Enantiomerically pure amino-alcohol quinolines: in vitro anti-malarial activity in combination with dihydroartemisinin, cytotoxicity and in vivo efficacy in a Plasmodium berghei mouse model

International audienceBackground: As resistance to marketed anti-malarial drugs continues to spread, the need for new molecules active on Plasmodium falciparum-resistant strains grows. Pure (S) enantiomers of amino-alcohol quinolines previously displayed a good in vitro anti-malarial activity. Therefore, a more thorough assessment of their potential clinical use through a rodent model and an in vitro evaluation of their combination with artemisinin was undertaken. Methods: Screening on a panel of P. falciparum clones with varying resistance profiles and regional origins was performed for the (S)-pentyl and (S)-heptyl substituted quinoline derivatives, followed by an in vitro assessment of their combination with dihydroartemisinin (DHA) on the 3D7 clone and an in vivo assay in a mouse model infected with Plasmodium berghei. Their haemolytic activity was also determined. Results: A steady anti-malarial activity of the compounds tested was found, whatever the resistance profile or the regional origin of the strain. (S)-quinoline derivatives were at least three times more potent than mefloquine (MQ), their structurally close parent. The in vitro combination with DHA yielded an additive or synergic effect for both that was as good as that of the DHA/MQ combination. In vivo, survival rates were similar to those of MQ for the two compounds at a lower dose, despite a lack of clearance of the parasite blood stages. A 50% haemolysis was observed for concentrations at least 1,000-fold higher than the antiplasmodial IC 50 s. Conclusions: The results obtained make those two (S)-amino-alcohol quinoline derivatives good candidates for the development of new artemisinin-based combination therapy (ACT), hopefully with fewer neurologic side effects than those currently marketed ACT, including MQ

Early treatment failure during treatment of Plasmodium falciparum malaria with atovaquone-proguanil in the Republic of Ivory Coast

The increased spread of drug-resistant malaria highlights the need for alternative drugs for treatment and chemoprophylaxis. The combination of atovaquone‐proguanil (Malarone®) has shown high efficacy against Plasmodium falciparum with only mild side-effects. Treatment failures have been attributed to suboptimal dosages or to parasite resistance resulting from a point mutation in the cytochrome b gene. In this paper, a case of early treatment failure was reported in a patient treated with atovaquone-proguanil; this failure was not associated with a mutation in the parasite cytochrome b gene, with impaired drug bioavailability, or with re-infection

Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

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Nouvelles approches thérapeutiques pour le traitement du paludisme (Inhibiteurs du métabolisme phospholipidique de Plasmodium. Validation de méthodes bioanalytiques en vue d'études précliniques et cliniques)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Molécules inhibitrices du métabolisme phospholipidique de plasmodium (développement préclinique d'une nouvelle approche thérapeutique)

Dans le cadre du développement de molécules ciblant le métabolisme phospholipidique de Plasmodium, nous présentons dans cette thèse la validation de méthodes analytiques ainsi que les études réalisés in vivo et in vitro sur quatre composés de cette nouvelle série chimique. Dans la première partie de notre thèse, les mécanismes physiopathologiques du neuropaludisme ainsi que les différentes axes de recherche sont développés. Dans une seconde partie, nous présenterons la série chimique sur laquelle nous avons travaillé. La troisième partie expose les résultats des méthodes analytiques validées selon les citères recommandés par la FDA pour la quantification des composés étudiés dans différentes matrices de différentes espèces animales. Le problème de l'effet matrice en spectrométrie de masse est également développé. Les résultats des études de distribution erythrocytes/plasma et de bioconversion prodrogue/drogue dans des matrices d'éspèces différentes sont présentés dans la quatrième partie. Enfin, dans une dernière partie nous rapporterons les études pharmacocinétiques et pharmacocinétiques / pharmacodynamiques réalisés chez le rat, la souris et le porc.MONTPELLIER-BU Pharmacie (341722105) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Evaluation de l'activité antipaludique de 4-aminoalcools quinoléines énantiomériquement pures

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Les biomarqueurs de l’intoxication par l’ypérite

International audienceSulfur mustard is a chemical warfare agent that damages the eyes, lungs and skin. In the latter, it induces severeburns that classify it as vesicant agents. Highly reactive, sulfur mustard has the ability to alkylate many biomolecules.The products derived from these reactions can be used, mainly using analytical chemistry methods, as biomarkersof exposure or effect. Sulfur mustard also greatly disrupts metabolism and protein induction. These responsescan be used to highlight longer-term effects.L’ypérite est un toxique de guerre endommageant les yeux, les poumons et la peau. Dans cette dernière, elle induitde graves brûlures qui la classent parmi les agents vésicants. Très réactive, elle possède des capacités d’alkylationde nombreuses biomolécules. Les produits qui en dérivent peuvent être utilisés, principalement en employantdes méthodes de chimie analytique, comme biomarqueurs d’exposition ou d’effet. L’ypérite perturbe égalementfortement le métabolisme et l’induction de protéines. Ces réponses sont utilisables pour mettre en évidencedes effets à plus long terme

Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

Abstract Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ) (+)- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The (S)-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ) and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R )-enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S) counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S) and (R)-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro.</p

Trojan horse strategy: synthesis of piperazine-based siderophores

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