Design and synthesis of tricyclic benzo[1, 3]oxazinyloxazolidinones as blood coagulation factor Xa inhibitors

The coagulation enzyme factor Xa (FXa) is a valuable target for developing anticoagulants to treat thrombotic diseases. In this work, we designed and synthesized a series of conformationally restricted compounds containing the benzo[1,3]oxazinyloxazolidinone scaffold. The target compounds were synthesized by 11 steps reaction. The preliminary SAR showed that on the phenyl ring of benzo[1,3]oxazinyloxazolidinone, lactam replacements at the 6-position were favorable for FXa inhibition. Compound 16b showed good FXa inhibitory activity with an IC50 of 0.43 μM. The results indicate that benzo[1,3]oxazinyloxazolidinone is a promising scaffold for developing FXa inhibitors as antithrombotic agents.</p

The relationship between apathy and nonparametric variables of rest activity rhythm in older adults with cerebral small vessel disease

The goal of the current study was to demonstrate if the rest-activity rhythm (RAR) was altered in apathetic older adults with cerebral small vessel disease (CSVD) and find out the relationship between apathy/depression severity and RAR features in CSVD patients. This is a cross-sectional observational investigation including 53 CSVD cases (54.74% men), aged 70.70 ± 6.18 years old. The participants were assessed by neuropsychiatric inventory (NPI) subscale of apathy (NPI-apathy) and depression (NPI-depression) in succession, according to updated diagnostic criteria for apathy (DCA). Each subject wore an actigraph device (ActiGraph GT3X) in their nondominant hand for 7 days to collect raw data. Using a non-parametric methodological analysis, this study determined RAR variables such as interdaily stability (IS), intraday variability (IV) and relative amplitude (RA). Patients in the apathy-positive group had a higher Fazekas score than those in the apathy-negative group. IS, but not IV, RA, or objective sleep variables, differed between elderly patients with varying degrees of CSVD burden. Furthermore, apathy severity was statistically correlated with RA after adjusting for age, gender and education level, whereas depression severity was not associated with RAR variables. Finally, we discovered that the severity of apathy had no significant relationship with the severity of depression. All these findings indicated that the RAR altered in apathetic older adults with CSVD, and apathy was associated with decreased RAR amplitude.</p

Numerical investigation into wave-induced progressive liquefaction based on a two-layer viscous fluid system

Based on a two-layered viscous fluid theory, a numerical model to capture the progressive nature of wave-induced liquefaction has been developed. Unlike the existing models, this model can consider the cyclic shear stress associated with vibrating liquefied soil layers and its effect on sub-liquefied soils during the wave-induced liquefaction. The reliability of this model is validated by simulating wave flume tests, which show a promising prediction when compared to analytical solutions, particularly after the onset of liquefaction where an increased amplitude in the oscillatory pore water pressure can be observed. The numerical results show that the moving characteristics of liquefied soil are similar to those of a water particle in the presence of surface water waves with the horizontal velocity being much greater than the vertical velocity. Unlike the model without considering the liquefied soil-induced cyclic shear stress, the proposed model predicts a prompt increase in residual pore pressure associated with the onset of liquefaction at shallow soil layers, which may change the curvature of residual pore pressure versus time in sub-liquefied soils from concave downwards to concave upwards at a certain depth. This phenomenon is consistent with many of the existing experiments for wave-induced seabed response and becomes more pronounced as the kinematic viscous characteristics of liquefied soil become more apparent, i.e., with a larger kinematic viscosity coefficient. Correspondingly, the cyclic shear stress induced by the vibrations of liquefied soil can accelerate the downward advancement of the liquefaction front and result in a larger depth of liquefaction

Numerical investigation of solute transport into deformable marine sediments driven by ocean waves

Most existing studies do not consider the effect that the deformability of submarine sediments may have on solute transport under the action of ocean waves. In this study a two-dimensional numerical model based on Biot's poro-elastic consolidation theory and an advection–dispersion equation is established to investigate the transport of non-reactive solute into a deformable porous seabed under the influence of ocean waves. The numerical model is then validated against experimental and analytical results in order to demonstrate its accuracy and robustness. The simulation results indicate that ignoring the deformability of seabed soil and associated seepage force due to ocean waves may lead to a significant underestimation of the rate of solute transport in shallow layers of marine sediment, particularly fine sand or silt. The effects of parameters such as the shear modulus, non-dimensional mechanical dispersion coefficient (related to particle size and permeability), dimensionless sediment thickness, wave steepness and the relative water depth have on solute transport into deformable sediments were investigated. The results indicate that the ratio of the longitudinal coefficient of mechanical dispersion between deformable and non-deformable sediments that can represent the enhancement of solute migration due to soil deformation may reach up to 85. This becomes more pronounced as the shear modulus and permeability of sediments decrease and the depth of water increases when the sediment thickness is less than 0.8 times the wavelength. The rate of solute transport in deformable sediments reaches its maximum when the sediment thickness is about 0.2 times the wavelength. In fact, as the relative water depth increases from 0.1 to 0.3, the enhancement of solute migration due to wave-induced soil deformation increases by about 60%-80%. In comparison to linear waves, shallow water waves, e.g., the first-order cnoidal waves, can increase the transport of solute more due to its strong non-linear behaviour, particularly in deformable seabed

An experimental investigation into the evolving instability of a subaqueous mild silty slope under progressive waves

The silty sediments that are widely distributed in estuaries and deltas are susceptible to slope instability due to ocean storms. Flume experiments were carried out in this study to investigate the characteristics and failure process of a subaqueous mild silty slope subjected to ocean waves. The results show that the wave steepness varies accordingly to wave propagation over the mild silty slope due to shoaling effect. Where the wave steepness is up to the threshold value of 0.04, liquefaction may occur in silty slopes due to the substantial amount of residual pore water pressure development. In this process, the maximum wave pressure appears near the wave breaking point where it may be increased by about 40% compared with that at bottom of the slope; this means that liquefaction may primarily first occur in regions near the wave breaking point and become the predominant trigger for the overall slope instability. The maximum liquefaction and sliding depth of silty seabed may reach 0.1–0.15 times the wavelength for wave steepness of 0.04–0.10. Unlike the failures of a loose sandy slope that are characterized by a slumping stage along with a sudden rise in pore water pressure, wave induced failure of the mild silty slope progresses in three distinct stages, i.e., (i) initial erosion and scouring, (ii) coupled development of liquefaction and scour, and (iii) oscillating and sliding of sediments

Numerical investigation of solute migration and release from sediments driven by wave-induced accumulation of pore water pressure

Sediments with poor drainage conditions are prone to build-up of excess pore water pressure when exposed to dynamic wave loading. This results in accumulated seepage flow that may have a significant impact on migration of solutes in marine sediments. In this study, the complex interplay between solute transport and wave-induced seepage process is investigated through a pioneering approach that combines and synchronously solves the two-dimensional advection-dispersion equation governing nonreactive solute transport with the governing equations for wave-induced oscillatory and residual pore pressures. The simulated results have demonstrated that the accumulated seepage flow significantly contributes to the advective and dispersive fluxes of solute, where the advection leads to movement of the solute layer and the hydrodynamic dispersion primarily enlarges the thickness of solute layer. The distribution of residual pore water pressure along depth exhibits two patterns that are primarily influenced by the thickness of the seabed. When the seabed is thinner than 0.3 times the wavelength, the residual pore pressure increases monotonically with depth (Pattern I). In this situation, the solute always migrates upwards to the seabed surface. Otherwise, Pattern II depicts the distribution of residual pore pressure, where the peak value of residual pore pressure attains at a certain depth and may advance downwards with wave action time. In this case, the direction of solute migration in regions shallower than a certain depth (e.g., 0.6 times the thickness of sediment) may alternate over time but the solute can eventually be transported upwards to seabed surface. The parametric study shows that when the seabed thickness is 0.2–0.3 times the wavelength, accumulated seepage flow has less effect on solute migration, whereas decreasing relative density and shear modulus, as well as increasing soil permeability can enhance the effect of accumulated pore water pressure on solute migration

Design, Synthesis, and Biological Evaluation of Pyrrole-2-carboxamide Derivatives as Mycobacterial Membrane Protein Large 3 Inhibitors for Treating Drug-Resistant Tuberculosis

In this work, pyrrole-2-carboxamides were designed with a structure-guided strategy based on the crystal structure of MmpL3 and a pharmacophore model. The structure–activity relationship studies revealed that attaching phenyl and pyridyl groups with electron-withdrawing substituents to the pyrrole ring and attaching bulky substituents to the carboxamide greatly improved anti-TB activity. Most compounds showed potent anti-TB activity (MIC < 0.016 μg/mL) and low cytotoxicity (IC50 > 64 μg/mL). Compound 32 displayed excellent activity against drug-resistant tuberculosis, good microsomal stability, almost no inhibition of the hERG K+ channel, and good in vivo efficacy. Furthermore, the target of the pyrrole-2-carboxamides was identified by measuring their potency against M. smegmatis expressing wild-type and mutated variants of the mmpL3 gene from M. tuberculosis (mmpL3tb) and determining their effect on mycolic acid biosynthesis using a [14C] acetate metabolic labeling assay. The present study provides new MmpL3 inhibitors that are promising anti-TB agents

Design, Synthesis, and Biological Evaluation of Pyrrole-2-carboxamide Derivatives as Mycobacterial Membrane Protein Large 3 Inhibitors for Treating Drug-Resistant Tuberculosis

In this work, pyrrole-2-carboxamides were designed with a structure-guided strategy based on the crystal structure of MmpL3 and a pharmacophore model. The structure–activity relationship studies revealed that attaching phenyl and pyridyl groups with electron-withdrawing substituents to the pyrrole ring and attaching bulky substituents to the carboxamide greatly improved anti-TB activity. Most compounds showed potent anti-TB activity (MIC < 0.016 μg/mL) and low cytotoxicity (IC50 > 64 μg/mL). Compound 32 displayed excellent activity against drug-resistant tuberculosis, good microsomal stability, almost no inhibition of the hERG K+ channel, and good in vivo efficacy. Furthermore, the target of the pyrrole-2-carboxamides was identified by measuring their potency against M. smegmatis expressing wild-type and mutated variants of the mmpL3 gene from M. tuberculosis (mmpL3tb) and determining their effect on mycolic acid biosynthesis using a [14C] acetate metabolic labeling assay. The present study provides new MmpL3 inhibitors that are promising anti-TB agents