An image-based high-content screening for compounds targeting repurposed inhibitors effective against the malaria parasite .

phylum includes numerous obligate intracellular protozoan parasites that are life threatening for humans and animals. In this context, and are of particular interest, as they are responsible for malaria and toxoplasmosis, respectively, for which efficient vaccines are presently lacking and therapies need to be improved. Apicomplexan parasites have a highly polarized morphology, with their apical end containing specific secretory organelles named rhoptries and micronemes, which depend on the unique receptor and transporter sortilin TgSORT for their biogenesis.

Tirap controls Mycobacterium tuberculosis phagosomal acidification.

Progression of tuberculosis is tightly linked to a disordered immune balance, resulting in inability of the host to restrict intracellular bacterial replication and its subsequent dissemination. The immune response is mainly characterized by an orchestrated recruitment of inflammatory cells secreting cytokines. This response results from the activation of innate immunity receptors that trigger downstream intracellular signaling pathways involving adaptor proteins such as the TIR-containing adaptor protein (Tirap).

Clofoctol inhibits SARS-CoV-2 replication and reduces lung pathology in mice.

Drug repurposing has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells.

The out-of-field dose in radiation therapy induces delayed tumorigenesis by senescence evasion.

A rare but severe complication of curative-intent radiation therapy is the induction of second primary cancers. These cancers preferentially develop not inside the planning target volume (PTV) but around, over several centimeters, after a latency period of 1-40 years. We show here that normal human or mouse dermal fibroblasts submitted to the out-of-field dose scattering at the margin of a PTV receiving a mimicked patient's treatment do not die but enter in a long-lived senescent state resulting from the accumulation of unrepaired DNA single-strand breaks, in the almost absence of double-strand breaks.

Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening.

Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis, remains the leading cause of death from a single infectious agent worldwide. The emergence of drug-resistant M.

Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds.

The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with MIC values ranging from 0.0625-2.

Dehydrojuncusol, a Natural Phenanthrene Compound Extracted from , Is a New Inhibitor of Hepatitis C Virus RNA Replication.

Recent emergence of direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) proteins has considerably enhanced the success of antiviral therapy. However, the appearance of DAA-resistant-associated variants is a cause of treatment failure, and the high cost of DAAs renders the therapy not accessible in countries with inadequate medical infrastructures. Therefore, the search for new inhibitors with a lower cost of production should be pursued.

Theaflavins, polyphenols of black tea, inhibit entry of hepatitis C virus in cell culture.

The treatment of hepatitis C virus (HCV) infection by combination of direct acting antivirals (DAA), with different mode of action, has made substantial progress in the past few years. However, appearance of resistance and high cost of the therapy is still an obstacle in the achievement of the therapy, more specifically in developing countries. In this context, search for affordable antivirals with new mechanisms of action is still needed.

The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase.

The search for compounds with biological activity for many diseases is turning increasingly to drug repurposing. In this study, we have focused on the European Union-approved antimalarial pyronaridine which was found to have in vitro activity against Mycobacterium tuberculosis (MIC 5 μg/mL). In macromolecular synthesis assays, pyronaridine resulted in a severe decrease in incorporation of C-uracil and C-leucine similar to the effect of rifampicin, a known inhibitor of M.

Identification of Piperazinylbenzenesulfonamides as New Inhibitors of Claudin-1 Trafficking and Hepatitis C Virus Entry.

Hepatitis C virus (HCV) infection causes 500,000 deaths annually, in association with end-stage liver diseases. Investigations of the HCV life cycle have widened the knowledge of virology, and here we discovered that two piperazinylbenzenesulfonamides inhibit HCV entry into liver cells. The entry of HCV into host cells is a complex process that is not fully understood but is characterized by multiple spatially and temporally regulated steps involving several known host factors.

A Bacterial Toxin with Analgesic Properties: Hyperpolarization of DRG Neurons by Mycolactone.

Mycolactone, a polyketide molecule produced by , is the etiological agent of Buruli ulcer. This lipid toxin is endowed with pleiotropic effects, presents cytotoxic effects at high doses, and notably plays a pivotal role in host response upon colonization by the bacillus. Most remarkably, mycolactone displays intriguing analgesic capabilities: the toxin suppresses or alleviates the pain of the skin lesions it inflicts.

[Practical guidelines to ensure the quality of compounded preparations in community pharmacies].

Compounded preparations are an additional therapeutic option besides registered medicines. Because of their <> they have a great value and thus an undeniable place in the therapeutic arsenal available to the physician. To maintain this position, however, they must be of unquestionable quality.

Automatic mechanism generation for pyrolysis of di-tert-butyl sulfide.

The automated Reaction Mechanism Generator (RMG), using rate parameters derived from ab initio CCSD(T) calculations, is used to build reaction networks for the thermal decomposition of di-tert-butyl sulfide. Simulation results were compared with data from pyrolysis experiments with and without the addition of a cyclohexene inhibitor. Purely free-radical chemistry did not properly explain the reactivity of di-tert-butyl sulfide, as the previous experimental work showed that the sulfide decomposed via first-order kinetics in the presence and absence of the radical inhibitor.

Kinetic modeling of hydrogen abstractions involving sulfur radicals.

One of the requisites for the development of detailed reaction networks is the availability of accurate kinetic data. Group additivity based models linking the Arrhenius parameters to structural characteristics of the transition state have proven to be a valuable tool to obtain those data. In this work, group additivity values are presented to allow a broad range of CH and SH hydrogen abstraction reactions by S radicals to be modeled.

Kinetics of homolytic substitutions by hydrogen atoms at thiols and sulfides.

Thermodynamic and kinetic data in the temperature range 300-1500 K are calculated for 94 homolytic substitution reactions by a hydrogen atom at thiols and sulfides with the CBS-QB3//BMK/6-311G(2d,d,p) method. The studied reactions were found to proceed according to a one-step mechanism. A group additivity (GA) method is presented to model the Arrhenius parameters of this reaction family.

Kinetics of α hydrogen abstractions from thiols, sulfides and thiocarbonyl compounds.

Hydrogen abstraction reactions involving organosulfur compounds play an important role in many industrial, biological and atmospheric processes. Despite their chemical relevance, little is known about their kinetics. In this work a group additivity model is developed that allows predicting the Arrhenius parameters for abstraction reactions of α hydrogen atoms from thiols, alkyl sulfides, alkyl disulfides and thiocarbonyl compounds by carbon-centered radicals at temperatures ranging from 300 to 1500 K.

Personality subtypes in female pre-bariatric obese patients: do they differ in eating disorder symptoms, psychological complaints and coping behaviour?

In the pre-bariatric psychological assessment of 102 morbidly obese women, two personality subtypes emerged: a resilient/high functioning subtype with a 'normal' personality profile and an emotional dysregulated/ undercontrolled subtype, characterized by high neuroticism and low extraversion/conscientiousness. Emotional dysregulated/ undercontrolled patients showed more concerns about eating/weight/shape, more binge eating driven by emotions and external triggers, more psychological complaints (such as depression and anxiety) and more avoidance and depressive coping reactions than resilient/high functioning patients. Further research should clarify whether these clearly different psychological profiles are related to different outcomes (weight loss or well-being) of bariatric surgery.

Modeling the gas-phase thermochemistry of organosulfur compounds.

Key to understanding the involvement of organosulfur compounds in a variety of radical chemistries, such as atmospheric chemistry, polymerization, pyrolysis, and so forth, is knowledge of their thermochemical properties. For organosulfur compounds and radicals, thermochemical data are, however, much less well documented than for hydrocarbons. The traditional recourse to the Benson group additivity method offers no solace since only a very limited number of group additivity values (GAVs) is available.

Theoretical study of the thermal decomposition of dimethyl disulfide.

Despite its use in a wide variety of industrially important thermochemical processes, little is known about the thermal decomposition mechanism of dimethyl disulfide (DMDS). To obtain more insight, the radical decomposition mechanism of DMDS is studied theoretically and a kinetic model is developed accounting for the formation of all the decomposition products observed in the experimental studies available in literature. Thermochemical data and rate coefficients are obtained using the high-level CBS-QB3 composite method.

Modeling the influence of resonance stabilization on the kinetics of hydrogen abstractions.

Resonance stabilization of the transition state is one of the key factors in modeling the kinetics of hydrogen abstraction reactions between hydrocarbons. A group additive model is developed which allows the prediction of rate coefficients for bimolecular hydrogen abstraction reactions over a broad range of hydrocarbons and hydrocarbon radicals between 300 and 1300 K. Group additive values for 50 groups are determined from rate coefficients determined using the high level CBS-QB3 ab initio method, corrected for tunneling and the hindered internal rotation around the transitional bond.

Theoretical study of the thermodynamics and kinetics of hydrogen abstractions from hydrocarbons.

Thermochemical and kinetic data were calculated at four cost-effective levels of theory for a set consisting of five hydrogen abstraction reactions between hydrocarbons for which experimental data are available. The selection of a reliable, yet cost-effective method to study this type of reactions for a broad range of applications was done on the basis of comparison with experimental data or with results obtained from computationally demanding high level of theory calculations. For this benchmark study two composite methods (CBS-QB3 and G3B3) and two density functional theory (DFT) methods, MPW1PW91/6-311G(2d,d,p) and BMK/6-311G(2d,d,p), were selected.