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The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C−H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal‐catalyzed C−H functionalization of a "programmed" 4‐hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity‐oriented functionalization, of which four were targeted. The C‐2 and C‐8 decorations were directed by an N‐oxide, before taking benefit of an O‐carbamoyl protection at C‐4 to perform a Fries rearrangement and install a carboxamide at C‐3. This also released the carbonyl group of 4‐quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C−H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential. [ABSTRACT FROM AUTHOR]

Gregarines, a polyphyletic group of apicomplexan parasites infecting mostly non‐vertebrates hosts, remains poorly known at taxonomic, phylogenetic and genomic levels. However, it represents an essential group for understanding evolutionary history and adaptive capacities of apicomplexan parasites to the remarkable diversity of their hosts. Because they have a mostly extracellular lifestyle, gregarines have developed other cellular developmental forms and host–parasite interactions, compared with their much better studied apicomplexan cousins, intracellular parasites of vertebrates (Hemosporidia, Coccidia, Cryptosporidia). This review highlights the promises offered by the molecular exploration of gregarines, that have been until now left on the side of the road of the comparative –omic exploration of apicomplexan parasites. Elucidating molecular bases for both their ultrastructural, functional and behavioural similarities and differences, compared with those of the typical apicomplexan models, is expected to provide entirely novel clues on the adaptive capacities developed by Apicomplexa over evolution. A challenge remains to identify which gregarines should be explored in priority, as recent metadata from open and host‐associated environments have confirmed how underestimated is our current view on true gregarine biodiversity. It is now time to turn to gregarines to widen the currently highly skewed view we have of adaptive mechanisms developed by Apicomplexa. [ABSTRACT FROM AUTHOR]

A series of substituted 3-azabicyclo[4.1.0]hept-4-ene derivatives were prepared and analysed by cyclic voltammetry. Preparative aerobic electrochemical oxidation reactions were then carried out. Three original endoperoxides were isolated, characterised and subjected to antimalarial and cytotoxicity activity assays. [ABSTRACT FROM AUTHOR]

The most severe form of human malaria is caused by the parasite Plasmodium falciparum. Despite the current need, there is no effective vaccine and parasites are becoming resistant to most of the antimalarials available. Therefore, there is an urgent need to discover new drugs from targets that have not yet suffered from drug pressure with the aim of overcoming the problem of new emerging resistance. Membrane transporters, such as P. falciparum Ca2+- ATPase 6 ( Pf ATP6), the P. falciparum sarcoplasmic/endoplasmic reticulum Ca2+- ATPase ( SERCA), have been proposed as potentially good antimalarial targets. The present investigation focuses on: (a) the large-scale purification of Pf ATP6 for maintenance of its enzymatic activity; (b) screening for Pf ATP6 inhibitors from a compound library; and (c) the selection of the best inhibitors for further tests on P. falciparum growth in vitro. We managed to heterologously express in yeast and purify an active form of Pf ATP6 as previously described, although in larger amounts. In addition to some classical SERCA inhibitors, a chemical library of 1680 molecules was screened. From these, we selected a pool of the 20 most potent inhibitors of Pf ATP6, presenting half maximal inhibitory concentration values in the range 1-9 μ m. From these, eight were chosen for evaluation of their effect on P. falciparum growth in vitro, and the best compound presented a half maximal inhibitory concentration of ~ 2 μ m. We verified the absence of an inhibitory effect of most of the compounds on mammalian SERCA1a, representing a potential advantage in terms of human toxicity. The present study describes a multidisciplinary approach allowing the selection of promising Pf ATP6-specific inhibitors with good antimalarial activity. [ABSTRACT FROM AUTHOR]

Probiotics are defined as live organisms, which confer benefits to the host. Their efficiency was demonstrated for the treatment of gastrointestinal disorders, respiratory infections, and allergic symptoms, but their use is mostly limited to bacterial and viral diseases. During the last decade, probiotics as means for the control of parasite infections were reported covering mainly intestinal diseases but also some nongut infections, that are all of human and veterinary importance. In most cases, evidence for a beneficial effect was obtained by studies using animal models. In a few cases, cellular interactions between probiotics and pathogens or relevant host cells were also investigated using in vitro culture systems. However, molecular mechanisms mediating the beneficial effects are as yet poorly understood. These studies indicate that probiotics might indeed provide a strain-specific protection against parasites, probably through multiple mechanisms. But more unravelling studies are needed to justify probiotic utilisation in therapeutics. [ABSTRACT FROM AUTHOR]