New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies

Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 μM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies

Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (Ki = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC99 = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition

Caractérisation aérothermique d’un échangeur de chaleur surfacique implémenté en veine secondaire

Les configurations innovantes de moteur d’aviation civile amèneront à d’importantes réductions de consommation de carburant. Actuellement, chez Safran Aircraft Engines, des nouveaux concepts tels que le Geared Turbofan et l’Open Rotor sont étudiés attentivement. Ces concepts sont caractérisés par des architectures de plus en plus complexes qui nécessitent d’être lubrifiés et refroidis. Par conséquent, les systèmes de gestion thermique sont un module fondamental des moteurs d’aujourd’hui. Dans cette thèse, on s’intéresse aux surface air-cooled oil coolers (SACOC). Un SACOC est généralement composé d’une sérié d’ailettes orientées dans la direction de l’écoulement. La source chaude est représentée par le lubrifiant du moteur. Le premier objectif de la thèse est de caractériser les interactions aérothermiques qui ont lieu entre le SACOC et le flux secondaire. Le deuxième but est de se doter de méthodologies prédictives, validées et accessibles qui permettent d’étudier ces interactions.Innovative civil aircraft engine configurations of the present and of the future are leading to important reductions of fuel consumption. At Safran Aircraft Engines, new concepts like the Geared Turbofan and the Open Rotor are currently under attentive study. These concepts are characterised by an increasingly complex architecture that demands lubrication and cooling. Thermal management systems, therefore, are a fundamental module of modern engines. In this work, we take an interest in surface aircooled oil coolers (SACOC). Common SACOC are composed of a series of staggered fins, aligned along the direction of the by-pass duct flow. The hot source is the engine lubricant. The objective of this thesis is twofold. The first goal is to characterise the aerothermal interactions taking place between the SACOC and the by-pass airflow. The second goal, is to provide predictive, validated and accessible methodologies for investigating such interactions

Caractérisation aérothermique d’un échangeur de chaleur surfacique implémenté en veine secondaire

Innovative civil aircraft engine configurations of the present and of the future are leading to important reductions of fuel consumption. At Safran Aircraft Engines, new concepts like the Geared Turbofan and the Open Rotor are currently under attentive study. These concepts are characterised by an increasingly complex architecture that demands lubrication and cooling. Thermal management systems, therefore, are a fundamental module of modern engines. In this work, we take an interest in surface aircooled oil coolers (SACOC). Common SACOC are composed of a series of staggered fins, aligned along the direction of the by-pass duct flow. The hot source is the engine lubricant. The objective of this thesis is twofold. The first goal is to characterise the aerothermal interactions taking place between the SACOC and the by-pass airflow. The second goal, is to provide predictive, validated and accessible methodologies for investigating such interactions.Les configurations innovantes de moteur d’aviation civile amèneront à d’importantes réductions de consommation de carburant. Actuellement, chez Safran Aircraft Engines, des nouveaux concepts tels que le Geared Turbofan et l’Open Rotor sont étudiés attentivement. Ces concepts sont caractérisés par des architectures de plus en plus complexes qui nécessitent d’être lubrifiés et refroidis. Par conséquent, les systèmes de gestion thermique sont un module fondamental des moteurs d’aujourd’hui. Dans cette thèse, on s’intéresse aux surface air-cooled oil coolers (SACOC). Un SACOC est généralement composé d’une sérié d’ailettes orientées dans la direction de l’écoulement. La source chaude est représentée par le lubrifiant du moteur. Le premier objectif de la thèse est de caractériser les interactions aérothermiques qui ont lieu entre le SACOC et le flux secondaire. Le deuxième but est de se doter de méthodologies prédictives, validées et accessibles qui permettent d’étudier ces interactions

Caractérisation aérothermique d’un échangeur de chaleur surfacique implémenté en veine secondaire

Innovative civil aircraft engine configurations of the present and of the future are leading to important reductions of fuel consumption. At Safran Aircraft Engines, new concepts like the Geared Turbofan and the Open Rotor are currently under attentive study. These concepts are characterised by an increasingly complex architecture that demands lubrication and cooling. Thermal management systems, therefore, are a fundamental module of modern engines. In this work, we take an interest in surface aircooled oil coolers (SACOC). Common SACOC are composed of a series of staggered fins, aligned along the direction of the by-pass duct flow. The hot source is the engine lubricant. The objective of this thesis is twofold. The first goal is to characterise the aerothermal interactions taking place between the SACOC and the by-pass airflow. The second goal, is to provide predictive, validated and accessible methodologies for investigating such interactions.Les configurations innovantes de moteur d’aviation civile amèneront à d’importantes réductions de consommation de carburant. Actuellement, chez Safran Aircraft Engines, des nouveaux concepts tels que le Geared Turbofan et l’Open Rotor sont étudiés attentivement. Ces concepts sont caractérisés par des architectures de plus en plus complexes qui nécessitent d’être lubrifiés et refroidis. Par conséquent, les systèmes de gestion thermique sont un module fondamental des moteurs d’aujourd’hui. Dans cette thèse, on s’intéresse aux surface air-cooled oil coolers (SACOC). Un SACOC est généralement composé d’une sérié d’ailettes orientées dans la direction de l’écoulement. La source chaude est représentée par le lubrifiant du moteur. Le premier objectif de la thèse est de caractériser les interactions aérothermiques qui ont lieu entre le SACOC et le flux secondaire. Le deuxième but est de se doter de méthodologies prédictives, validées et accessibles qui permettent d’étudier ces interactions

Évaluation et validation numérique d'une analyse de stabilité en mode normal pour le couplage aérothermique

International audienceThis paper aims to evaluate and validate a mathematical coupling model, based on a normal mode stability analysis, for steady conjugate heat transfer problems. In order to achieve this goal, an aerothermal computational code was designed specifically ex novo to meet the needs of the current study. A large number of numerical simulations were carried out within the framework of the Dirichlet-Robin fluid-solid interface procedure and with conditions strictly identical to those adopted in the mathematical model. These coupled computations have been synthesized in five representative cases. The computed results show that the stability limit and the numerical Biot number derived from the coupling model are very reliable parameters. Many other physical and numerical aspects, such as the splitting of the coupling period are also considered in this work from which some interesting and promising results are obtained. At the end of this paper, we assess the general potential, limits and constraints of the mathematical model and its extension to multidimensional cases is discussed.Cet article a pour but d'évaluer et de valider un modèle mathématique de couplage, basé sur une analyse de stabilité en mode normal, pour des problèmes de transfert de chaleur conjugués stationnaires. Afin d'atteindre cet objectif, un code de calcul couplé a été conçu ex novo pour répondre aux besoins de l’étude. Dans le cadre du schéma de couplage d'interface fluide-solide Dirichlet-Robin, un grand nombre de simulations numériques ont été réalisées en adoptant des conditions strictement identiques à celles du modèle mathématique. Cinq cas représentatifs sont exposés dans cette étude. Les calculs montrent que la limite de stabilité et le nombre de Biot numérique, directement issus du modèle de couplage, sont des paramètres très fiables. De nombreux autres aspects physiques et numériques, tels que le fractionnement de la période de couplage, sont également pris en compte dans ce travail, ce qui permet d'obtenir des résultats intéressants et prometteurs. A la fin de cet article, nous évaluons le potentiel général, les limites et les contraintes du modèle mathématique et son extension aux cas multidimensionnels est discutée

Physical study of the non-equilibrium development of a turbulent thermal boundary layer

The direct numerical simulation of a non-equilibrium turbulent heat transfer case is performed in a channel flow, where non-equilibrium is induced by a step change in surface temperature. The domain is thus made of two parts in the streamwise direction. Upstream, the flow is turbulent, homogeneous in temperature and the channel walls are adiabatic. The inflow conditions are extracted from a recycling plane located further downstream so that a fully developed turbulent adiabatic flow reaches the second part. In the domain located downstream, isothermal boundary conditions are prescribed at the walls. The boundary layer, initially at equilibrium, is perturbed by the abrupt change of boundary conditions and a non-equilibrium transient phase is observed until, further downstream, the flow reaches a new equilibrium state presenting a fully developed thermal boundary layer. The study focuses on the spatial transient phase, identifies the main non-equilibrium effects and contrasts these results with usual assumptions of equilibrium turbulent heat transfer. Mean and root-mean-square profiles of temperature and velocity, as well as the respective energy and momentum balances, are presented and discussed along with budgets of second-order moment balance equations for the enthalpy variance and the wall-normal heat flux. For several quantities, an equilibrium near-wall region is identified even near the leading edge while the boundary layer is still developing. Finally, the evolution of the turbulent Prandtl number along the channel flow is investigated and shows that it reaches equilibrium only further downstream

DNS of a turbulent thermal boundary layer spatially evolving on an isothermal wall from a fully turbulent adiabatic flow

International audienc