In vivo and in vitro metabolite profiling of nirmatrelvir using LC–Q-ToF–MS/MS along with the in silico approaches for prediction of metabolites and their toxicity

Nirmatrelvir (NRV), a 3C-like protease or M^pro inhibitor of SARS-CoV-2, is used for the treatment of COVID-19 in adult and paediatric patients. The present study was accomplished to investigate the comprehensive metabolic fate of NRV using in vitro and in vivo models. The in vitro models used for the study were microsomes (human liver microsomes, rat liver microsomes, mouse liver microsomes) and S9 fractions (human liver S9 fractions and rat liver S9 fractions) with the appropriate cofactors, whereas Sprague–Dawley rats were used as the in vivo models. Nirmatrelvir was administered orally to Sprague–Dawley rats, which was followed by the collection of urine, faeces and blood at pre-determined time intervals. Protein precipitation was used as the sample preparation method for all the samples. The samples were then analysed by liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (LC-Q-ToF-MS/MS) using an Acquity BEH C18 column with 0.1% formic acid and acetonitrile as the mobile phase. Four metabolites were found to be novel, which were formed via amide hydrolysis, oxidation and hydroxylation. Furthermore, an in silico analysis was performed using Meteor Nexus software to predict the probable metabolic changes of NRV. The toxicity and mutagenicity of NRV and its metabolites were also determined using DEREK Nexus and SARAH Nexus.     

Glass transition temperature and thermal stability of ZnS/PMMA nanocomposites

In this article, ZnS nanoparticles were prepared by wet chemical precipitation method using zinc sulphate (ZnSO₄), sodium sulphide (Na₂S) and thio-glycerol. These nanoparticles were characterized through X-ray diffraction (XRD) and transmission electron microscope (TEM) measurements. The solution-based processing was used to prepare Poly methyl methacrylate (PMMA) nanocomposites with different weight percents (0, 2, 4, 6 and 8) of ZnS nanoparticles. The obtained ZnS/PMMA nanocomposites were characterized through XRD, scanning electron microscope and TEM measurements. The dynamic mechanical analyzer was used to obtain the storage modulus and glass transition temperature (T _g) of the nanocomposites. The apparent activation energy of the glass transition region was also determined using the Vogel–Fulcher–Tammann equation. The results indicated that the thermal stability of ZnS/PMMA nanocomposites was higher than PMMA and 6 wt. % of ZnS nanoparticles in PMMA matrix showed the maximum activation energy, which indicated that this nanocomposite had higher thermal stability than other composites.     

1-Selenolato-2-phenyl-o-carborane complexes of palladium(II) and platinum(II): Synthesis, spectroscopy and structures

The reactions of PhCb^oSeNa (Cb^o = o-C₂B₁₀H₁₀), prepared by reductive cleavage of Se-Se bond in (PhCb^oSe)₂ by NaBH₄ in methanol, with Na₂PdCl₄, MCl₂(PR₃)₂ and [M₂Cl₂(μ-Cl)₂(PR₃)₂] afforded a variety of complexes, viz., [Pd(SeCb^oPh)Cl] (1), [M(SeCb^oPh)₂(PR₃)₂], [M₂Cl₂(μ-SeCb^oPh)(μ-Cl)(PR₃)₂] (M = Pd, Pt) and [Pd₂Cl(SeCb⁰Ph)(μ-Cl)(μ-SeCb^oPh)(PEt₃)₂] (7) have been isolated. These complexes were characterized by elemental analyses and NMR (¹H, ³¹P, ⁷⁷Se, ¹⁹⁵Pt) spectroscopy. The structures of [Pd(SeCb^oPh)₂(PEt₃)₂] (2), [Pt(SeCb^oPh)₂(PMe₂Ph)₂] (3), [Pd₂Cl₂(μ-SeCb^oPh)(μ-Cl)(PMe₂Ph)₂] (5) and [Pd₂Cl(SeCb^oPh)(μ-Cl)(μ-SeCb^oPh)(PEt₃)₂] (7) were established by X-ray crystallography. The latter represents the first example of asymmetric coordination of selenolate ligands in binuclear bis chalcogenolate complexes of palladium and platinum. Thermolysis of [Pd(SeCb^oPh)₂(PEt₃)₂] (2) in HDA (hexadecylamine) at 330 °C gave nano-crystals of Pd₁₇Se₁₅.     

Synthesis, spectroscopy and structures of palladium(II) and platinum(II) complexes containing mercapto-o-carborane

The reactions of [M₂Cl₂(μ-Cl)₂(PMe₂Ph)₂] with mercapto-o-carboranes in the presence of pyridine afforded mono-nuclear complexes of composition, [MCl(SCb°R)(py)(PMe₂Ph)] (M = Pd or Pt; Cb° = o-C₂B₁₀H₁₀; R = H or Ph). The treatment of [PdCl₂(PEt₃)₂] with PhCb°SH yielded trans-[Pd(SCb°Ph)₂(PEt₃)₂] (4) which when left in solution in the presence of pyridine gave another substitution product, [Pd(SCb°Ph)₂(py)(PEt₃)] (5). The structures of [PdCl(SCb°Ph)(py)(PMe₂Ph)] (1), [Pd(SCb°Ph)₂(PEt₃)₂] (4) and [Pd(SCb^oPh)₂(py)(PEt₃)] (5) were established unambiguously by X-ray crystallography. The palladium atom in these complexes adopts a distorted square-planar configuration with neutral donor atoms occupying the trans positions. Thermolysis of [PdCl(SCb°)(py)(PMe₂Ph)] (2) in TOPO (trioctylphosphine oxide) at 200 °C gave nanocrystals of TOPO capped Pd₄S which were characterized by XRD pattern and SEM.     

Glass transition activation energy of CdS/PMMA nano-composite and its dependence on composition of CdS nano-particles

CdS/PMMA nano-composites at different weight percent of CdS (0, 2, 4, 6, and 8) have been prepared using solution casting method. The obtained nano-composites are characterized through the transmission electron microscope (TEM). The differential scanning calorimetry (DSC) measurements have been done on the nano-composites at different heating rates. The peak glass transition temperature is determined using the DSC thermograms. It is found that the glass transition temperature increases with the increase of CdS content up to 6 wt% and then decreases for higher weight percent (8). It is explained on the basis of molecular motion of PMMA, which is restricted when CdS is added into PMMA. An effort is also made to study the activation energy of glass transition in the case of nano-composites of different weight percent of CdS. Variation of activation energy with CdS nano-particle concentration has also been theoretically predicted by using an empirical relation. Thermal stability of these nano-composites has been explained with the help of activation energy in the glassy region.     

Synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives

Different approaches for the synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives from simple amino acids have been investigated. A library of 33 precursors for the preparation of N-hydroxy pyrazinones was obtained in moderate to good yields.     

Involvement of Phytochemical-Encapsulated Nanoparticles’ Interaction with Cellular Signalling in the Amelioration of Benign and Malignant Brain Tumours

Brain tumours have unresolved challenges that include delay prognosis and lower patient survival rate. The increased understanding of the molecular pathways underlying cancer progression has aided in developing various anticancer medications. Brain cancer is the most malignant and invasive type of cancer, with several subtypes. According to the WHO, they are classified as ependymal tumours, chordomas, gangliocytomas, medulloblastomas, oligodendroglial tumours, diffuse astrocytomas, and other astrocytic tumours on the basis of their heterogeneity and molecular mechanisms. The present study is based on the most recent research trends, emphasising glioblastoma cells classified as astrocytoma. Brain cancer treatment is hindered by the failure of drugs to cross the blood–brain barrier (BBB), which is highly impregnableto foreign molecule entry. Moreover, currently available medications frequently fail to cross the BBB, whereas chemotherapy and radiotherapy are too expensive to be afforded by an average incomeperson and have many associated side effects. When compared to our current understanding of molecularly targeted chemotherapeutic agents, it appears that investigating the efficacy of specific phytochemicals in cancer treatment may be beneficial. Plants and their derivatives are game changers because they are efficacious, affordable, environmentally friendly, faster, and less toxic for the treatment of benign and malignant tumours. Over the past few years, nanotechnology has made a steady progress in diagnosing and treating cancers, particularly brain tumours. This article discusses the effects of phytochemicals encapsulated in nanoparticles on molecular targets in brain tumours, along with their limitations and potential challenges.     

Development of an ultrasensitive rGO/AuNPs/ssDNA-based electrochemical aptasensor for detection of Pb2+

Journal of Solid State Electrochemistry - The present work is performed on Pb2+ detection via electrochemical sensor. The novel aptasensor was developed by modification of glassy carbon...