Absolute Configuration and Antimalarial Activity of <i>erythro</i>‐Mefloquine Enantiomers

Dassonville‐Klimpt, Alexandra; Cézard, Christine; Mullié, Catherine; Agnamey, Patrice; Jonet, Alexia; Nascimento, Sophie Da; Marchivie, Mathieu; Guillon, Jean; Sonnet, Pascal

doi:10.1002/cplu.201300074

Cited by 18 publications

(22 citation statements)

References 23 publications

(21 reference statements)

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“…Data for all known isomeric mefloquine [21,22] and mefloquinium cations [23][24][25][26][27][28][29][30] that have been characterised crystallographically are collected in Table 3. It is remarkable that the 28 characterised mefloquine/mefloquinium species dis-play a high degree of homogeneity in their molecular structures.…”

Section: Structural Correlations In Mefloquinium Cationsmentioning

confidence: 99%

Crystal structure and Hirshfeld analysis of the kryptoracemate: bis(mefloquinium) chloride p-fluorobenzenesulphonate

Jotani¹,

Wardell

Tiekink

2016

Zeitschrift Für Kristallographie - Crystalline Materials

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The crystal structure analysis of the bis(mefloquinium) chloride p-fluorobenzenesulphonate salt reveals a rare example of a kryptoracemate given that the cations exhibit a non-crystallographic enantiomeric relationship. The conformations of the cations are based on a skewed letter L with the (piperidinium-2-yl)methanol group sitting almost normal to and directed away from the quinolinyl residue. The most prominent feature of the molecular packing is the formation of supramolecular helical chains along the

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Section: Structural Correlations In Mefloquinium Cationsmentioning

confidence: 99%

Crystal structure and Hirshfeld analysis of the kryptoracemate: bis(mefloquinium) chloride p-fluorobenzenesulphonate

Jotani¹,

Wardell

Tiekink

2016

Zeitschrift Für Kristallographie - Crystalline Materials

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“…In Plasmodium, mefloquine inhibits the formation of hemozoin, an essential step in heme detoxification upon hemoglobin degradation ( Egan et al, 1994 ). Additional proposed targets are the ribosomes ( Wong et al, 2017 ), phosphatidylinositol, volume-regulated anion channels and endocytosis ( Dassonville-Klimpt et al, 2011 ). Mefloquine is also active against the helminth parasite Schistosoma ( Keiser and Utzinger, 2012 ), where inhibition of hemozoin formation ( Corrêa Soares et al, 2009 ) as well as impairment of enolase activity ( Manneck et al, 2012 ) were postulated as potential mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis

Rufener

Ritler

Zielinski

et al. 2018

International Journal for Parasitology: Drugs and Drug Resistan

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The cestode E. multilocularis causes the disease alveolar echinococcosis (AE) in humans. The continuously proliferating metacestode (larval stage) of the parasite infects mostly the liver and exhibits tumor-like growth. Current chemotherapeutical treatment options rely on benzimidazoles, which are rarely curative and have to be applied daily and life-long. This can result in considerable hepatotoxicity and thus treatment discontinuation. Therefore, novel drugs against AE are urgently needed. The anti-malarial mefloquine was previously shown to be active against E. multilocularis metacestodes in vitro, and in mice infected by intraperitoneal inoculation of metacestodes when administered at 100 mg/kg by oral gavage twice a week for 12 weeks. In the present study, the same dosage regime was applied in mice infected via oral uptake of eggs representing the natural route of infection. After 12 weeks of treatment, the presence of parasite lesions was assessed in a liver squeeze chamber and by PCR, and a significantly reduced parasite load was found in mefloquine-treated animals. Assessment of mefloquine plasma concentrations by HPLC and modeling using a two-compartment pharmacokinetic model with first-order absorption showed that >90% of the expected steady-state levels (Cmin 1.15 mg/L, Cmax 2.63 mg/L) were reached. These levels are close to concentrations achieved in humans during long-term weekly dosage of 250 mg (dose applied for malaria prophylaxis). In vitro structure-activity relationship analysis of mefloquine and ten derivatives revealed that none of the derivatives exhibited stronger activities than mefloquine. Activity was only observed, when the 2-piperidylmethanol group of mefloquine was replaced by an amino group-containing residue and when the trifluoromethyl residue on position 8 of the quinoline structure was present. This is in line with the anti-malarial activity of mefloquine and it implies that the mode of action in E. multilocularis might be similar to the one against malaria.

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“…4.5E). This is consistent with previous data supporting a stronger antiplasmodial activity of (+) enantiomer (248)(249)(250) and further supports that the PfPNP inhibition contributes to the antimalarial activity of MFQ. Subsequently, we evaluated the antimalarial activity of both drugs in combination with ImmH in the absence of purines.…”

Section: Structural Evidence For the Drug Interaction With Pfpnpsupporting

confidence: 93%

Molecular analysis of antimalarial therapies : from drug development to mode of action

Dziekan¹

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Absolute Configuration and Antimalarial Activity of erythro‐Mefloquine Enantiomers

Cited by 18 publications

References 23 publications

Crystal structure and Hirshfeld analysis of the kryptoracemate: bis(mefloquinium) chloride p-fluorobenzenesulphonate

Crystal structure and Hirshfeld analysis of the kryptoracemate: bis(mefloquinium) chloride p-fluorobenzenesulphonate

Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis

Molecular analysis of antimalarial therapies : from drug development to mode of action

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