Structure-Based Design and Synthesis of Piperidinol-Containing Molecules as New Mycobacterium abscessus Inhibitors

Non-tuberculous mycobacterium (NTM) infections, such as those caused by Mycobacterium abscessus, are increasing globally. Due to their intrinsic drug resistance, M. abscessus pulmonary infections are often difficult to cure using standard chemotherapy. We previously demonstrated that a piperidinol derivative, named PIPD1, is an efficient molecule both against M. abscessus and Mycobacterium tuberculosis, the agent of tuberculosis, by targeting the mycolic acid transporter MmpL3. These results prompted us to design and synthesize a series of piperidinol derivatives and to determine the biological activity against M. abscessus. Structure-activity relationship (SAR) studies pointed toward specific sites on the scaffold that can tolerate slight modifications. Overall, these results identified FMD-88 as a new promising active analogue against M. abscessus. Also, we determined the pharmacokinetics properties of PIPD1 and showed that intraperitoneal administration of this compound resulted in promising serum concentration and an elimination half-life of 3.2 hours.     

Applications of level set methods in computational biophysics

We describe in this paper two applications of Eulerian level set methods to fluid-structure problems arising in biophysics. The first one is concerned with three-dimensional equilibrium shapes of phospholipidic vesicles. This is a complex problem, which can be recast as the minimization of the curvature energy of an immersed elastic membrane, under a constant area constraint. The second deals with isolated cardiomyocyte contraction. This problem corresponds to a generic incompressible fluid-structure coupling between an elastic body and a fluid. By the choice of these two quite different situations, we aim to bring evidence that Eulerian methods provide efficient and flexible computational tools in biophysics applications.     

Experimental characterization of the instability of the vortex rings. Part II: Non-linear phase

The first stage of the instability of a vortex ring is linear and characterized by the growth of an azimuthal stationary wave which develops around the ring. Theoretical works predict its origin, shape, number of waves and growth rate. Apart for the growth rate, experimental and numerical results in viscous fluids fit well with the predictions based on an ideal fluid hypothesis. On the other hand, the next stages of the development of the instability (which are non-linear) are not well known. Only few phenomena are described, in an isolated way, in various partial contributions. The aim of this paper is to report on a complete experimental investigation of the non-linear phase of the instability of the vortex ring. The vortices were produced in water and their Reynolds number Re _p was varied from 2,650 to 6,100. Visualizations were performed using planar laser induced fluorescence and measurements with 2D2C and 2D3C particle image velocimetry. Based on a Fourier analysis of the results, it appears that the non-linear phase begins with the development of harmonics of the linear modes (first unstable modes). But the growth of those harmonics is rapidly stopped by the development of low order modes. Then appears an m=0 mode, which corresponds to a mean azimuthal velocity around the vortex. Simultaneously, secondary vortical structures develop all around the vortex in its peripheral zone. These vortical structures are linked with the ejection of vorticity in the wake of the ring and they appear just before the transition towards turbulence. A tentative is made here to place all these phenomena chronologically, in order to propose a scenario for the transition from the linear phase to turbulence.     

Experimental characterization of the instability of the vortex ring. Part I: Linear phase

The results of experiments performed to study the linear phase of the instability of vortex rings are presented. The experiments were performed in water. The vortex rings are generated by pushing water through the cylindrical nozzle of a pipe submerged in an aquarium. The experiments were made with the help of planar laser induced fluorescence as well as 2D2C and 2D3C particle image velocimetry. They show the straining field causing the instability, and for the first time experimentally the growth of a band of linear unstable modes. They also confirm previous studies concerning the shape of the instability and theories predicting the number of waves and the bandwidth of unstable modes. However, the measurement of the growth rate shows the influence of viscous damping, and consequently, the limit of the theories based on the hypothesis of an ideal fluid.     

Main results of the Second International PIV Challenge

This paper presents the main results of the Second International PIV Challenge which took place in Busan (Korea) on the 19th and 20th of September 2003. This workshop was linked to the PIV03 International Symposium, which was held at the same place the following week. The present contribution gives the objectives of the Challenge, describes the test cases and the algorithms used by the participants, and presents the main results together with some discussion and conclusions on the accuracy and robustness of various PIV and PTV algorithms. As all the results obtained cannot be detailed, this contribution should serve as a guide for the use of the full database of images and results which is available at .     

Chirality transfer. A stereospecific palladium salt catalyzed phenylation of chiral butenols.

(R)-(|) and (S)-(+)-3-phenyl butanones have been obtained by a 20% stereospecific palladium catalyzed β-phenylation of the corresponding chiral butenols, the catalyst acting preferentially, through an alkoxide complex, by one face of the alcohol double bond, e.g. the si face of (R)-(|)3-butene-2-ol(I).     

New Ionic Liquid Based on the CMPO Pattern for the Sequential Extraction of U(VI), Am(III) and Eu(III)

Extraction of U(VI), Eu(III) and Am(III) has been performed from acidic aqueous solutions (HNO₃, HClO₄) into the ionic liquid [C₄mim][Tf₂N] in which a new extracting task-specific ionic liquid, based on the CMPO unit {namely 1-[3-[2-(octylphenylphosphoryl)acetamido]propyl]-3-methyl-1H-imidazol-3-ium bis(trifluoromethane)sulfonamide, hereafter noted OctPh-CMPO-IL}, was dissolved at low concentration (0.01 mol·L^?1). EXAFS and UV–Vis spectroscopy measurements were performed to characterize the extracted species. The extraction of U(VI) is more efficient than the extraction of trivalent Am and Eu using this TSIL, for both acids and their concentration range. We obtained evidence that the metal ions are extracted as a solvate (UO₂(OctPh-CMPO-IL)₃) by a cation exchange mechanism. Nitrate or perchlorate ions do not play a direct role in the extraction by being part of the extracted complexes, but the replacement of nitric acid for perchloric acid entails a drop in the selectivity between U and Eu. However, our TSIL allows a sequential separation of U(VI) and Eu/Am(III) using the same HNO₃ concentration and same nature of the organic phase, just by changing the ligand concentration.     

Synthesis of 3,5-disubstituted 1-amino-1,3,5-triazine-2,4,6-triones (or 1-aminocyanurates) by cyclic transformation of 1,3,4-oxadiazol-2(3H)-one derivatives

The 5-aryl(or methyl)-3-phenylcarbamoyl-1,3,4-oxadiazol-2(3H)-ones 2 , in the presence of sodium hydride in anhydrous dimethylformamide, were transformed into 1-benzamido(or acetamido)-3,5-diphenyl-1,3,5-triazine-2,4,6-trione derivatives 7 in poor yields. However, compounds 7 were obtained in better yields when the sodium salts of 5-aryl(or methyl)-1,3,4-oxadiazol-2(3H)-ones 1 were treated with two equivalents of aryl(or ethyl)isocyanates. Acidic hydrolysis of 1-acetamido-3,5-diphenyl-1,3,5-triazine-2,4,6-trione ( 7i ) provided the corresponding free N-amino derivative 9 . Nitrous deamination of 9 gave the known 3,5-diphenyl-1,3,5-triazine-2,4,6-trione ( 11 ). This cyclic transformation is the first one to be reported providing 1,3,5-triazine-2,4,6-trione derivatives.     

New methods in fluid-structure coupling with application to biomechanics

An Eulerian approach is presented for generic fluid-structure coupling of an elastic body with an incompressible fluid. We consider the coupling as a multiphysics problem where fluid-solid interfaces are captured by a level-set method. The main features of the method are its simplicity, and its natural control of mass and energy. We are indeed able to prove an energy equation which ensures in particular that the regularization of the force does not involve any energy dissipation. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)