Development of a SPE/HPLC/DAD method for the determination of antileishmanial 2-substituted quinolines and metabolites in rat plasma

Desrivot, Julie; Moussa, Fathi; Champy, Pierre; Fournet, Alain; Figadère, Bruno; Herrenknecht, Christine

doi:10.1016/j.jchromb.2007.04.029

Cited by 5 publications

(5 citation statements)

References 26 publications

(44 reference statements)

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“…The first approach is to understand the biodistribution of 2-substituted quinolines, which requires an analytical method to quantify them. For this, a SPE/HPLC/DAD method was developed for the in vivo monitoring of several antileishmanial 2-substituted quinolines [ 75 ]. Two linear gradients were used to ensure the resolution of metabolites.…”

Section: The Potential Of 2-substituted Quinolines As Antileishmanial...mentioning

confidence: 99%

“…The recovery of quinolines from rat plasma was in the range of 80 to 88%. From a drug development perspective, the apparent pK(a), lipophilicity and solubility were determined, as well as the extent of binding to albumin and other plasma proteins [ 75 ]. Using this method, liver microsome and hepatocyte-mediated biotransformation of some 2-substituted quinolines could be studied [ 76 ], as well as the different isoforms of rat cytochrome P450 responsible for the biotransformation of 2 -n- propyl quinoline.…”

Section: The Potential Of 2-substituted Quinolines As Antileishmanial...mentioning

confidence: 99%

“…Compounds containing a propenyl chain functionalized at the gamma position by either a nitrile or an alcohol (the latter compound being 2-(2-hydroxyprop-2-enyl)quinoline) mainly reacted with glutathione and underwent no further metabolism. However, since this reaction is reversible, the compound 2-(2-hydroxyprop-2-enyl)quinoline could be released from glutathione and underwent alternative reaction pathways [ 75 , 76 ]. Therefore, this analytical method revealed that the nature of the substitution on the carbon-2 position determines the metabolic routes that the compound follows [ 75 ].…”

Section: The Potential Of 2-substituted Quinolines As Antileishmanial...mentioning

confidence: 99%

“…However, since this reaction is reversible, the compound 2-(2-hydroxyprop-2-enyl)quinoline could be released from glutathione and underwent alternative reaction pathways [ 75 , 76 ]. Therefore, this analytical method revealed that the nature of the substitution on the carbon-2 position determines the metabolic routes that the compound follows [ 75 ]. Moreover, some quinolines substituted on their carbon-2 could not be detected in plasma during pharmacokinetic studies, suggesting their possible sequestration by blood components.…”

Section: The Potential Of 2-substituted Quinolines As Antileishmanial...mentioning

confidence: 99%

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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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Section: The Potential Of 2-substituted Quinolines As Antileishmanial...mentioning

confidence: 99%

Section: The Potential Of 2-substituted Quinolines As Antileishmanial...mentioning

confidence: 99%

Section: The Potential Of 2-substituted Quinolines As Antileishmanial...mentioning

confidence: 99%

Section: The Potential Of 2-substituted Quinolines As Antileishmanial...mentioning

confidence: 99%

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The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

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“…Found at: doi:10.1371/journal.pone.0006215.s001 (.15 MB PDF) [49]. b see ref [50]. c in water with 1% ethanol.…”

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confidence: 99%

3.231 Chemicals Possessing a Neurotrophin-Like Activity on Dopaminergic Neurons in Primary Culture

Raisman‐Vozari¹,

Schmidt²,

Champy³

et al. 2012

Parkinsonism & Related Disorders

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Background: Neurotrophic factors have been shown to possess strong neuroprotective and neurorestaurative properties in Parkinson's disease patients. However the issues to control their delivery into the interest areas of the brain and their surgical administration linked to their unability to cross the blood brain barrier are many drawbacks responsible of undesirable side effects limiting their clinical use. A strategy implying the use of neurotrophic small molecules could provide an interesting alternative avoiding neurotrophin administration and side effects. In an attempt to develop drugs mimicking neurotrophic factors, we have designed and synthesized low molecular weight molecules that exhibit neuroprotective and neuritogenic potential for dopaminergic neurons.Principal Findings: A cell-based screening of an in-house quinoline-derived compound collection led to the characterization of compounds exhibiting both activities in the nanomolar range on mesencephalic dopaminergic neurons in spontaneous or 1-methyl-4-phenylpyridinium (MPP + )-induced neurodegeneration. This study provides evidence that rescued neurons possess a functional dopamine transporter and underlines the involvement of the extracellular signalregulated kinase 1/2 signaling pathway in these processes. Conclusion:Cell-based screening led to the discovery of a potent neurotrophic compound possessing expected physicochemical properties for blood brain barrier penetration as a serious candidate for therapeutic use in Parkinson disease.

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