Metabolism of 2-substituted quinolines with antileishmanial activity studied in vitro with liver microsomes, hepatocytes and recombinantly expressed enzymes analyzed by LC/MS

Desrivot, Julie; Edlund, Per-Olof; Svensson, Richard; Baranczewski, Paweł; Fournet, Alain; Figadère, Bruno; Herrenknecht, Christine

doi:10.1016/j.tox.2007.03.003

Cited by 12 publications

(10 citation statements)

References 23 publications

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“…One compound emerged as the single compound with satisfactory activity across the in vivo models employed, containing a propenyl chain functionalized by an -OH group [78]. Biotransformation of this and other 2-substituted quinolines and their in vitro behavior in the blood compartment was studied showing discrepancies of affinity to erythrocytes amongst this series [79,80]. …”

Section: Recent Developments and Selected Drug Classes – From Discovementioning

confidence: 99%

Structures, Targets and Recent Approaches in Anti-Leishmanial Drug Discovery and Development

Seifert¹

2011

Open Med Chem J

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Recent years have seen a significant improvement in available treatment options for leishmaniasis. Two new drugs, miltefosine and paromomycin, have been registered for the treatment of visceral leishmaniasis (VL) in India since 2002. Combination therapy is now explored in clinical trials as a new treatment approach for VL to reduce the length of treatment and potentially prevent selection of resistant parasites. However there is still a need for new drugs due to safety, resistance, stability and cost issues with existing therapies. The search for topical treatments for cutaneous leishmaniasis (CL) is ongoing. This review gives a brief overview of recent developments and approaches in anti-leishmanial drug discovery and development.

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Section: Recent Developments and Selected Drug Classes – From Discovementioning

confidence: 99%

Structures, Targets and Recent Approaches in Anti-Leishmanial Drug Discovery and Development

Seifert¹

2011

Open Med Chem J

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“…We found the ␣-and the ␥-hydroxylated and also the epoxide phase I metabolites of compound 1 in accordance with previous results [18], but the dihydroxylated compound was not observed. However, a new ␤-hydroxylated metabolite was identified under our experimental conditions [19].…”

Section: Introductionmentioning

confidence: 79%

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

Desrivot

Moussa

Champy

et al. 2007

Journal of Chromatography B

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“…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. Incubation of 2 -n- propylquinoline with microsomes led mainly to hydroxylation of the side chain, involving many cytochromes: predominantly CYP2B1, CYP2A6 and CYP1A1 (at more than 80%).…”

Section: The Potential Of 2-substituted Quinolines As Antileishmanial...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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Metabolism of 2-substituted quinolines with antileishmanial activity studied in vitro with liver microsomes, hepatocytes and recombinantly expressed enzymes analyzed by LC/MS

Cited by 12 publications

References 23 publications

Structures, Targets and Recent Approaches in Anti-Leishmanial Drug Discovery and Development

Structures, Targets and Recent Approaches in Anti-Leishmanial Drug Discovery and Development

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

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

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