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Malaria and schistosomiasis are two of the most socioeconomically devastating parasitic diseases in tropical and subtropical countries. Since current chemotherapeutic options are limited and defective, there is an urgent need to develop novel antiplasmodials and antischistosomals. Hemozoin is a disposal product formed from the hemoglobin digestion by some blood-feeding parasites. Hemozoin formation is an essential process for the parasites to detoxify free heme, which is a reliable therapeutic target for identifying novel antiparasitic agents. A series of novel carbazole aminoalcohols were designed and synthesized as potential antiplasmodial and antischistosomal agents, and several compounds showed potent in vitro activities against Plasmodium falciparum 3D7 and Dd2 strains and adult and juvenile Schistosoma japonicum. Investigations on the dual antiparasitic mechanisms showed the correlation between inhibitory activity of β-hematin formation and antiparasitic activity. Inhibiting hemozoin formation was identified as one of the mechanisms of action of carbazole aminoalcohols. Compound 7 displayed potent antiplasmodial (Pf3D7 IC50 = 0.248 μM, PfDd2 IC50 = 0.091 μM) and antischistosomal activities (100% mortality of adult and juvenile schistosomes at 5 and 10 μg/mL, respectively) and exhibited low cytotoxicity (CC50 = 7.931 μM), which could be considered as a promising lead for further investigation. Stoichiometry determination and molecular docking studies were also performed to explain the mode of action of compound 7., Graphical abstract Image 1, Highlights • Carbazole aminoalcohol was confirmed as a novel antiplasmodial and antischistosomal scaffold. • The mechanism of action relied on β-hematin formation inhibition. • The carbazole aminoalcohols interacted with hematin through forming a 1:1 complex. • Compound 7 showed potent antiplasmodial ability (Pf3D7 IC50 = 0.248 μM, PfDd2 IC50 = 0.091 μM). • In vitro antischistosomal effect of 7 meets the WHO's criterion of “hit” for schistosomiasis control.

The parasitic disease malaria places almost half of the world’s population at risk of infection and is responsible for more than 400,000 deaths each year. The first-line treatment, artemisinin combination therapies (ACT) regimen, is under threat due to emerging resistance of Plasmodium falciparum strains in e.g. the Mekong delta. Therefore, the development of new antimalarial agents is crucial in order to circumvent the growing resistance. Chloroquine, the long-established antimalarial drug, still serves as model compound for the design of new quinoline analogues, resulting in numerous new active derivatives against chloroquine-resistant P. falciparum strains over the past twenty years. In this work, a set of functionalized quinoline analogues, decorated with a modified piperidine-containing side chain, was synthesized. Both amino- and (aminomethyl)quinolines were prepared, resulting in a total of 18 novel quinoline-piperidine conjugates representing four different chemical series. Evaluation of their in vitro antiplasmodium activity against a CQ-sensitive (NF54) and a CQ-resistant (K1) strain of P. falciparum unveiled highly potent activities in the nanomolar range against both strains for five 4-aminoquinoline derivatives. Moreover, no cytotoxicity was observed for all active compounds at the maximum concentration tested. These five new aminoquinoline hit structures are therefore of considerable value for antimalarial research and have the potency to be transformed into novel antimalarial agents upon further hit-to-lead optimization studies., Graphical abstract Image 1, Highlights • Four different series of new quinoline analogues decorated with a piperidine-containing side chain were synthesized. • Antiplasmodium assessments in NF54 (CQ-sensitive) and K1 (CQ-resistant) strains of P. falciparum were performed. • Five 4-aminoquinoline-piperidine compounds displayed nanomolar activities against both NF54 and K1 and no CHO toxicity.

International audience; In this work, a quantitative kinetic model for investigating the heme-induced peroxidation of linoleic acid and its inhibition by two important dietary antioxidants, quercetin and α-tocopherol, is developed. The main conclusions of this work are: (1) The time dependence of the lipid hydroperoxide concentration is critically dependent on the rate constant for lipid hydroperoxide cleavage, initial fraction of lipid hydroperoxides among the pool of conjugated dienes, and rate of heme degradation. (2) The lipophilic antioxidant α-tocopherol acts as a chain-breaking antioxidant that quickly reduces 1–2 eq of lipid peroxyl radicals (inhibition of propagation), whereas the more hydrophilic antioxidant quercetin is only marginally chain-breaking but capable of reducing 4–5 eq of iron-oxo initiator (inhibition of initiation). (3) Based on comparisons between experimental peroxidation curves and simulated curves assuming additivity, it can be concluded that combinations of α-tocopherol and quercetin are generally synergistic. The kinetic analysis and HPLC titrations of the antioxidants both suggest that synergism mainly arises from a capacity of α-tocopherol to regenerate some quercetin oxidation products still endowed with a reducing activity.

Approximately 70% of the initial ferriprotoporphyrin IX polymerizing activity in cell-free preparations of erythrocytes infected with Plasmodium berghei was recovered in a chloroform extract. No polymerizing activity remained in the residue. In studies to identify substances that promote FP polymerization, arachidonic, linoleic, oleic, and palmitoleic acids, 1-mono- and di-oleoylglycerol, and the detergents, SDS, Tween 80, and n-octyl-glucopyranoside, were active. Tri-oleoylglycerol, cholesterol, di-oleoylphosphatidylethanolamine, and stearic and palmitic acids were inactive. The model lipid, mono-oleoylglycerol (250 nmol), co-precipitated with FP from a 0.09 M acetate medium at pH 5 and promoted the polymerization of 215 nmol (61%) of the ferriprotoporphyrin IX in the precipitate during a 24-h incubation at 37 degrees C. Polymerization was maximal at pH 5, it was approximately linear for 2 h, and it continued at a decreasing rate for 24 h. The polymer contained exclusively ferriprotoporphyrin IX (97+/-1.3%, mean+/-S.E., n=4) and exhibited the solubility and the electronic absorption and infrared spectral characteristics of the sequestered ferriprotoporphyrin IX of hemozoin. Detergents presumably promote polymerization in an acid medium by helping to dissolve monomeric FP. We suggest that unsaturated lipids co-precipitate with FP in the parasite's acidic food vacuole and also dissolve sufficient monomeric FP to allow polymerization.