Heterocyclic compounds as antiviral drugs: Synthesis,structure–activity relationship and traditional applications

A virus outbreak challenges the economic, medical, and public health infrastructure worldwide. More than one virus capable of triggering diseases have been identified per year since 1972, which requires the development of new ways of treatment and prevention, however, such processes are not rapid and easy. With the pandemic scenario experienced since early 2020, several drugs with well-known purposes have gained prominence, due to speculation of their use in the treatment against the new coronavirus. Among the main drugs studied, the vast majority contain a heterocyclic structure. In this review, we presented the traditional and efficient synthesis of 15 drugs that have been studied for the COVID-19 treatment, containing in their structure heterocycles like indole, quinoline, pyrimidone, tetrahydrofuran, pyrrolidine, triazole, pyridazine, pyrazole, pyrrolopyrimidine, azetidine, pyrrolotriazine, pyrazine, tetrahydropyran, benzofuran, spiroketal, and thiazole. Furthermore, we have shown the original applications, as well as their structure–activity relationship and what is their situation as a drug candidate against COVID-19. Thus, the objective was to consolidate the main synthetic and pharmacological aspects involving clinically developed heterocycles that at some point were presented as promising against SARS-CoV-2.     

Synthesis,Aromaticity, and Application of peri-Pentacenopentacene: Localized Representation of Benzenoid Aromatic Compounds

We report the synthesis and optoelectronic properties of TIPS-peri-pentacenopentacene ( TIPS-PPP ), a vertical extension of TIPS-pentacene ( TIPS-PEN ) and a low-band-gap material with remarkable stability. We found the synthetic conditions to avoid the competition between 1,2- and 1,4-addition of lithium acetylide on the large aromatic dione. The high stability of TIPS-PPP is due to the peri-fusion which increases the aromaticity by generating two localized aromatic sextets that are flanked with 2 diene fragments, similar to two fused-anthracenes. Like TIPS-PEN , TIPS-PPP shows the archetypal 2D brickwall motif in crystals with a larger transfer integral and smaller reorganization energy. The high mobility of up to 1 cm² V^?1 s^?1 was obtained in an organic field-effect transistor fabricated by a wet process. Also, TIPS-PPP was used as a near-infrared (NIR) emitter for NIR organic-light-emitting-diode devices resulting in a high external quantum efficiency at 800 nm.     

Suppression of Liquid-Liquid Phase Separation and Aggregation of Antibodies by Modest Pressure Application

The high colloidal stability of antibody (immunoglobulin) solutions is important for pharmaceutical applications. Inert cosolutes, excipients, are generally used in therapeutic protein formulations to minimize physical instabilities, such as liquid–liquid phase separation (LLPS), aggregation and precipitation, which are often encountered during manufacturing and storage. Despite their widespread use, a detailed understanding of how excipients modulate the specific protein-protein interactions responsible for these instabilities is still lacking. In this work, we demonstrate the high sensitivity to pressure of globulin condensates as a suitable means to suppress LLPS and subsequent aggregation of concentrated antibody solutions. The addition of excipients has only a minor effect. The high pressure sensitivity observed is due to the fact that these flexible Y-shaped molecules create a considerable amount of void volume in the condensed phase, leading to an overall decrease in the volume of the system upon dissociation of the droplet phase by pressure already at a few tens of to hundred bar. Moreover, we show that immunoglobulin molecules themselves are highly resistant to unfolding under pressure, and can even sustain pressures up to about 6 kbar without conformational changes. This implies that immunoglobulins are resistant to the pressure treatment of foods, such as milk, in high-pressure food-processing technologies, thereby preserving their immunological activity.     

Inhomogeneous ‘longitudinal’ plane waves in a deformed elastic material

By definition, a homogeneous isotropic compressible Hadamard material has the property that an infinitesimal longitudinal homogeneous plane wave may propagate in every direction when the material is maintained in a state of arbitrary finite static homogeneous deformation. Here, as regards the wave, homogeneous means that the direction of propagation of the wave is parallel to the direction of eventual attenuation; and longitudinal means that the wave is linearly polarized in a direction parallel to the direction of propagation. In other words, the displacement is of the form u = ncos k(n · x – ct), where n is a real vector. It is seen that the Hadamard material is the most general one for which a longitudinal inhomogeneous plane wave may also propagate in any direction of a predeformed body. Here, inhomogeneous means that the wave is attenuated, in a direction distinct from the direction of propagation; and longitudinal means that the wave is elliptically polarized in the plane containing these two directions, and that the ellipse of polarization is similar and similarly situated to the ellipse for which the real and imaginary parts of the complex wave vector are conjugate semi-diameters. In other words, the displacement is of the form u = {S exp i(S · x – ct)}, where S is a complex vector (or bivector). Then a Generalized Hadamard material is introduced. It is the most general homogeneous isotropic compressible material which allows the propagation of infinitesimal longitudinal inhomogeneous plane circularly polarized waves for all choices of the isotropic directional bivector. Finally, the most general forms of response functions are found for homogeneously deformed isotropic elastic materials in which longitudinal inhomogeneous plane waves may propagate with a circular polarization in each of the two planes of central circular section of the ⁿ -ellipsoid, where is the left Cauchy-Green strain tensor corresponding to the primary pure homogeneous deformation.     

Epitaxy of Binary Compounds and Alloys

The present work aims at constructing a theoretical framework within which to address the issues of morphological instabilities (one-dimensional step bunching and two-dimensional step meandering), alloying, and phase segregation in binary systems in the context of (physical or chemical) vapor deposition. The length scale of interest, although nanoscopic, is sufficiently large that the steps on a vicinal surface can be viewed as smooth curves and, correspondingly, the theory is a continuum one. In a departure from theories inaugurated by Burton, Cabrera, and Frank [The growth of crystals and the equilibrium structure of their surfaces. Phil. Trans. Roy. Soc. A 243 (1951) 299–358] the steps are endowed with a thermodynamic structure whose main ingredients are a step free-energy density and edge species chemical potentials. Moreover, crystal anisotropy, with its altering of the dynamics of steps and the associated morphological instabilities, is accounted for – in a manner consistent with the second law – both in the thermodynamic and kinetic properties of terraces and, more importantly, of steps. Additionally, in contrast with most of the literature on the subject (cf. [J. Krug, Introduction to step dynamics and step instabilities. In: A. Voigt (ed.) Multiscale Modeling in Epitaxial Growth. Birkhäusser, Berlin (2005)]), adsorption–desorption along the steps, bulk atomic diffusion, and chemical reactions (both on the terraces and along the step edges) are incorporated and coupled to the other mechanisms, e.g., terrace adatom diffusion and step attachment–detachment kinetics, whose interplay governs the evolution of steps on vicinal surfaces. Importantly, aided by the concept of configurational forces for which a separate balance law is postulated Configurational Forces as Basic Concepts of Continuum Physics. Springer, Berlin Heidelberg New York (2000)]), the proposed theory allows the steps to evolve away from local equilibrium thus contributing to a general treatment of the dynamics of steps. Finally, a specialization to the epitaxy of binary compounds and alloys is afforded, yielding a generalization of the classical Gibbs–Thomson relation in the former and novel evolution equations for an individual step in the latter.     

Continuum modeling for the modulated vibration modes of large repetitive structuresModèle continu pour les modes de vibrations modulés des longues structures répétitives

By homogenization theory, one can predict the vibrations of long repetitive structures in the low frequency range. Beyond this range, many modes have a modulated shape. Based on a multiple scale analysis, a continuum model is presented, that is able to account for this class of modes. This model involves a real coefficient that can be computed from the finite element resolution of problems defined on a few basic cells. An application in 2D elasticity is presented. To cite this article: E.M. Daya et al., C. R. Mecanique 330 (2002) 333–338.     

A two scale method for modulated vibration modes of large,nearly repetitive,structuresUne méthode asymptotique à deux échelles pour les modes de vibrations modulés des longues structures presque répétitives

Nearly repetitive structures can present at least two kinds of vibration modes: localized modes and modulated ones. In this Note, the multiple scale method is applied to characterize a packet of modulated modes. In this respect, only small size problems are to be solved: periodic problems posed on a few basic cells and amplitude equations, which define a sort of homogenized model for this type of modes. It is established that the influence of the non-repetitive part of the structure is accounted by a boundary condition. To cite this article: E.M. Daya et al., C. R. Mecanique 331 (2003).     

Dispersion de Taylor généralisée à un fluide à propriétés physiques variablesGeneralized Taylor dispersion for heterogeneous fluid

The investigation of non-reactive miscible solute dispersion in a vertical Hele–Shaw cell is considered. An asymptotic method is used to extend Taylor model to the case of the fluid density, the dynamic viscosity and the molecular diffusion coefficient are solute concentration-dependent. It is demonstrated that the averaged variables over the gap are governed by a convection–dispersion equation in which the dispersion tensor is concentration-dependent. To cite this article: C. Felder et al., C. R. Mecanique 332 (2004).     

Mean stress in a granular medium in dynamics

In this paper we propose to construct a mean stress tensor for a granular medium, valid in static and in dynamics, which takes into account the contact reactions and the body forces acting at the grain level. A simple analytical example shows that taking account of inertia forces is essential to insure the symmetry of the mean stress tensor in dynamics. Finally, numerical simulations illustrating this definition of the mean stress tensor are presented for a granular medium ensiled.     

Espaces d'écoulements dits « universels », 3

Universal motions with uniform steady vorticity form a corolla of linear spaces derived from rigid body motions. Closely related to potential flows, they satisfy two extensions of Lagrange theorem, are investigated with the help of complex functions, as stand celebrated when be plane. They take place in hydrodynamics, aerodynamics, geophysics, astrophysics, turbulence, physics of plasmas and superfluid helium. In all the cases, arbitrary unsteady span-wise translations permit to generalise as well as to exhibit helical or 3D universal motions. Three misunderstood periodic flows illustrate our purpose, as they approach shear instabilities in numerous fluids. To cite this article: M. Bouthier, C. R. Mecanique 332 (2004).