Insights into the structural patterns of the antileishmanial activity of bi- and tricyclic N-heterocycles

Herrera, Lizzi; Stephens, David E.; D'Avila, Abigail; George, Kathryn G.; Arman, Hadi D.; Perry, George; Lleonart, Ricardo; Larionov, Oleg V.; Fernández, Patricia L.

doi:10.1039/c6ob01149g

Cited by 13 publications

(16 citation statements)

References 47 publications

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“…We then choose to test a subclass of nitroxy compounds for their capacity to inhibit this interaction. Nitroxy compounds have recently emerged as a privileged scaffold for applications in drug discovery 15, 16 . In particular, 1,2-oxazines represent a new structural framework with significant potential for structure diversification.…”

Section: Introductionmentioning

confidence: 99%

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

Doens

Valiente

Mfuh³

et al. 2017

ACS Chem. Neurosci.

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Neuroinflammation is one of the hallmarks of Alzheimer's disease pathology. Amyloid β has a central role in microglia activation and the subsequent secretion of inflammatory mediators that are associated with neuronal toxicity. The recognition of amyloid β by microglia depends on the expression of several receptors implicated in the clearance of amyloid and in cell activation. CD36 receptor expressed on microglia interacts with fibrils of amyloid inducing the release of pro-inflammatory cytokines and amyloid internalization. The interruption of the interaction CD36-amyloid β compromises the activation of microglia cells. We have developed and validated a new colorimetric assay to identify potential inhibitors of the binding of amyloid β to CD36. We have found 7 molecules, structural analogues of the Trichodermamide family of natural products that interfere with the interaction CD36-amyloid β. Molecular docking simulations have suggested the large luminal hydrophobic tunnel, present in the extracellular domain of CD36, as a target of these compounds. These molecules also inhibited the production of TNF-α, IL-6 and IL-1β by peritoneal macrophages stimulated with fibrils of amyloid β. This work serves as a platform for the identification of new potential anti-inflammatory agents for the treatment of Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

Doens

Valiente

Mfuh³

et al. 2017

ACS Chem. Neurosci.

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“…Our results demonstrate the importance of the 1,4-dihydroquinolinic nucleus in the study of compounds with antileishmanial properties. Recent works have confirmed the interesting antileishmanial properties of quinoline derivatives (Antinarelli et al 2015;Herrera et al 2016;Navneetha et al 2017). In these works, various quinoline derivatives have been synthesized and showed results that attest to the importance of this pharmacophore nucleus for leishmanicidal activity against the promastigote form.…”

Section: Antileishmanicidal Activitiesmentioning

confidence: 81%

In vitro leishmanicidal activity of lactone 1,4-dihydroquinoline derivatives against Leishmania (Leishmania) amazonensis

et al. 2018

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A series of lactone 1,4-dihydroquinoline derivatives 4 (4 and 4aa-4cm) was screened for in vitro antileishmanial activity against the promastigote form of Leishmania (Leishmania) amazonensis. Screening results indicate that all of the synthesized compounds significantly reduced the growth of promastigote forms of promastigotes of L. (L.) amazonensis. The cytotoxicity of the most active compounds was also measured on peritoneal macrophage cells. Compounds 4ah and 4bn showed better activities than other derivatives with IC 50 values of 6.22 and 9.05 μM, respectively, with selectivity index 22 and 15 times less toxicity to macrophages cells than to parasites, respectively. The experimental data propose that the compounds may be further investigated against amastigote forms and may contribute to the search of new candidates drugs for treatment of cutaneous leishmaniasis.

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“…In a previous study, we identified chloroquine analog 1 as an inhibitor of L. panamensis growth in vitro ( Herrera et al., 2016 ). Herein, we developed a simple model of L. panamensis infection in mice to evaluate the in vivo effect of this and other compounds with a suspected antileishmanial effect.…”

Section: Resultsmentioning

confidence: 99%

“…Its chemical scaffold is used in the design of many pharmacologically-active synthetic compounds ( Kouznetsov et al., 2005 ). In a previous study, we observed that the chloroquine analog N 4 -(7-chloro-2-cyclohexanylquinolin-4-yl)- N 1 , N 1 -diethylpentane-1,4-diamine (here called compound 1 ) inhibited the growth of L. panamensis amastigotes in vitro with a half maximal inhibitory concentration (IC 50 ) of 1.07 ± 0.51 μM and with the concomitant inhibition of the production of IL-10 by infected murine macrophages ( Herrera et al., 2016 ). Here, we studied the in vivo effect of this compound on a murine model of L. panamensis infection.…”

Section: Introductionmentioning

confidence: 99%

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

Herrera

Llanes

Álvarez

et al. 2020

International Journal for Parasitology: Drugs and Drug Resistan

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Leishmania panamensis is a relevant causative agent of tegumentary leishmaniasis in several Latin American countries. Available antileishmanial drugs have several limitations including relatively high toxicity, difficult administration, high production costs and the emergence of resistance in circulating strains. Therefore, the identification of new molecules as potential therapeutics for leishmaniasis is of great relevance. Here, we developed a murine model of L. panamensis infection and evaluated the effect of a new compound in vivo . After treatment of animals with the compound, we observed a significant reduction of inflammation and parasite load at the inoculation site, in a dose-dependent manner. We observed a reduction in IL-10 production by popliteal lymph nodes cells of infected mice. These results pave the way for future evaluation of this compound as a potential antileishmanial drug or as a suitable scaffold for lead optimization strategies.

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Insights into the structural patterns of the antileishmanial activity of bi- and tricyclic N-heterocycles

Cited by 13 publications

References 47 publications

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

In vitro leishmanicidal activity of lactone 1,4-dihydroquinoline derivatives against Leishmania (Leishmania) amazonensis

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

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