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To address the global challenge of emerging antimicrobial resistance, the hitherto most successful strategy to new antibiotics has been the optimization of validated natural products; most of these efforts rely on semisynthesis. Herein, we report the semisynthetic modification of amidochelocardin, an atypical tetracycline obtained via genetic engineering of the chelocardin producer strain. We report modifications at C4, C7, C10 and C11 by the application of methylation, acylation, electrophilic substitution, and oxidative C-C coupling reactions. The antibacterial activity of the reaction products was tested against a panel of Gram-positive and Gram-negative pathogens. The emerging structure-activity relationships (SARs) revealed that positions C7 and C10 are favorable anchor points for the semisynthesis of optimized derivatives. The observed SAR was different from that known for tetracyclines, which underlines the pronounced differences between the two compound classes.

The Mitidja plain area, located in north Algeria, is one of the main agricultural plains in the Mediterranean basin where water supplies are mainly provided by groundwater resource. Due to the effects of a rapid population increase, followed by an intensification of agricultural activities, a proper groundwater vulnerability assessment became urgent. In this study, the DRASTIC model has been utilized to produce a map of groundwater vulnerability for nitrate pollution. To improve the standard DRASTIC vulnerability map, and to offer an innovative and easy tools for water resource protection and water forensics, the rating classes of the DRASTIC model was modified using the real nitrate concentrations analyzed in 44 groundwater sample while sensitivity analysis was used to change the parameter’s weights. The validation of the standard DRASTIC model shows a coincidence rate of 67% while the validation of the modified DRASTIC model shows a coincidence rate of 82% (improvement of 15%) with nitrates. The results highlighted two main findings: i) the reliability of modified DRASTIC model, and ii) the dependence of nitrate vulnerability on net recharge, aquifer type, soil texture and topography. The proposed approach demonstrated to be more appropriate in assessing the groundwater vulnerability compared to standard DRASTIC proving to be easy applicable and suitable in any arid and semi-arid region around the world.

Increasing antimicrobial resistance is evolving to be one of the major threats to public health. To reduce the selection pressure and thus to avoid a fast development of resistance, novel approaches aim to target bacterial virulence instead of growth. Another strategy is to restore the activity of antibiotics already in clinical use. This can be achieved by the inhibition of resistance factors such as metallo-β-lactamases (MBLs). Since MBLs can cleave almost all β-lactam antibiotics, including the “last resort” carbapenems, their inhibition is of utmost importance. Here, we report on the synthesis and in vitro evaluation of N-aryl mercaptoacetamides as inhibitors of both clinically relevant MBLs and the virulence factor LasB from Pseudomonas aeruginosa. All tested N-aryl mercaptoacetamides showed low micromolar to submicromolar activities on the tested enzymes IMP-7, NDM-1 and VIM-1. The two most promising compounds were further examined in NDM-1 expressing Klebsiella pneumoniae isolates, where they restored the full activity of imipenem. Together with their LasB-inhibitory activity in the micromolar range, this class of compounds can now serve as a starting point for a multi-target inhibitor approach against both bacterial resistance and virulence, which is unprecedented in antibacterial drug discovery., Simultaneous inhibition of metallo-β-lactamases (MBLs) and virulence factors such as LasB from Pseudomonas aeruginosa offers a new approach to combat antibiotic-resistant pathogens.

Antimicrobial resistance is currently one of the serious global public health threats. Unlike the conventional antimicrobial drugs, antivirulence agents disarm rather than kill bacterial pathogens and therefore represent an alternative option to skirt the problem of resistance. Pseudomonas aeruginosa elastase (LasB) and Clostridium histolyticum collagenase (ColH) are extracellular bacterial proteases which play a critical role in the establishment and progression of the respective bacterial infection. In this study, we report the modulation of the α-position of the previously reported N aryl mercaptoacetamide class leading to a new type of highly potent LasB and ColH inhibitors (N aryl 2-iso-butylmercaptoacetamides). In addition to their non-toxicity and high selectivity over several human off-targets, selected derivatives may be considered unprecedented dual inhibitors of both LasB and ColH. Among the prepared derivatives, compound 37 showed the most promising properties: it had a favorable safety profile, maintained the viability and integrity of both skin- and lung-cells treated with P. aeruginosa supernatant, demonstrated in vivo efficacy in Galleria mellonella larvae, and revealed a good volume of distribution and moderate in vivo clearance in mice. Taking together, these results demonstrate that compound 37 is a promising candidate for antivirulence drug development.

Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.

In light of the global antimicrobial-resistance crisis, there is an urgent need for novel bacterial targets and antibiotics with novel modes of action. It has been shown that Pseudomonas aeruginosa elastase (LasB) and Clostridium histolyticum (Hathewaya histolytica) collagenase (ColH) play a significant role in the infection process and thereby represent promising antivirulence targets. Here, we report novel N-aryl-3-mercaptosuccinimide inhibitors that target both LasB and ColH, displaying potent activities in vitro and high selectivity for the bacterial over human metalloproteases. Additionally, the inhibitors demonstrate no signs of cytotoxicity against selected human cell lines and in a zebrafish embryo toxicity model. Furthermore, the most active ColH inhibitor shows a significant reduction of collagen degradation in an ex vivo pig-skin model.

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Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a sub-micromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in viv o efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates.

This work describes the conception, synthesis, in vitro and in vivo biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT4 receptors, block 5-HT6 receptors and inhibit acetylcholinesterase activity (AChE), in order to exert a synergistic anti-amnesic effect, potentially useful in the treatment of Alzheimer’s disease (AD). Indeed, both activation of 5-HT4 and blockage of 5-HT6 receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT4 receptor agonists are able to promote the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and to favor the production of the neurotrophic protein sAPPα. Finally, we identified a pleiotropic compound, [1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(3-methylbenzyl)piperidin-4-yl)propan-1-one fumaric acid salt (10)], which displayed in vivo an anti-amnesic effect in a model of scopolamine-induced deficit of working memory at a dose of 0.3 mg/kg.

Rigidification of the isobutyl side chain of drug-like AT(2) receptor agonists and antagonists that are structurally related to the first reported selective AT(2) receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers 7a, 7b, 8a, 8b, 9a, 9b, 10a and 10b bind to the AT(2) receptor with moderate (K-i = 54-223 nM) to high affinity (K-i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives 7b and 10a are among the most potent AT(2) receptor antagonists reported so far. As illustrated by the enantiomer pairs 7a/b and 10a/b, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT(2) receptor, and can convert agonists to antagonists and vice versa.

In article number 2004369, Martin Empting and colleagues describe a new generation of dual‐loaded nanoparticles enabling efficient eradication of Pseudomonas aeruginosa biofilms. The squalene‐based nanocarrier facilitates co‐delivery of a novel pathogenspecific Quorum Sensing Inhibitor (QSI) together with the standard‐of‐care antibiotic tobramycin. The QSI itself shows high anti‐virulence efficacy, favorable DMPK and no overt safety pharmacology. When applied as the nanoparticle formulation the QSI potentiates biofilm eradication capabilities of tobramycin by at least 32‐fold. [Image: see text]

Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry‐driven hit‐to‐lead optimization and in‐depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter‐gene with IC50 values as low as 200 and 11 × 10−9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI‐tobramycin (Tob) combination against PA biofilms using a tailor‐made squalene‐derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32‐fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker‐mediated therapy against PA infections opening up avenues for preclinical development., The discovery and profiling of a novel Pseudomonas aeruginosa‐targeting Quorum Sensing Inhibitor (QSI) with high anti‐virulence efficacy, favorable DMPK and no overt safety pharmacology is reported. The in vivo target engagement of the lead QSI in a mucoid lung‐infection mouse model is demonstrated. Importantly, the application of a state‐of‐the‐art squalene‐based nanocarrier formulation boosts tobramycin susceptibility of biofilms.

International audience; 5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip

The controlled derivatization of natural products is of great importance for their use in drug discovery. The ideally rapid generation of compound libraries for structure-activity relationship studies is of particular concern. We here use modified biosynthesis for the generation of such a library of reduced polyketides to interfere with the oncogenic KRas pathway. The polyketide is derivatized via side chain alteration, and variations in its redox pattern and in its backbone chain length through manipulation in the corresponding polyketide synthase. Structural and biophysical analyses revealed the nature of the interaction between the polyketides and KRas-interacting protein PDE6δ. Non-natural polyketides with low nanomolar affinity to PDE6δ were identified.

Twelve isatin Schiff bases (1a-7a, 1b-5b) were prepared by reacting isatin and 5-bromoisatin with different anilines using green chemistry (microwave (MW) and ultrasound (US) assisted synthesis). The antibacterial activity of each compound was evaluated against nine standard and clinical bacterial strains using the Agar-well diffusion method. The lowest-obtained Minimum Inhibitory Concentration (MIC) was 78 μg/mL against Pseudomonas aeruginosa for 1a and 1b. All the synthesized compounds were identified using IR, 1H NMR, 13C NMR and microanalysis. Quantitative Structure Activity Relationship (QSAR) and Molecular Electrostatic Potential Surface (MEPS) analyses were carried out to rationalize antibacterial activity of the synthesized compounds. Based on the QSAR analysis, including DFT-based, steric and hydrophobic descriptors, it was found that molecules with more hydrophobic character associated with less dipole moment act as antibacterial agents against Klebsiella pneumoniae ATCC700603.

International audience; A set of variously substituted aurones was synthesized and evaluated against Methicillin-Resistant S. aureus (MRSA) and P. aeruginosa. Several analogues were found active against MRSA, but no effect was recorded against P. aeruginosa. Compounds 27, 30 and 33 showed low cytotoxicity, and were tested against a full range of bacterial (Gram-positive and Gram-negative) and fungal species, including resistant strains. These aurones displayed a selective inhibition of Gram-positive bacteria with excellent Therapeutic Index values, while showing no significant action on several Gram-negative strains, H. pylori and V. alginolyticus being the only susceptible strains among the Gram-negative bacteria tested. A per-meabilization assay showed that the antibacterial activity of at least some of the aurones could be linked to alterations of the bacterial membrane. Overall, this study endorses the use of the aurone scaffold for the development of new potent and selective antibacterial agents.

The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs).

SummaryPolyketides are natural products frequently used for the treatment of various diseases, but their structural complexity hinders efficient derivatization. In this context, we recently introduced enzyme-directed mutasynthesis to incorporate non-native extender units into the biosynthesis of erythromycin. Modeling and mutagenesis studies led to the discovery of a variant of an acyltransferase domain in the erythromycin polyketide synthase capable of accepting a propargylated substrate. Here, we extend molecular rationalization of enzyme-substrate interactions through modeling, to investigate the incorporation of substrates with different degrees of saturation of the malonic acid side chain. This allowed the engineered biosynthesis of new erythromycin derivatives and the introduction of additional mutations into the AT domain for a further shift of the enzyme's substrate scope. Our approach yields non-native polyketide structures with functional groups that will simplify future derivatization approaches, and provides a blueprint for the engineering of AT domains to achieve efficient polyketide synthase diversification.

This paper analyzes the drying rates of humid porous grains of poly(vinyl)chloride PVC by thermogravimetry. Grains have variable volume fractions of pores, representing between 16 and 33% g water/g PVC, with pore sizes varying between 0.6 and 1 μm. It is shown that the humid cakes exhibit three different drying rate regimes at constant temperature, characterizing evaporation of free water, of interstitial water and of water inside the pores. The constant rate period (CRP) and the falling rate period (FRP) of drying are clearly identified. The drying rates and drying times are presented in adimensional units by comparison with evaporation of pure water. The thermogravimetric analysis identifies a fraction of water which dries very slowly inside the pores. A method of quantifying the strongly bound water is presented. Numerical simulations of water evaporation were performed on a 2D array of channels and illustrate the contribution of geometrical effects (diameter of channels, tortuosity, etc.) in pore drying. Visual observations of the drying of droplets of solutions containing dispersants used in PVC synthesis show interesting patterns. The phase separated solutions of dispersants are analyzed and their role in drying is highlighted.

Concentration of aqueous suspensions of solid particles (called slurries in industrial processes) is achieved by centrifugation at high accelerations and it is an important step in dry powder productions; dehydration precedes drying. In aqueous suspensions of porous particles, water is both the interstitial fluid, which disperses the particles and the imbibition fluid, which fills the pores inside particles. This is the case in the pastes of poly(vinyl)chloride (PVC) polymerized in suspensions after centrifugation. PVC grains are non-colloidal particles with diameters close to 150 μm and variable inner porosity, which are synthetized in aqueous solutions using dispersants such as various poly(vinyl)alcohols (PVA). In this paper we determine the dehydration by centrifugation of different grades PVC suspensions with laboratory scale experiments. It is shown that the humid pastes reach a pendular state at high accelerations and that the compaction of the grains and their surface properties determine the final retention of the water by capillary forces. In such conditions, internal water, inside the pores of the grains can be eliminated only by evaporation. Drying was investigated in controlled relative humidity atmospheres ( RH ) in desiccators by measuring the equilibrium moisture content of the grains and the evaporation rates. The evaporation rate of the superficial water is similar to pure water and can be interpreted using Stefan's equation, whereas substantial differences exist between the total drying times of grades.

The use of nonstandard geometries like the vane is essential to measure the rheological characteristics of complex fluids such as non-Newtonian fluids or particle dispersions. For this geometry which is of Couette type, there is no analytical simple model defining the relation between the shear stress and the torque or relating the angular velocity to the shear rate. This study consists on calibrating a nonstandard vane geometry using a finite volume method with the Ansys Fluent software. The influence of geometrical parameters and rheological characteristics of the complex fluids are considered. First, the Newtonian fluid flow in a rotative vane geometry was simulated and a parametric model is derived therefrom. The results show an excellent agreement between the calculated torque and the measured one. They provide the possibility to define equivalent dimensions by reference to a standard geometry with concentric cylinders where the relationships between shear stress (resp. shear rate) and the torque (resp. the angular rotation) are classical. Non-Newtonian fluid flows obeying a power law rheology with different indices were then simulated. The results of these numerical simulations are in very good agreement with the preceding Newtonian-based model in some ranges of indices. The absolute difference still under 5 % provided the index is below 0.45. Finally, this study provides a calibration protocol in order to use nonstandard vane geometries with various heights, gaps, and distance to the cup bottom for measuring the rheology of complex fluids like shear thinning fluids and concentrated suspensions.

The formation of tau aggregates is strongly linked to the neurodegenerative process in tauopathies such as Alzheimer's disease (AD). Yet only a few molecules have shown to efficiently prevent the in vitro formation of those aggregates, and the identification of such molecules is still an ongoing interest in a therapeutic context. Herein, we report the in vitro evaluation of a series of aurones against the fibrillation of the tau-derived hexapeptide AcPHF6 model. Using thioflavin T-based fluorescence assays, circular dichroism and atomic force microscopy, we showed that aurones are capable of efficiently interacting with the tau-derived hexapeptide. Importantly, this work reveals a significant activity observed for polyhydroxylated aurones. In particular, aurone 23 displayed an almost complete inhibition of fibers formation as shown by AFM at a peptide/inhibitor 1:1 ratio. It is similar to that observed for myricetin, a polyphenolic compound, well-known to prevent the in vitro elongation of tau fibers. Moreover, a tetrahydroxylated isomer, compound 24, was shown as a chemical probe of fibers rather than an inhibitor. Consequently, these results highlight aurones as a new promising scaffold to interfere with tau aggregation for both treatment and diagnosis of AD.

The naturally occurring aurones (2-benzylidene-3(2H)-benzofuran-3-ones) can be easily converted to another class of natural products 2-benzoylbenzo[b]furans, via an effective reduction, acid-mediated rearrangement, and oxidation cascade. This easy conversion was conducted without purification of intermediates. This straightforward conversion may be considered as a possible biosynthesis pathway of 2-benzoylbenzo[b]furans in plants.

Melanin play a major role in human skin protection and their biosynthesis is vital. Due to their color, they contribute to the skin pigmentation. Tyrosinase is a key enzyme involved in the first stage of melanin biosynthesis, it catalyzes the transformation of tyrosine into l-dopaquinone. The aim of the present study was to study molecules able to inhibit tyrosinase to be used in treating depigmentation-related disorders. In this study, we targeted arylthiosemicarbazone analogs with the aim to contribute to the identification of the optimal aryl ring to be linked to the thiosemicarbazone moiety. The biological activity was evaluated on commercial mushroom tyrosinase which was purified prior use. The results demonstrated that several of our compounds (1a-h, 1j, 1r and 5) had more potent inhibitory activities than kojic acid which was used as the reference inhibitor.

Our previous studies have shown that several 7-substituted-4-imidazolylflavans are potent inhibitors of aromatase. These compounds were designed considering the anti-aromatase effect of some natural flavonoids and the importance of an azole ring for synthetic inhibitors such as letrozole or anastrozole towards binding to the heme iron of aromatase. In this study, we report the optimization of these lead compounds by the modulation of flavan A ring. The resulting 7,8-benzo-4-imidazolylflavans were tested in order to assess their ability to inhibit aromatase. Biological data concerning enantiomers obtained from the chiral separation of the racemate compound 4-imidazolyl-7-methoxyflavan are also presented.

Multidrug-resistance protein 1 (MRP1) belongs to the ATP-binding cassette (ABC) transporter family. MRP1 mediates MDR (multidrug resistance) by causing drug efflux either by conjugation to glutathione (GSH) or by co-transport with free GSH (without covalent bonding between the drug and GSH). We recently reported that the calcium channel blocker verapamil can activate massive GSH efflux in MRP1-overexpressing cells, leading to cell death through apoptosis. However, clinical use of verapamil is hampered by its cardiotoxicity. Then, in the search for compounds that act similarly to verapamil, but without major side effects, we investigated xanthones. Herein we show that xanthones induce apoptosis among resistant cells overexpressing MRP1 similarly to the verapamil effect. Among the xanthones studied, 1,3-dihydroxy-6-methoxyxanthone was identified as the most active derivative, able to specifically kill cells transfected with human MRP1 with even greater potency than verapamil. Under the same conditions, the active xanthones have no toxic effect on control (sensitive) cells. Xanthones could therefore be considered as new potential anticancer agents for the selective treatment of MRP1-positive tumors.

A palladium(II)-catalyzed Heck-Mizoroki/Suzuki-Miyaura domino reaction involving metal coordinating dimethylaminoethyl vinyl ethers and a number of electron-rich and electron-deficient arylboronic acids has been developed. Through variation of the temperature and the concentration of the p-benzoquinone (p-Bq) ligand/reoxidant, conditions for the robust and convenient one-pot generation of diarylated-saturated ethers were identified. With the aid of coordination of the dimethylamino group to the arylpalladium intermediate, the otherwise predominant formation of the β-arylated olefin could be reversed. A reaction route involving a chelation-controlled carbopalladation, providing a p-Bq stabilized six-membered palladacycle, followed by transmetalation and reductive elimination is suggested to explain the selective formation of saturated diarylated ether products.

The approach to a wall of a non-Brownian rigid spherical particle, settling in a viscous fluid with a Reynolds number of the order of unity, is studied experimentally. Far from the wall, the fluid motion around the particle is driven by inertia and viscosity forces. The particle Stokes number is also of the order of unity, so that the particle motion far from the wall is driven by inertia. In the close vicinity of the wall, however, the particle–wall hydrodynamic interaction decelerates the particle significantly. An interferometric device is used to measure the vertical displacement of a millimetric size spherical bead at distances from the wall smaller than 0.1 sphere radius, with a spatial resolution of 100 nm. For the range of impact Stokes number (St*, based on the limit velocity of the sphere in an unbounded fluid) explored here (up to St* ≅ 5), the measurements reveal that a small region of negligible particle inertia still exists just prior to contact of the sphere with the wall. In this lubrication-like region, the particle velocity decreases linearly with decreasing particle–wall distance and vanishes at contact, ruling out the possibility of a rebound. The vertical extent of this region decreases with increasing Stokes number and is e.g. only 10 μm large at impact Stokes number St* ≅ 5.

International audience; In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer’s disease.

Enzyme-directed mutasynthesis is an emerging strategy for the targeted derivatization of natural products. Here, data on the synthesis of malonic acid derivatives for feeding studies in Saccharopolyspora erythraea , the mutagenesis of DEBS and bioanalytical data on the experimental investigation of studies on the biosynthetic pathway towards erythromycin are presented. CA extern

The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway producing the universally essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the cramped substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM. De tre (3) första författarna delar förstaförfattarskapet.

Not in the public domain: Site-directed mutagenesis of megasynthases was the key to the generation of a library of polyketides in bacteria. Redox derivatizations are used to change the bioactivity profile of the compounds.

The three-step process involves the reduction of aurones (I), an acid-mediated rearrangement of the resulting dihydrobenzofuranols to benzofurylmethanols, and final oxidation to give the desired ketones (II).

Mycobacterium tuberculosis glutamine synthetase (MtGS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of MtGS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-tert-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of MtGS inhibitors with submicromolar IC(50) values and promising antituberculosis MIC values.

The treatment of vinyl ethers (I) and (IV) with various arylboronic acids and vinylboronic acid (IIj) in the presence of benzoquinone allows formation of a number of 1,2-difunctionalized ethers.

A mild and novel palladium(II)-catalyzed domino Heck/Suzuki α,β-diarylation-reduction of a dimethylaminoethyl substituted chelating vinyl ether was developed by using electron-rich arylboronic acids in combination with p-benzoquinone. Based on the preparative results, a catalytic cycle is proposed. Further, highly regioselective palladium(II)-catalyzed α- or β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions.

Glutamine synthetase (GS, EC 6.3.1.2; also known as gamma-glutamyl:ammonia ligase) catalyzes the ATP-dependent condensation of glutamate and ammonia to form glutamine. The enzyme has essential roles in different tissues and species, which have led to its consideration as a drug or an herbicide target. In this article, we describe studies aimed at the discovery of new antimicrobial agents targeting Mycobacterium tuberculosis, the causative pathogen of tuberculosis. A number of distinct classes of GS inhibitors with an IC(50) of micromolar value or better were identified via high-throughput screening. A commercially available purine analogue similar to one of the clusters identified (the diketopurines), 1-[(3,4-dichlorophenyl)methyl]-3,7-dimethyl-8-morpholin-4-yl-purine-2,6-dione, was also shown to inhibit the enzyme, with a measured IC(50) of 2.5+/-0.4 microM. Two X-ray structures are presented: one is a complex of the enzyme with the purine analogue alone (2.55-A resolution), and the other includes the compound together with methionine sulfoximine phosphate, magnesium and phosphate (2.2-A resolution). The former represents a relaxed, inactive conformation of the enzyme, while the latter is a taut, active one. These structures show that the compound binds at the same position in the nucleotide site, regardless of the conformational state. The ATP-binding site of the human enzyme differs substantially, explaining why it has an approximately 60-fold lower affinity for this compound than the bacterial GS. As part of this work, we devised a new synthetic procedure for generating l-(SR)-methionine sulfoximine phosphate from l-(SR)-methionine sulfoximine, which will facilitate future investigations of novel GS inhibitors.

Some natural compounds such as flavonoids are known to possess a moderate inhibitory activity against aromatase, this enzyme being an interesting target for hormone-dependent breast cancer treatment. It has been demonstrated that the modulation of flavonoid skeleton could increase anti-aromatase effect. Therefore, new 7,8-benzoflavanones were synthesized and tested for their activity toward aromatase inhibition. It was observed that the introduction of a benzo ring at position C-7 and C-8 on flavanone skeleton led to new potent aromatase inhibitors, the resulting 7,8-benzoflavanones being until nine times more potent than aminogluthetimide (the first aromatase inhibitor used clinically).

Aromatase is a target of pharmacological interest for the treatment of estrogen-dependent cancers. Azole derivatives such as letrozole or anastrozole have been developed for aromatase inhibition and are used for the treatment of breast tumors. In this paper, four 4-triazolylflavans were synthesized and were found to exhibit moderate to high inhibitory activity against aromatase.

Analytical solutions are presented for axisymmetric creeping flows around a spherical particle near a wall, when the unperturbed flow velocity varies as polynomial with the coordinates. The perturbed fluid velocity and pressure are calculated directly with the method of bipolar coordinates. They are obtained with a 10−16 precision, even for small gaps of the order of 10−6 sphere radius. For a constant unperturbed flow, the problem is equivalent to that of a sphere moving perpendicularly to a wall in a fluid at rest. An alternative indirect solution for the fluid velocity and pressure is obtained in this case from the solution of Brenner [Chem. Eng. Sci. 16, 242 (1961)] and Maude [Brit. J. Appl. Phys. 12, 293 (1961)] for the stream function. For a small gap between the sphere and the wall, the values of the pressure are compatible with the ones from the lubrication approximation but are systematically larger; this may be important for applications. Calculations are also performed when the unperturbed flow ...

A series of 4-imidazolylflavans having a variety of substituents on the 2-phenyl ring was synthesized and investigated for their inhibitory effect against aromatase. Structure-activity relationships of these compounds were determined. An additional chlorine atom or a cyano group at the 4' position did not enhance aromatase inhibition as well as a 3'-hydroxyl group. The influence of an additional 4'-hydroxyl group depends on the substitution pattern of A ring. Among these molecules, 4'-hydroxy-4-imidazolyl-7-methoxyflavan is only 2.2-fold less active than the letrozole (as assessed by IC50 values). Letrozole is used as the first-line therapy for metastatic breast cancer.

Based on an imidazo[1,2-a]pyridine hit from a high-throughput screening directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a number of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 μM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified with single-digit micromolar potency and one with sub-micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize many of the structure–activity relationships observed.

A mild and novel palladium(II)-catalyzed domino Heck/Suzuki alpha,beta-diarylation-reduction of a dimethylaminoethyl substituted chelating vinyl ether was developed by using electron-rich arylboronic acids in combination with p-benzoquinone. Based on the preparative results, a catalytic cycle is proposed. Further, highly regioselective palladium(II)-catalyzed alpha- or beta-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions.