Regioselective Synthesis of Potential Non-Quinonoid Prodrugs of Plasmodione: Antiparasitic Properties Against Two Hemoglobin-Feeding Parasites and Drug Metabolism Studies.

Ψ-1,4-naphthoquinones (Ψ-NQ) are non-quinoid compounds in which aromaticity-found in 1,4-naphthoquinones-is broken by the introduction of an angular methyl at C-4a or -8a. This series was designed to act as prodrugs of 1,4-naphthoquinones in an oxidative environment. Furthermore, from a medicinal chemistry point of view, the loss of planarity of the scaffold might lead to an improved solubility and circumvent the bad reputation of quinones in the pharmaceutical industry.

Chemoselective Synthesis and Anti-Kinetoplastidal Properties of 2,6-Diaryl-4-tetrahydro-thiopyran-4-one -Oxides: Their Interplay in a Cascade of Redox Reactions from Diarylideneacetones.

2,6-Diaryl-4-tetrahydro-thiopyran-4-ones and corresponding sulfoxide and sulfone derivatives were designed to lower the major toxicity of their parent anti-kinetoplatidal diarylideneacetones through a prodrug effect. Novel diastereoselective methodologies were developed and generalized from diarylideneacetones and 2,6-diaryl-4-tetrahydro-thiopyran-4-ones to allow the introduction of a wide substitution profile and to prepare the related -oxides. The in vitro biological activity and selectivity of diarylideneacetones, 2,6-diaryl-4-tetrahydro-thiopyran-4-ones, and their -sulfoxide and sulfone metabolites were evaluated against , , and various species in comparison with their cytotoxicity against human fibroblasts MRC-5.

Synthesis of plasmodione metabolites and C-enriched plasmodione as chemical tools for drug metabolism investigation.

Malaria is a tropical parasitic disease threatening populations in tropical and sub-tropical areas. Resistance to antimalarial drugs has spread all over the world in the past 50 years, thus new drugs are urgently needed. Plasmodione (benzylmenadione series) has been identified as a potent antimalarial early lead drug, acting through a redox bioactivation on asexual and young sexual blood stages.

Synthesis, biological evaluation and molecular modeling studies on novel quinonoid inhibitors of CDC25 phosphatases.

The cell division cycle 25 phosphatases (CDC25A, B, and C; E.C. 3.

In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids.

Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted.

Antimalarial NADPH-Consuming Redox-Cyclers As Superior Glucose-6-Phosphate Dehydrogenase Deficiency Copycats.

Aims: Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum were shown to protect G6PD-deficient populations from severe malaria. Here, we investigated the mechanism of a novel antimalarial series, namely 3-[substituted-benzyl]-menadiones, to understand whether these NADPH-consuming redox-cyclers, which induce oxidative stress, mimic the natural protection of G6PD deficiency.

Results: We demonstrated that the key benzoylmenadione metabolite of the lead compound acts as an efficient redox-cycler in NADPH-dependent methaemoglobin reduction, leading to the continuous formation of reactive oxygen species, ferrylhaemoglobin, and subsequent haemichrome precipitation.

Electrochemical properties of substituted 2-methyl-1,4-naphthoquinones: redox behavior predictions.

In the context of the investigation of drug-induced oxidative stress in parasitic cells, electrochemical properties of a focused library of polysubstituted menadione derivatives were studied by cyclic voltammetry. These values were used, together with compatible measurements from literature (quinones and related compounds), to build and evaluate a predictive structure-redox potential model (quantitative structure-property relationship, QSPR). Able to provide an online evaluation (through Web interface) of the oxidant character of quinones, the model is aimed to help chemists targeting their synthetic efforts towards analogues of desired redox properties.

1,4-naphthoquinones and other NADPH-dependent glutathione reductase-catalyzed redox cyclers as antimalarial agents.

The homodimeric flavoenzyme glutathione reductase catalyzes NADPH-dependent glutathione disulfide reduction. This reaction is important for keeping the redox homeostasis in human cells and in the human pathogen Plasmodium falciparum. Different types of NADPH-dependent disulfide reductase inhibitors were designed in various chemical series to evaluate the impact of each inhibition mode on the propagation of the parasites.

Synthesis and biological evaluation of 1,4-naphthoquinones and quinoline-5,8-diones as antimalarial and schistosomicidal agents.

Improving the solubility of polysubstituted 1,4-naphthoquinone derivatives was achieved by introducing nitrogen in two different positions of the naphthoquinone core, at C-5 and at C-8 of menadione through a two-step, straightforward synthesis based on the regioselective hetero-Diels-Alder reaction. The antimalarial and the antischistosomal activities of these polysubstituted aza-1,4-naphthoquinone derivatives were evaluated and led to the selection of distinct compounds for antimalarial versus antischistosomal action. The Ag(II)-assisted oxidative radical decarboxylation of the phenyl acetic acids using AgNO(3) and ammonium peroxodisulfate was modified to generate the 3-picolinyl-menadione with improved pharmacokinetic parameters, high antimalarial effects and capacity to inhibit the formation of β-hematin.

Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase.

Menadione is the 2-methyl-1,4-naphthoquinone core used to design potent antimalarial redox-cyclers to affect the redox equilibrium of Plasmodium-infected red blood cells. Exploring the reactivity of fluoromethyl-1,4-naphthoquinones, in particular trifluoromenadione, under quasi-physiological conditions in NADPH-dependent glutathione reductase reactions, is discussed in terms of chemical synthesis, electrochemistry, enzyme kinetics, and antimalarial activities. Multitarget-directed drug discovery is an emerging approach to the design of new antimalarial drugs.

A physico-biochemical study on potential redox-cyclers as antimalarial and anti-schistosomal drugs.

The role of redox enzymes in establishing a microenvironment for parasite development is well characterized. Mimicking human glucose-6-phosphate dehydrogenase and glutathione reductase (GR) deficiencies by redox-cycling compounds thus represents a challenge to the design of new preclinical antiparasitic drug candidates. Schistosomes and malarial parasites feed on hemoglobin.

Solution-phase mechanistic study and solid-state structure of a tris(bipyridinium radical cation) inclusion complex.

The ability of the diradical dicationic cyclobis(paraquat-p-phenylene) (CBPQT(2(•+))) ring to form inclusion complexes with 1,1'-dialkyl-4,4'-bipyridinium radical cationic (BIPY(•+)) guests has been investigated mechanistically and quantitatively. Two BIPY(•+) radical cations, methyl viologen (MV(•+)) and a dibutynyl derivative (V(•+)), were investigated as guests for the CBPQT(2(•+)) ring. Both guests form trisradical complexes, namely, CBPQT(2(•+))⊂MV(•+) and CBPQT(2(•+))⊂V(•+), respectively.

Glutathione reductase-catalyzed cascade of redox reactions to bioactivate potent antimalarial 1,4-naphthoquinones--a new strategy to combat malarial parasites.

Our work on targeting redox equilibria of malarial parasites propagating in red blood cells has led to the selection of six 1,4-naphthoquinones, which are active at nanomolar concentrations against the human pathogen Plasmodium falciparum in culture and against Plasmodium berghei in infected mice. With respect to safety, the compounds do not trigger hemolysis or other signs of toxicity in mice. Concerning the antimalarial mode of action, we propose that the lead benzyl naphthoquinones are initially oxidized at the benzylic chain to benzoyl naphthoquinones in a heme-catalyzed reaction within the digestive acidic vesicles of the parasite.

Isomerization mechanism in hydrazone-based rotary switches: lateral shift, rotation, or tautomerization?

Two intramolecularly hydrogen-bonded arylhydrazone (aryl = phenyl or naphthyl) molecular switches have been synthesized, and their full and reversible switching between the E and Z configurations have been demonstrated. These chemically controlled configurational rotary switches exist primarily as the E isomer at equilibrium and can be switched to the protonated Z configuration (Z-H(+)) by the addition of trifluoroacetic acid. The protonation of the pyridine moiety in the switch induces a rotation around the hydrazone C=N double bond, leading to isomerization.

Enantiomeric differentiation of atropine/hyoscyamine by (13) C NMR spectroscopy and its application to Datura stramonium extract.

Introduction: The two enantiomers of hyoscyamine, an alkaloid found in many plant species, have distinct pharmacological and biological properties. Methods for the discrimination of both enantiomers are almost exclusively based on chiral HPLC/UV. Determination of the enantiomeric ratio (e.

Bioactive phenylpropanoids from Daucus crinitus Desf. from Algeria.

The volatile constituents of Daucus crinitus Desf. from Algeria were analyzed by GC and GC-MS, The main constituent was isochavicol isobutyrate (39.0%), an uncommon phenylpropanoid.

Enantiomeric differentiation of oxygenated p-menthane derivatives by 13C NMR using Yb(hfc)3.

The (13)C NMR behaviour of 21 p-menthanic terpene bearing an oxygenated function (alcohol, ketone, acetate) was examined in the presence of a chiral lanthanide shift reagent (Yb(hfc)(3)). For each monocyclic compound, we measured the lanthanide-induced shift (LIS) on the signals of the carbons and the splitting of signals allowing the enantiomeric differentiation. Some general features were found about their LIS behaviour: experimental data establishing distinct patterns for carvomenthone-like compounds and menthone-like compounds.

Composition, enantiomeric distribution, and antibacterial activity of the essential oil of Achillea ligustica All. from Corsica.

The essential oil of Achillea ligustica from Corsica was investigated by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). A total of 82 compounds representing 94.0% of the oil were tentatively identified.

Asymmetric Diels-Alder reactions of a new enantiomerically pure sulfinylquinone: a straightforward access to functionalized Wieland-Miescher ketone analogues with (R) absolute configuration.

An efficient and highly stereocontrolled preparation, on a large scale, of two new Wieland-Miescher-type diketones is described. The approach centers on a diastereoselective Diels-Alder reaction using a new enantiomerically pure sulfinylquinone. Mechanistic investigations of this cycloaddition on several dienes are described.