC50 value of 0.2 µM against Leishmania donovani, and a selectivity index value of 187, together with in vivo activity on the L. donovani/hamster model. Attempts to establish structure–activity relationships are described, as well as studies that have attempted to determine the mechanism of action. For the latter, it appears that molecules of this series act on multiple targets, possibly including the immune system, which could explain the observed lack of drug resistance after in vitro drug pressure. We also show how nanotechnology strategies could valorize these drugs through adapted formulations and how a mechanistic targeting approach could generate new compounds with increased activity.

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Antileishmanial activity of a new chloroquine analog in an animal model of Leishmania panamensis infection

Cited by 8 publications

References 51 publications

Gene expression patterns associated with Leishmania panamensis infection in macrophages from BALB/c and C57BL/6 mice

Gene expression patterns associated with Leishmania panamensis infection in macrophages from BALB/c and C57BL/6 mice

Evolution of the Quinoline Scaffold for the Treatment of Leishmaniasis: A Structural Perspective

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

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