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Siderophores are chelators with a high selectivity for Fe(III) and a good affinity for divalent metals, including Cd(II) and Ni(II). Inoculation with siderophore-producing bacteria (SPB) has thus been proposed as an alternative to chelator supply in phytoremediation. Accurate assessments of the potential of this association require a dissection of the interaction of siderophores with metals at the soil-root interface. This study focuses on pyoverdine (Pvd), the main siderophore produced by Pseudomonas aeruginosa. We first assessed the ability of Pvd to coordinate Ni(II). The stability constant of Pvd-Ni(II) (log K = 10.9) was found to be higher than that of Pvd-Cd(II) (log K = 8.2). We then investigated the effect of a direct supply of Pvd on the mobilization, speciation, and phytoavailability of Cd and Ni in hydroponics. When supplied at a concentration of 50 μM, Pvd selectively promoted Ni mobilization from smectite. It decreased plant Ni and Cd contents and the free ionic fractions of these two metals, consistent with the free ion activity model. Pvd had a more pronounced effect for Ni than for Cd, as predicted from its coordination properties. Inoculation with P. aeruginosa had a similar effect on Ni phytoavailability to the direct supply of Pvd. [ABSTRACT FROM AUTHOR]

This study explores the synthesis and evaluation of novel 1,2,3-triazole-methyl-1,4-naphthoquinone hybrids, focusing on their electrochemical properties and antiparasitic efficacies against two human blood-dwelling parasites Plasmodium falciparum and Schistosoma mansoni. Using copper-catalyzed azide-alkyne cycloaddition (CuAAC), a well-established tool in click chemistry, two synthetic routes were assessed to develop a- and b-[triazole-methyl]-menadione derivatives. By optimizing the CuAAC reaction conditions, yields were significantly improved, reaching up to 94% for key intermediates and resulting in the formation of a library of approximately 30 compounds. Biological evaluation of the compounds in antiparasitic drug assays demonstrated notable antischistosomal potencies, while no significant activity was observed for the same series against P. falciparum parasites. Electrochemical and 'benzylic' oxidation studies confirmed that the active 'benzoyl' metabolite responsible for the antiplasmodial activity of plasmodione cannot be generated. These findings highlight the potential of triazole-linked menadione hybrids as promising early candidates for antischistosomal drug development, and provides insights into structure-activity relationships crucial for future therapeutic strategies., (© 2024 Wiley‐VCH GmbH.)

The development of redox-sensitive molecular fluorescent probes for the detection of redox changes in Plasmodium falciparum-parasitized red blood cells remains of interest due to the limitations of current genetically encoded biosensors. This study describes the design, screening and synthesis of new pro-fluorophores based on flavylium azido dyes coupled by CuAAC click chemistry to alkynyl analogues of plasmodione oxide, the key metabolite of the potent redox-active antimalarial plasmodione. The photophysical and electrochemical properties of these probes were evaluated, focusing on their fluorogenic responses. The influence of both the redox status of the quinone and the length of the PEG chain separating the fluorophore from the electrophore on the photophysical properties was investigated. The fluorescence quenching by photoinduced electron transfer is reversible and of high amplitude for probes in oxidized quinone forms and fluorescence is reinstated for reduced hydroquinone forms. Our results demonstrate that shortening the PEG chain has the effect of enhancing the fluorogenic response, likely due to non-covalent interactions between the two chromophores. All these systems were evaluated for their antiparasitic activities and fluorescence imaging suggests the efficacy of the fluorescent flavylium dyes in P. falciparum-parasitized red blood cells, paving the way for future parasite imaging studies to monitor cellular redox processes., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

With their rigid and preorganized skeleton, bispidine (3,7-diazabicyclo[3.3.1]nonane) chelators are very appealing for the preparation of metal complexes with high kinetic inertness. With the aim to develop new Tb(III)-based medical imaging probes, this study describes the synthesis and physicochemical properties of two novel terbium(III) complexes with octadentate bispidine-based ligands substituted with either pyridine-phosphonate (H 6 L 1 ) or picolinate (H 4 L 2 ) subunits. Thermodynamic stability constants of the corresponding Tb(III) complexes have been determined by potentiometric, UV-visible absorption spectrophotometric and spectrofluorimetric methods. Despite their apparent similarity, these two octadentate ligands differ in their most stable conformation: chair - chair conformation for H 4 L 2 M concentration. The complex was also very inert in the presence of a 50-fold excess of Zn(II) in H boat - chair conformation for H 6 L 1 , as confirmed by 1 H NMR studies and suggested by physicochemical investigations. This conformational change induces different protonation schemes for the two ligands. The kinetic inertness of the Tb complexes has been studied in various media and assessed by transmetalation and transchelation experiments. In particular, Tb( L 2 ) displayed a remarkable kinetic inertness with no measurable dissociation over two months in mouse serum at 10 -5 M concentration. The complex was also very inert in the presence of a 50-fold excess of Zn(II) in H 2 O at pH = 7.4 (7% of dissociation over two months). The complexes with ligand L 1 are significantly less inert, emphasizing the influence of the ligand conformation on the kinetic inertness of the Ln(III) complexes. Finally, the luminescence properties of the isolated complexes have also been investigated. A bright green luminescence was observed, especially for Tb( L 2 ), which displays a high quantum yield value of 50% in H 2 O (60% in D 2 O; λ exc = 263 nm). In addition, luminescence lifetimes of 1.9(2) and 1.7(2) ms have been measured for Tb( L 1 ) and Tb( L 2 ), respectively, hence confirming the formation of nona-coordinated complexes with one inner-sphere water molecule. These data on a bispidine scaffold pave the way for developing bright, inert luminescent probes for bioimaging and for radiolabeling applications with Tb(III) radioisotopes.

Understanding the mechanisms of drug action in malarial parasites is crucial for the development of new drugs to combat infection and to counteract drug resistance. Proteomics is a widely used approach to study host-pathogen systems and to identify drug protein targets. Plasmodione is an antiplasmodial early-lead drug exerting potent activities against young asexual and sexual blood stages in vitro with low toxicity to host cells. To elucidate its molecular mechanisms, an affinity-based protein profiling (AfBPP) approach was applied to yeast and P. falciparum proteomes. New (pro-) AfBPP probes based on the 3-benz(o)yl-6-fluoro-menadione scaffold were synthesized. With optimized conditions of both photoaffinity labeling and click reaction steps, the AfBPP protocol was then applied to a yeast proteome, yielding 11 putative drug-protein targets. Among these, we found four proteins associated with oxidoreductase activities, the hypothesized type of targets for plasmodione and its metabolites, and other proteins associated with the mitochondria. In Plasmodium parasites, the MS analysis revealed 44 potential plasmodione targets that need to be validated in further studies. Finally, the localization of a 3-benzyl-6-fluoromenadione AfBPP probe was studied in the subcellular structures of the parasite at the trophozoite stage., (© 2024 The Author(s). ChemBioChem published by Wiley-VCH GmbH.)

This work describes the reactivity and properties of fluorinated derivatives ( F-PD and F-PDO ) of plasmodione ( PD ) and its metabolite, the plasmodione oxide ( PDO ). Introduction of a fluorine atom on the 2-methyl group markedly alters the redox properties of the 1,4-naphthoquinone electrophore, making the compound highly oxidizing and particularly photoreactive. A fruitful set of analytical methods (electrochemistry, absorption and emission spectrophotometry, and HRMS-ESI) have been used to highlight the products resulting from UV photoirradiation in the absence or presence of selected nucleophiles. With F-PDO and in the absence of nucleophile, photoreduction generates a highly reactive ortho -quinone methide ( o -QM) capable of leading to the formation of a homodimer. In the presence of thiol nucleophiles such as β-mercaptoethanol, which was used as a model, o -QMs are continuously regenerated in sequential photoredox reactions generating mono- or disulfanylation products as well as various unreported sulfanyl products. Besides, these photoreduced adducts derived from F-PDO are characterized by a bright yellowish emission due to an excited-state intramolecular proton transfer (ESIPT) process between the dihydronapthoquinone and benzoyl units. In order to evidence the possibility of an intramolecular coupling of the o -QM intermediate, a synthetic route to the corresponding anthrones is described. Tautomerization of the targeted anthrones occurs and affords highly fluorescent stable hydroxyl-anthraquinones. Although probable to explain the intense visible fluorescence emission also observed in tobacco BY-2 cells used as a cellular model, these coupling products have never been observed during the photochemical reactions performed in this study. Our data suggest that the observed ESIPT-induced fluorescence most likely corresponds to the generation of alkylated products through reduction species, as demonstrated with the β-mercaptoethanol model. In conclusion, F-PDO thus acts as a novel (pro)-fluorescent probe for monitoring redox processes and protein alkylation in living cells.

A series of heptamethine-oxonol dyes featuring different heterocyclic end groups were designed with the aim to explore structure-property relationships in π-extended coupled polymethines. These dyes can be stabilised under three different protonation states, affording dicationic derivatives with an aromatic core, cationic heptamethines, and zwitterionic bis-cyanine forms. The variation of the end groups directly impacts the absorption and emission properties and mostly controls reaching either a colourless neutral dispirocyclic species or near-infrared zwitterions. The acidochromic switching between the three states involves profound electronic rearrangements leading to notable shifts of their optical properties that were investigated using a parallel experiment-theory approach, providing a comprehensive description of these unique systems., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A second generation of cyanine-based near-infrared photocatalysts has been developed to accelerate organic transformations. Cyanines were prepared and fully characterized prior to evaluation of their photocatalytic activities. Catalyst efficiency was determined by using two model oxidation and reduction reactions. For the aza-Henry reaction, cyanines bearing an amino group on the heptamethine chain led to the best results. For trifluoromethylation, the stability of the photocatalyst was found to be the key parameter for efficient and rapid conversion., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Photodynamic therapy (PDT) is a photochemistry-based medical treatment combining light at a specific wavelength and a photosensitizer (PS) in the presence of oxygen. Application of PDT as a conventional treatment is limited and clearly the approval in clinics of new PS is challenging. The selective accumulation of the PS in the targeted malignant cells is of paramount importance to reduce the side effects that are typical of the current worldwide approved PS. Here we report a new series of aniline- and iodine-substituted BODIPY derivatives (1-3) as promising lysosome-targeting and pH-responsive theranostic PS, which displayed a significant in vitro light-induced cytotoxicity, efficient imaging properties and low dark toxicity (for 2 and 3). These compounds were obtained in few reproducible synthetic steps and good yields. Spectroscopic and electrochemical measurements along with computational calculations confirmed the quenching of the emissive properties of the PS, while both fluorescence and 1 O 2 emission were obtained only under acidic conditions inducing amine protonation. The pK a values and pH-dependent emissive properties of 1-3 being established, their cellular uptake and activation in the lysosomal vesicles (pH≈4-5) were confirmed by their co-localization with the commercial LysoTracker deep red and light-induced cytotoxicity (IC 50 between 0.16 and 0.06 μM) against HeLa cancer cells., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

The straightforward access to N- or C-substituted dinitro-tetraamino-phenazines ( P1-P5 ) is enabled in oxidative conditions via formation of two intermolecular C-N bonds from accessible 5-nitrobenzene-1,2,4-triamine precursors. The photophysical studies revealed green absorbing and orange-red emitting dyes, with enhanced fluorescence in the solid state. Further reduction of the nitro functions led to the isolation of a benzoquinonediimine-fused quinoxaline ( P6 ), which undergoes diprotonation to form a dicationic coupled trimethine dye absorbing beyond 800 nm.

Herein, unprecedented uses of squaraine derivatives as new organic near-infrared photocatalysts are reported. These efficient molecular tools are able to promote oxidation and reduction for organic transformations through photocatalytic conditions. A mechanistic investigation is performed to distinguish between competitive Single Electron Transfer and Energy Transfer pathways.

A series of ferrocenyl-containing γ-hydroxy-γ-lactam tetramates were prepared in 2-3 steps through ring opening-ring closure (RORC) process of γ-ylidene-tetronate derivatives in the presence of ferrocenyl alkylamines. The compounds were screened in vitro for their antiplasmodial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) clones of P. falciparum, displaying activity in the range of 0.12-100 μM, with generally good resistance index. The most active ferrocene in these series exhibited IC 50 equal to 0.09 μM (3D7) and 0.12 μM (W2). The low cytotoxicity of the ferrocenyl-containing γ-hydroxy-γ-lactam tetramates against Human Umbilical Vein Endothelial (HUVEC) cell line demonstrated selective antiparasitic activity. The redox properties of these ferrocene-derived tetramates were studied and physico-biochemical studies evidenced that these derivatives can exert potent antimalarial activities via a mechanism distinct from ferroquine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Ionic covalent organic frameworks (iCOFs) are new examples of porous materials and have shown great potential for various applications. When functionalized with suitable emission sites, guest uptake via the ionic moieties of iCOFs can cause a significant change in luminescence, making them excellent candidates for chemosensors. In here, we present a luminescence sensor in the form of an ionic covalent organic framework (TGH + •PD) composed of guanidinium and phenanthroline moieties for the detection of ammonia and primary aliphatic amines. TGH + •PD exhibits strong emission enhancement in the presence of selective primary amines due to the suppression of intramolecular charge transfer (ICT) with an ultra-low detection limit of 1.2 × 10 ‒7 M for ammonia. The presence of ionic moieties makes TGH + •PD highly dispersible in water, while deprotonation of the guanidinium moiety by amines restricts its ICT process and signals their presence by enhanced fluorescence emission. The presence of ordered pore walls introduces size selectivity among analyte molecules, and the iCOF has been successfully used to monitor meat products that release biogenic amine vapors upon decomposition due to improper storage., (© 2022. The Author(s).)

Intraerythrocytic malaria parasites proliferate bounded by a parasitophorous vacuolar membrane (PVM). The PVM contains nutrient permeable channels (NPCs) conductive to small molecules, but their relevance for parasite growth for individual metabolites is largely untested. Here we show that growth-relevant levels of major carbon and energy sources pass through the NPCs. Moreover, we find that NPCs are a gate for several antimalarial drugs, highlighting their permeability properties as a critical factor for drug design. Looking into NPC-dependent amino acid transport, we find that amino acid shortage is a reason for the fitness cost in artemisinin-resistant (ART R ) parasites and provide evidence that NPC upregulation to increase amino acids acquisition is a mechanism of ART R parasites in vitro and in human infections to compensate this fitness cost. Hence, the NPCs are important for nutrient and drug access and reveal amino acid deprivation as a critical constraint in ART R parasites., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The development of methodologies to control on demand and reversibly supramolecular transformations from self-assembled metalla-structures requires the rational design of architectures able to answer to an applied stimulus. While solvent or concentration changes, light exposure or addition of a chemical have been largely explored to provide these transformations, the case of pH sensitive materials is less described. Herein, we report the first example of a pH-triggered dissociation of a coordination-driven self-assembled interlocked molecular link. It incorporates a pH sensitive benzobisimidazole-based ligand that can be selectively protonated on its bisimidazole moieties. This generates intermolecular electrostatic repulsions that reduces drastically the stability of the interlocked structure, leading to its dissociation without any sign of protonation of the pyridine moieties involved in the coordination bonds. Importantly, the dissociation process is reversible through addition of a base., (© 2021 Wiley-VCH GmbH.)

Two calix[4]arene systems, C23 4+ and C24 4+ - where 2 corresponds to the number of viologen units and 3-4 corresponds to the number of carbon atoms connecting the viologen units to the macrocyclic core - have been synthesized and led to the formation of [3]pseudorotaxanes when combined with either CB[7] or CB[8]. The [3]pseudorotaxanes spontaneously dissociate upon reduction of the bipyridinium units as the result of intramolecular dimerization of the two face-to-face viologen radical cations. CB[7] and CB[8]-based [2]pseudorotaxanes containing monomeric viologen guest model compounds, MC3 2+ and MC 4+ , do not undergo decomplexation and dimerization following electrochemical reduction of their bipyridinium units., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Vismione H (VH) is a fluorescent prenylated anthranoid produced by plants from the Hypericaceae family, with antiprotozoal activities against malaria and leishmaniosis. Little is known about its biosynthesis and metabolism in plants or its mode of action against parasites. When VH is isolated from Psorospermum glaberrimum , it is rapidly converted into madagascine anthrone and anthraquinone, which are characterized by markedly different fluorescent properties. To locate the fluorescence of VH in living plant cells and discriminate it from that of the other metabolites, an original strategy combining spectral imaging (SImaging), confocal microscopy, and non-targeted metabolomics using mass spectrometry, was developed. Besides VH, structurally related molecules including madagascine (Mad), emodin (Emo), quinizarin (Qui), as well as lapachol (Lap) and fraxetin (Fra) were analyzed. This strategy readily allowed a spatiotemporal characterization and discrimination of spectral fingerprints from anthranoid-derived metabolites and related complexes with cations and proteins. In addition, our study validates the ability of plant cells to metabolize VH into madagascine anthrone, anthraquinones and unexpected metabolites. These results pave the way for new hypotheses on anthranoid metabolism in plants.

3-Benzylmenadiones were obtained in good yield by using a blue-light-induced photoredox process in the presence of Fe(III), oxygen, and γ-terpinene acting as a hydrogen-atom transfer agent. This methodology is compatible with a wide variety of diversely substituted 1,4-naphthoquinones as well as various cheap, readily available benzyl bromides with excellent functional group tolerance. The benzylation mechanism was investigated and supports a three-step radical cascade with the key involvement of the photogenerated superoxide anion radical.

Plasmodione (PD) is a potent antimalarial redox-active 3-benzyl-menadione acting at low nanomolar range concentrations on different malaria parasite stages. The specific bioactivation of PD was proposed to occur via a cascade of redox reactions starting from one-electron reduction and then benzylic oxidation, leading to the generation of several key metabolites including corresponding benzylic alcohol (PD-bzol, for PD benzhydrol) and 3-benzoylmenadione (PDO, for PD oxide). In this study, we showed that the benzylic oxidation of PD is closely related to the formation of a benzylic semiquinone radical, which can be produced under two conditions: UV photoirradiation or catalysis by Plasmodium falciparum apicoplast ferredoxin-NADP + reductase ( Pf FNR) redox cycling in the presence of oxygen and the parent PD. Electrochemical properties of both PD metabolites were investigated in DMSO and in water. The single-electron reduction potential values of PD, PD-bzol, PDO, and a series of 3-benzoylmenadiones were determined according to ascorbate oxidation kinetics. These compounds possess enhanced reactivity toward Pf FNR as compared with model quinones. Optimal conditions were set up to obtain the best conversion of the starting PD to the corresponding metabolites. UV irradiation of PD in isopropanol under positive oxygen pressure led to an isolated yield of 31% PDO through the transient semiquinone species formed in a cascade of reactions. In the presence of Pf FNR, PDO and PD-bzol could be observed during long lasting redox cycling of PD continuously fueled by NADPH regenerated by an enzymatic system. Finally, we observed and quantified the effect of PD on the production of oxidative stress in the apicoplast of transgenic 3D7 [Api-roGFP2-hGrx1] P. falciparum parasites by using the described genetically encoded glutathione redox sensor hGrx1-roGFP2 methodology. The observed fast reactive oxygen species (ROS) pulse released in the apicoplast is proposed to be mediated by PD redox cycling catalyzed by Pf FNR.

Plasmodione ( PD ) is a potent antimalarial redox-active drug acting at low nM range concentrations on different malaria parasite stages. In this study, in order to determine the precise PD protein interactome in parasites, we developed a class of (pro-)activity-based protein profiling probes (ABPP) as precursors of photoreactive benzophenone-like probes based on the skeleton of PD metabolites ( PDO ) generated in a cascade of redox reactions. Under UV-photoirradiation, we clearly demonstrate that benzylic oxidation of 3-benzylmenadione 11 produces the 3-benzoylmenadione probe 7 , allowing investigation of the proof-of-concept of the ABPP strategy with 3-benzoylmenadiones 7 - 10 . The synthesized 3-benzoylmenadiones, probe 7 with an alkyne group or probe 9 with -NO 2 in para position of the benzoyl chain, were found to be the most efficient photoreactive and clickable probes. In the presence of various H-donor partners, the UV-irradiation of the photoreactive ABPP probes generates different adducts, the expected "benzophenone-like" adducts (pathway 1) in addition to "benzoxanthone" adducts (via two other pathways, 2 and 3). Using both human and Plasmodium falciparum glutathione reductases, three protein ligand binding sites were identified following photolabeling with probes 7 or 9 . The photoreduction of 3-benzoylmenadiones ( PDO and probe 9 ) promoting the formation of both the corresponding benzoxanthone and the derived enone could be replaced by the glutathione reductase-catalyzed reduction step. In particular, the electrophilic character of the benzoxanthone was evidenced by its ability to alkylate heme, as a relevant event supporting the antimalarial mode of action of PD . This work provides a proof-of-principle that (pro-)ABPP probes can generate benzophenone-like metabolites enabling optimized activity-based protein profiling conditions that will be instrumental to analyze the interactome of early lead antiplasmodial 3-benzylmenadiones displaying an original and innovative mode of action., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Herein we present the preparation of two novel cyclam-based macrocycles ( te1pyp and cb-te1pyp ), bearing phosphonate-appended pyridine side arms for the coordination of copper(II) ions in the context of 64 Cu PET imaging. The two ligands have been prepared through conventional protection-alkylation sequences on cyclam, and their coordination properties have been thoroughly investigated. The corresponding copper complexes have been fully characterized in the solid state (X-ray diffraction analysis) and in solution (EPR and UV-vis spectroscopies). Potentiometric studies combined with spectrometry have also allowed us to determine their thermodynamic stability constants, confirming their high affinity for copper(II) cations. The kinetic inertness of the complexes has been verified by acid-assisted dissociation experiments, enabling their use in 64 Cu-PET imaging in mice for the first time. Indeed, the two ligands could be quantitatively radiolabeled under mild conditions, and the resulting 64 Cu complexes have demonstrated excellent stability in serum. PET imaging demonstrated a set of features emerging from the combination of picolinates and phosphonate units: high stability in vivo , fast clearance from the body via renal elimination, and most interestingly, very low fixation in the liver. This is in contrast with what was observed for monopicolinate cyclam ( te1pa ), which had a non-negligible accumulation in the liver, owing probably to its different charge and lipophilicity. These results thus pave the way for the use of such phosphonated pyridine chelators for in vivo 64 Cu-PET imaging.